EMJ Hematology 13.1 2025 by European Medical Journal

Hematology

Interviews

EHA President Elect Konstanze Döhner discusses the recent congress and the pressing issues currently facing the field

The Immunotherapy Landscape for Multiple Myeloma Infographic

04 Editorial Board

07 Welcome

09 Foreword

Congress Review

10 Review of the 2025 European Hematology Association (EHA) Congress, 12ᵗʰ–15ᵗʰ June 2025

Congress Features

20 Prognostic Assessment in Light Chain Amyloidosis: Emerging Models and Biomarkers

Selin Küçükyurt

24 Putting Patients First: Insights from the Specialized Working Group Session on Quality of Life in Haematology

Deniz Özmen

27 Highlights in Acute Lymphoblastic Leukaemia: European Hematology Association (EHA) 2025

Josep-María Ribera

31 Advancing Frontiers in Myeloproliferative Neoplasms

Erika Morsia

36 Measurable Residual Disease in Clinical and Regulatory Decision Making

Helena Bradbury

40 Evolving Endpoint Strategies: Navigating New Therapies and Regulatory Acceptance

Helena Bradbury

Congress Sessions Review

44 CLL Highlights from EHA 2025: Expert Perspectives and Clinical Developments

Abstract Reviews

53 Spectrum, Prevalence, and Clinical Correlates of PPM1D Mutations in Patients with Clonal Haematopoiesis and Clonal Cytopenias

Badar T et al.

58 Hydroxyurea Improves Mesenteric Blood Flow and Reduces Gut Permeability in Sickle Cell Disease Mice

Gotardo Azevedo EMF et al.

61 Long-Term Follow-Up after Allogeneic Haematopoietic Stem Cell Transplantation for Acute Lymphoblastic Leukaemia

Baazizi M et al.

63 Microfluidic Testing in Patients with Bleeding Disorder of Unknown Cause

Monard A et al.

66 Durable Responses to Lenzilumab: Azacitidine Combination Therapy in High Risk Proliferative Chronic Myelomonocytic Leukaemia with Suppression of CBL and RAS Mutant Subclones

Thomas D et al. Congress Interviews

68 Konstanze Döhner

72 Martin Dreyling Interviews

75 Elena Zamagni

79 Joshua Richter

82 Lydia Scarfò Infographics

86 A Multi-Criteria Decision Framework to Guide Treatment Decision-Making in Patients with Lenalidomide-Refractory Multiple Myeloma Post-DRd

88 The Immunotherapy Landscape for Multiple Myeloma Features

90 Gene Therapy: Living With(out) Haemophilia?

Lieke Baas

94 Re-evaluating European Haemophilia Standards: Towards a More Inclusive Global Framework

John and Ross Articles

100 Editor's Pick: Low-dose Rituximab in Adults with Autoimmune Haematological Disorders: A Review

Montelongo-Cepeda JE et al.

109 100 Years of von Willebrand Disease

Favaloro E et al.

121 Synchronous Twin Malignancies in a 32-Year-Old Female: A Rare and Complex Case Report

Mohite A et al.

128 Bleeding Due to Vitamin K-Dependent Factor Deficiency in a Patient Taking Topiramate: A Case Report

Gouli and Canary

Editorial Board

Editor-in-Chief

Emanuele Angelucci

Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Genova, Italy

Chair, Hematology and Cellular Therapy Unit, Ospedale Policlinico

San Martino; Transplant Program Director, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Genova, Italy

Dimitar Efremov

International Centre for Genetic Engineering & Biotechnology, Trieste, Italy

David Gómez Almaguer

Hospital Universitario "Dr. Jose E. González", Universidad Autónoma de Nuevo León, México

Loredana Bury

University of Perugia, Italy

Sabri Kemahli Yeditepe University, Istanbul, Türkiye

Dominique Bonnet

Francis Crick Institute, London, UK

Utkarsh Acharya

Brigham & Women’s Hospital, Boston, Massachusetts, USA

Ahmet Muzaffer Demir

Trakya University, Edirne, Türkiye

Aims and Scope

EMJ Hematology is an open access, peer-reviewed eJournal committed to publishing the highest quality medical research concerning all aspects of diseases of the blood and bone marrow to help advance the development of this field.

The journal is published annually, approximately six weeks after the European Hematology Association (EHA) Congress, and features highlights from this congress, alongside interviews with experts in the field, reviews of abstracts presented at the congress, as well as in-depth features on congress sessions. The journal also covers advances within the clinical and pharmaceutical arenas by publishing sponsored content from congress symposia, which is of high educational value for healthcare professionals. This undergoes rigorous quality control checks by independent experts and the in-house editorial team.

EMJ Hematology also publishes peer-reviewed research papers, review articles, and case reports in the field. In addition, the journal welcomes the submission of features and opinion pieces intended to create a discussion around key topics in the field and broaden readers’ professional interests. The journal is managed by a dedicated editorial team that adheres to a rigorous double-blind peer-review process, maintains high standards of copy editing, and ensures timely publication.

EMJ Hematology endeavours to increase knowledge, stimulate discussion, and contribute to a better understanding of blood disorders. Our focus is on research that is relevant to healthcare professionals in this field. We do not publish veterinary science papers or laboratory studies not linked to patient outcomes. We have a particular interest in topical studies that advance research and inform of coming trends affecting clinical practice in haematology.

Further details on coverage can be found here: www.emjreviews.com

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EMJ is supported by various levels of expertise:

• Guidance from an Editorial Board consisting of leading authorities from a wide variety of disciplines.

• Invited contributors who are recognised authorities in their respective fields.

• Peer review, which is conducted by expert reviewers who are invited by the Editorial team and appointed based on their knowledge of a specific topic.

• An experienced team of editors and technical editors.

Peer Review

On submission, all articles are assessed by the editorial team to determine their suitability for the journal and appropriateness for peer review.

Editorial staff, following consultation with a member of the Editorial Board if necessary, identify three appropriate reviewers, who are selected based on their specialist knowledge in the relevant area.

All peer review is double blind. Following review, papers are either accepted without modification, returned to the author(s) to incorporate required changes, or rejected.

Editorial staff have final discretion over any proposed amendments.

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We welcome contributions from professionals, consultants, academics, and industry leaders on relevant and topical subjects. We seek papers with the most current, interesting, and relevant information in each therapeutic area and accept original research, review articles, case reports, and features.

We are always keen to hear from healthcare professionals wishing to discuss potential submissions, please email: editorial.assistant@emjreviews.com

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This is an open-access journal in accordance with the Creative Commons Attribution-Non Commercial 4.0 (CC BY-NC 4.0) license.

Congress Notice

Staff members attend medical congresses as reporters when required.

This Publication Launch Date: 2013 Frequency: Yearly Online ISSN: 2053-6631

All information obtained by EMJ and each of the contributions from various sources is as current and accurate as possible. However, due to human or mechanical errors, EMJ and the contributors cannot guarantee the accuracy, adequacy, or completeness of any information, and cannot be held responsible for any errors or omissions. Although EMJ is independent of the EHA2025 review event, EMJ has received feedback on the congress interviews, congress features authored by EMJ, and certain aspects of the congress review. The use of the organisations does not constitute endorsement or media partnership in any form whatsoever. The cover photo is of Milan, Italy, the location of EHA2025.

Front cover and contents photograph: Milan, Italy

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Welcome

Dear Readers,

We are delighted to welcome you to the 2025 issue of EMJ Hematology, which brings you key highlights from this year’s European Hematology Association (EHA) 2025 Congress, including the latest clinical guideline recommendations for haemophilia, multiple myeloma, aggressive large B cell lymphomas, and peripheral T cell lymphomas. We also present four expert-written features, summarising pivotal insights in amyloid lightchain amyloidosis, acute lymphoblastic leukaemia, myeloproliferative neoplasms, and patient-centred care that were delivered during the event.

Alongside this, you can also find several abstract reviews covering the latest research updates across the discipline, as well as an infographic on immunotherapy in multiple myeloma. Plus, be sure not to miss our exclusive interviews with EHA President-Elect Konstanze Döhner, and Scientific Program Committee Chair Martin Dreyling, as well as interviews with specialists in plasma cell disorders, multiple myeloma, and chronic lymphocytic leukaemia.

Amongst our peer-reviewed content, explore the history and current diagnostic and treatment landscape of von Willebrand disease, a review of monoclonal antibody treatment for autoimmune haematological disorders, and several interesting case reports.

Packed with content covering the breadth of the field, we hope you find valuable insights for your daily practice in this issue. We would like to thank our Editorial Board, the authors, peer reviewers, and interviewees for their contributions to this issue. We hope you enjoy reading!

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EHA2026 Congress

where we connect the global hematology community.

June 11-14, 2026

Stockholm, Sweden

EHA2026 will once again offer an exceptional scientiﬁc program, featuring a seamless ﬂow of engagement across Plenary Sessions—including the Opening Ceremony, Plenary Abstract Session, and Presidential Sessions— alongside carefully curated Sponsor Symposiums.

This is your opportunity to engage with leading experts, foster new connections, and learn about the latest advancements and cutting-edge developments in hematology.

Save the date for EHA2026 to stay at the forefront of hematology.

ehaweb.org

Foreword

Dear Colleagues,

I am pleased to introduce the 2025 edition of EMJ Hematology. This issue offers a broad mix of reviews, case reports, interviews, and insights from the European Hematology Association (EHA) Congress 2025, held in Milan, Italy, from the 12th–15th of June, which reflect the continuing progress and complexity of our field.

Among the highlights is a centenary piece on von Willebrand disease, alongside a review exploring low-dose rituximab in autoimmune haematological disorders. Our case reports also present rare and instructive clinical scenarios, including synchronous twin malignancies and coagulopathy linked to medication.

In this issue, you will find features that tackle timely themes such as equity in haemophilia care and the real-world implications of gene therapy, as well as an infographic offering a visual overview of the immunotherapy landscape in multiple myeloma.

Additionally, we are proud to present expert interviews with both Congress and nonCongress participants, offering practical and personal perspectives on current challenges in haematology.

We also feature abstract reviews that cover topics ranging from clonal haematopoiesis and chronic myelomonocytic leukaemia treatment to transplant outcomes and diagnostics in bleeding disorders.

In this issue, you will find features that tackle timely themes such as equity in haemophilia care and the real-world implications of gene therapy

This edition of EMJ Hematology includes comprehensive Congress coverage, with discussions on measurable residual disease, endpoint strategies, and disease-specific insights from EHA2025. I would like to thank our contributors and the Editorial team for their efforts in assembling another rich and timely issue, as well the Editorial Board, authors, interviewees, and peer reviewers for coming together to make this possible. I hope you find the content both useful and engaging in your practice.

Emanuele Angelucci

Chair, Hematology and Cellular Therapy Unit, Ospedale Policlinico San Martino, Genova, Italy; Transplant Program Director, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Genova, Italy

EHA2025

Congress Review

Review of the European Hematology Association (EHA) 2025 Congress

Location: Milan, Italy

Date: 12th–15th June

Citation: EMJ Hematol. 2025;13[1]:10-19. https://doi.org/10.33590/emjhematol/XHRK7471

The theme for this year’s Congress was "Borderless Hematology", highlighting the importance of providing high-quality care to all haematology patients

THE 30ᵗʰ EUROPEAN Hematology Association (EHA) Congress was held in the beautiful city of Milan, Italy from the 12ᵗʰ–15ᵗʰ of June 2025. The theme for this year’s Congress was "Borderless Hematology", highlighting the importance of providing high-quality care to all haematology patients. As members of the society emphasised, the word ‘borderless’ suggests limitless possibilities, encouraging us to envision a world where knowledge and access to treatment is shared regardless of physical or geographical constraints.

During his opening speech, António Almeida, the EHA President, paid tribute to the late Professor Jacques-Louis Binet, who sadly passed away in December 2024. He was internationally recognised for developing the prognostic classification of chronic lymphocytic leukaemia, which bears his name and continues to be used in clinical practice to this day. “Today we celebrate the extraordinary legacy of a visionary who transcended boundaries and steered us into the future.”

Martin Dreyling, Scientific Program Committee Chair, then took to the stage to present the programme planned for the EHA2025 Congress. He introduced a newly launched format, with scientific sessions now spread across 3.5 days. This structure allows for a greater number of sessions, extended time for each, and reduced topic overlap. In total, more than 575 sessions were offered in this year’s programme, a testament to EHA’s role as a leader in haematology and the Congress’s significance as a global forum for collaboration and networking. Additionally, over 4,000 abstracts were submitted from across the globe, covering basic, translational, and clinical areas of research.

The Grants Ceremony followed, presented by Dominique Bonnet (University College London, UK), which highlighted innovative research from more than 17 countries, with a noticeable increase in female awardees. Almeida subsequently presented the prestigious EHA Clinical Excellence award, recognising extraordinary achievement and commitment to the clinical and clinical-research field of haematology.

This year’s recipient, Khaled Musallam, Thalassemia & Sickle Cell Center, Burjeel Medical City, Abu Dhabi, UAE, delivered an insightful talk on his work in nontransfusion-dependent thalassemia. Finally, Alberto Orfao (University of Salamanca, Spain), the recipient of the EHA Research Excellence Award, gave a presentation on the early detection and clinical relevance of small clones of haematopoietic cells.

Throughout the Congress, attendees experienced a rich array of keynote lectures, poster presentations, and satellite symposia, all designed to foster global collaboration and ignite new ideas. Of particular note were the four guideline sessions for peripheral T cell lymphoma, multiple myeloma, mild and moderate haemophilia A and B, and aggressive large B cell lymphoma. These guidelines are covered in greater detail in the guidelines section of our Congress review.

In conclusion, the 30th EHA Congress provided a valuable platform for sharing the latest developments in haematology and encouraging collaboration across the global community. The range of sessions, research contributions, and opportunities for discussion highlighted the ongoing commitment to improving patient care and advancing the field. The Congress in Milan, Italy, reflected the importance of continued international cooperation and knowledge exchange in shaping the future of haematology.

Guidelines Overview

At the EHA2025 Congress, new guidelines across multiple haematologic conditions introduced refined risk classifications, updated diagnostic tools, and evolving treatment strategies. Emphasising precision, personalisation, and evidence-based care, these updates reflect ongoing advances in research and clinical practice.

Updated European Hematology

Association-European Myeloma Network Recommendations for Multiple Myeloma

THE EHA2025 Congress saw the European Myeloma Network (EMN) and EHA jointly present comprehensive new guidelines for the management of multiple myeloma.1 Developed by a panel of 34 European myeloma experts, the guidelines incorporate data through May 31st 2025, reflecting both high-level evidence and expert consensus following extensive review rounds.

A major advancement is the redefinition of high-risk multiple myeloma. Translocations t(4;14), t(14;16), and t(14;20) are no longer considered high-risk if they occur alone, they only qualify as high-risk when cooccurring with 1q gain/amplification or monoallelic 1p deletion. Similarly, 1q gain alone is no longer sufficient for high-risk classification. High-risk now includes del(17p) in >20% of plasma cells, TP53 mutations, biallelic 1p32 deletions, and high β2-microglobulin with normal renal function.

Key diagnostic updates include the use of next-generation flow or sequencing for detecting clonal plasma cells and assessing minimal residual disease (MRD).

Urine testing is now limited to diagnosis and relapse settings, with 24-hour urine collection no longer required for routine follow-up. MRD testing is now integral for monitoring treatment response, and MRD negativity must be confirmed every 12 months for sustained status. Imaging has evolved to include either PET-CT or diffusion-weighted MRI, with the latter favoured for its bone marrow sensitivity.

For high-risk smouldering myeloma, daratumumab (Dara) monotherapy for 3 years may be considered, though regulatory approval is pending. In transplanteligible patients, quadruplet induction regimens, such as Dara or isatuximab

Key diagnostic updates include the use of next-generation flow or sequencing and assessing minimal residual disease

(Isa) with bortezomib, lenalidomide, and dexamethasone (VRd), are now recommended, followed by transplant, consolidation, and maintenance. Daralenalidomide maintenance can be stopped after 24 months if sustained MRD negativity is achieved. The PERSEUS trial showed that Dara-VRd nearly doubled MRD negativity, and extended median progression-free survival to a projected 17 years versus 7.3 years with VRd alone. Similar benefits were shown with Isa-VRd in a German study.

For non-transplant-eligible patients, quadruplets (e.g., Isa-VRd) are preferred over triplets. In patients who are frail, Dara with lenalidomide and dexamethasone remains standard, but Dara with lenalidomide without dexamethasone shows promise in reducing toxicity while maintaining efficacy.

MRD negativity must be confirmed every 12 months for sustained status

Treatment after first relapse depends on prior anti-CD38 exposure. For patients who are lenalidomide-refractory but antiCD38-naïve, options include Dara plus carfilzomib and dexamethasone, Isa plus carfilzomib and dexamethasone, ciltacabtagene autoleucel (cilta-cel) CAR-T cell therapy, or belantamab combinations. Recent approvals of cilta-cel and belantamab with bortezomib and dexamethasone show significantly improved progression-free survival and MRD rates.

In later lines, CAR-T therapies (cilta-cel, idecabtagene vicleucel) and bispecifics (teclistamab, elranatamab, linvoseltamab, talquetamab) show high efficacy, especially when sequenced appropriately. Importantly, CAR-T efficacy diminishes if administered after bispecifics or antibody drug conjugates, thus, sequencing remains a key challenge. Data support giving CAR-T before B cell maturation antigentargeted bispecifics.

New European Society for Medical OncologyEuropean Hematology Association Clinical Guidelines for Peripheral T Cell Lymphomas

THE EHA2025 Congress saw the European Society for Medical Oncology (ESMO) and EHA jointly present comprehensive new guidelines for the management of peripheral T cell lymphomas (PTCL).

Francesco d’Amore, Aarhus University Hospital, Denmark, emphasised the significant evolution seen over the past decade, not only in therapeutic approaches, but also in diagnostic tools and our understanding of disease biology.

These updates reflect a rapidly evolving landscape, and underscore the importance of precision, research, and international collaboration in improving outcomes for patients with PTCL

The revised guidelines are structured using a matrix that categorises first-line and relapsed/refractory treatments across nodal, extranodal, and leukaemic PTCL entities. Crucially, the guidelines stress the importance of enrolling patients, especially those with less common subtypes, into clinical trials.

Stem cell transplantation continues to play a central role. Autologous transplantation is generally recommended in the first-line treatment for nodal PTCL, while allogeneic transplantation is considered for relapsed disease or more aggressive extranodal forms. A landmark German-French trial, published in both 2019 and 2024,2,3 compared autologous and allogeneic stem cell transplantation in PTCL. While the study found no statistically significant difference in overall survival or event-free survival between the two approaches, it did reveal notable contrasts in relapse risk and treatment-related mortality. Autologous transplant had a treatment-related mortality of 0% in 2019 and 3% in 2024, compared to 31% for allogeneic transplant in both years. Conversely, the relapse risk was higher with autologous transplantation (36% in 2019

and 55% in 2024), while it remained much lower with allogeneic transplantation, at 0% and 8%, respectively. These findings underscore the trade-off between reduced relapse risk and higher treatment toxicity with allogeneic transplantation. From these findings, the authors concluded that allogeneic stem cell transplantation is the recommended treatment choice for younger, treatment-eligible patients with relapsed/ refractory PTCL, whilst allogeneic stem cell transplantation is generally not recommended as part of first-line consolidation.

Referring to the ESMO-EHA clinical practice guidelines for PTCL, D’Amore recommended that, at diagnosis, a PET-CT is the preferred imaging modality for all nodal and extranodal (non-leukaemic) PTCLs. Moreover, in all cases, a bone marrow biopsy is recommended for accurate staging, and a rebiopsy is recommended at relapse or progression. Finally, for nodal PTCL, the International Prognostic Factor Index is still the preferred prognostic tool.

New therapies also feature prominently in the updated guidance. Oral azacitidine has shown encouraging results in the ORACLE trial,4 and checkpoint inhibitors, particularly when combined with chemotherapy, are demonstrating high complete response rates in extranodal natural killer/T cell lymphomas.5 The guidelines also include novel treatment strategies for specific subtypes, such as enteropathy-associated T cell lymphoma6 and breast implant-associated anaplastic large cell lymphoma.

These updates reflect a rapidly evolving landscape, and underscore the importance of precision, research, and international collaboration in improving outcomes for patients with PTCL.

For each domain, the panel formulated specific clinical questions using the Population, Intervention, Comparator, Outcome method

Overview of the Forthcoming Guidelines on Mild and Moderate Haemophilia A and B

THE EHA2025 Congress session on the forthcoming European Association for Haemophilia and Allied Disorders (EAHAD)-EHA recommendations for mild and moderate haemophilia A and B delved into the guideline development process, key clinical questions, and the main topics that will be covered in upcoming guidelines.7

Over 20% of patients with mild or moderate haemophilia

A or B met the criteria for severe bleeding disorders based on clinical phenotype, not just factor levels.

The session began with a description of the methodology used to develop the guidelines, with a systematic approach based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses framework. The panel identified four major domains for clinical questions that the guidelines will be based on: women’s issues (including prevention of postpartum haemorrhage, anaesthesia management, and heavy menstrual bleeding); surgery and procedures (covering the management of minor/major surgery, tooth extraction, and the duration of haemostatic therapy); treatment (such as the role of DDAVP trials, the management of non-severe bleeding, and frequent bleeding episodes); and general management (with a focus on genetic investigations for asymptomatic carriers).

For each domain, the panel formulated specific clinical questions using the Population, Intervention, Comparator, Outcome method. For example, in patients with mild or moderate haemophilia A undergoing minor surgery, the team compared DDAVP plus antifibrinolytics versus replacement therapy, analysing

outcomes such as bleeding severity, adverse events, and inhibitor development.

A comprehensive literature search with 2,202 papers revealed that over 20% of patients with mild or moderate haemophilia A or B met the criteria for severe bleeding disorders based on clinical phenotype, not just factor levels. This finding supports the need for a new classification system that incorporates both clinical phenotype and factor levels, recognising the dynamic nature of disease severity.

The session also highlighted ongoing work to address gynaecological and obstetric bleeding in women and girls, including recommendations for managing heavy menstrual bleeding with hormonal therapy, DDAVP, or replacement therapy based on individual response and severity.

Based on the research done by the panel, the forthcoming recommendations aim to refine diagnosis, personalise management, and improve outcomes by integrating clinical presentation with laboratory measures in mild and moderate haemophilia A and B.

European Hematology Association Guidelines for Large B Cell Lymphomas

At the EHA2025 Congress, Catherine Thieblemont, Hôpital Saint-Louis, Paris, France, presented the new EHA guidelines for large B cell lymphomas (LBCL) on behalf of a multidisciplinary panel of 23 European haematology experts.8

The group conducted a rigorous systematic review of the literature using the Grading of Recommendations Assessment, Development and Evaluation framework to establish evidence-based recommendations. The guidelines will be updated biennially, with treatment algorithms reviewed annually on the EHA website.

The new guidelines stress the importance of expert haematopathology, with full immunohistochemistry and molecular profiling for accurate diagnosis, particularly in detecting high-risk subtypes such as double-hit lymphomas. While cell-oforigin classification (Germinal Centre B cell versus Activated B cell) remains useful, it holds no current therapeutic consequence.

Genetic profiling, although not yet routine, is deemed increasingly crucial.

PET-CT is now firmly established as the gold standard for staging, surpassing bone marrow biopsy in detecting extranodal involvement. The International Prognostic Index (IPI) remains essential, with central nervous system (CNS)-IPI strongly recommended for risk-adapted therapy. Novel metrics such as metabolic tumour volume, distance maximum, and circulating tumour DNA offer superior prognostic insights.

Supportive care is highlighted, with cardiac and osteoporosis assessments and frailty evaluations encouraged, especially in

PET-CT is now firmly established as the gold standard for staging, surpassing bone marrow biopsy in detecting extranodal involvement

For fit patients under 80 with no risk factors, R-CHOP21 for 4–6 cycles remains standard

elderly patients. Clinicians are urged to ensure that patients receive clear, jargon-free information and have their preferences considered.

Treatment recommendations vary by risk profile. For fit patients under 80 with no risk factors, R-CHOP21 for 4–6 cycles remains standard, depending on tumour size. For higher-risk cases, PolaR-CHP is preferred. PET-based response assessment using the Deauville scale is central to therapy guidance.

Special populations, including those with CNS relapse risk, primary mediastinal or testicular lymphomas, intravascular LBCL, and elderly or frail patients, require tailored

approaches. Notably, CNS prophylaxis strategies have shifted away from intrathecal therapy towards high-dose methotrexate when warranted.

Post-treatment care focuses on survivorship, end-of-treatment consultations, limited imaging in patients who are asymptomatic, cardiac monitoring, and addressing long-term effects such as fatigue and neuropathy. Psychological support and lifestyle interventions, such as smoking cessation, are also emphasised.

These comprehensive, regularly updated guidelines aim to enhance diagnostic accuracy, personalisation of therapy, and long-term patient wellbeing in LBCL.

References

1. Terpos E. Multiple myeloma: EHAEMN clinical practice guidelines for diagnosis, treatment and follow-up. Presentation p573-2. EHA Congress, 12-15 June, 2025.

2. Shmitz N et al. First-line therapy of T-cell lymphoma: allogeneic or autologous transplantation for consolidation—final results of the AATT study. J Clin Oncol. 2019;37(Suppl 15):7503.

3. Tournilhac O et al. Long-term followup of the prospective randomized AATT study (autologous or allogeneic transplantation in patients with peripheral T-cell lymphoma). J Clin Oncol. 2024;42(32):3788-94.

4. Dupuis J. Oral azacitidine compared with standard therapy in patients with relapsed or refractory follicular helper T-cell lymphoma (ORACLE): an openlabel randomised, phase 3 study. Lancet Haematol. 2024;11(6):e406-14.

5. Tian XP et al. First-line sintilimab with pegaspargase, gemcitabine, and oxaliplatin in advanced extranodal natural killer/T cell lymphoma (SPIRIT): a multicentre, single-arm, phase 2 trial. 2024;11(5):e336-44.

6. Sibon D et al. The Eatl-001 trial: results of a phase 2 study of brentuximab vedotin and CHP followed by consolidation with high-dose therapy - autologous stem-cell transplantation (HDT-ASCT) in the frontline treatment of patients with enteropathyassociated T-cell lymphoma. Blood. 2021;138(Suppl 1):136.

7. Casini A. EAHAD EHA forthcoming recommendations for mild and moderate hemophilia A and B: Background and main topics. Presentation p572-2. EHA Congress, 12-15 June, 2025.

8. Catherine Theiblemon. Overview of guidelines. EHA guideline on the management of aggressive large B-cell lymphomas: first line and beyond. Presentation p-571-2. EHA Congress, 12-15 June, 2025.

Awards Summary

The 2025 EHA Congress Awards honoured outstanding contributions across clinical care, research, education, and advocacy in haematology. Recognitions included achievements in scientific publishing, mentorship, innovation, and the work of early-career professionals.

Opening Ceremony Awards

EHA Clinical Excellence Award:

Khaled Musallam

Burjeel Holdings, Burjeel Medical City, Abu Dhabi, United Arab Emirates

EHA Diversity, Equity, and Inclusion Award

Anna Schuh University of Oxford, UK

EHA Education & Mentoring Award

Jan Cools

KU Leuven, Belgium

Hemasphere Awards 2025

> Top Cited Article (Clinical): Kai Rejeski et al.

Title: An International Survery on Grading, Diagnosis, and Management of Immune Effector Cell-Associated Hematotoxicity (ICAHT) Following CAR-T cell Therapy on Behalf of the EBMT and EHA

> Top Cited Article (Biology): Milad Rasouli et al

Title: The MLL-Menin Interaction is a Therapeutic Vulnerability in NUP98-rearranged AML

> EHA Lifetime Achievement Award

Jesús San-Miguel, Cancer Centre, Clinica Universidad de Navarra, Spain

Young EHA Award:

Mandy Lauw Erasmus Medical Center Rotterdam, the Netherlands

EHA Research Excellence Award

Alberto Orfao Universidad de Salamanca, Spain

Young EHA Best Abstract Awards

> Luca Bertamini Erasmus Medical Center Rotterdam, the Netherlands

> Lisa Leypoldt University Medical Center Hamburg-Eppendorf, Germany

> Hangjie Fu Zhejiang Chinese Medical University Hangzhou, China

> Noelia Collado-Gisbert Cancer Center Clinica Universidad de Navarra Centro de Investigacion Medica Aplicada, Instituto de Investigacion Sanitaria de Navarra, CIBER-ONC CB16/12/00369 and CB16/12/00489 Pamplona, Spain

Prognostic Assessment in Light Chain Amyloidosis: Emerging Models

and Biomarkers

Author: *Selin Küçükyurt1,2

1. Division of Hematology, Department of Internal Medicine, Cerrahpaşa Faculty of Medicine, Istanbul University-Cerrahpaşa, Türkiye

2. Department of Hematology, Ankara Etlik City Hospital, Türkiye

*Correspondence to dr.skucukyurt@hotmail.com

Disclosure: The author has declared no conflicts of interest.

Keywords: Circulating tumour cells (CTC), daratumumab, European Hematology Association (EHA), global longitudinal strain, light chain (AL) amyloidosis, N-terminal pro-B-type natriuretic peptide (NT-proBNP), prognosis, staging system, troponin.

Citation: EMJ Hematol. 2025;13[1]:20-23. https://doi.org/10.33590/emjhematol/RQXT1454

THIS YEAR’S European Hematology Association (EHA) 2025 Congress spotlighted a transformative shift in the prognostic landscape of systemic light chain amyloidosis. Among more than 30 abstracts showcased, two studies stood out: one redefining ultra-high-risk cardiac disease through the Mayo Stage IIIc model, and another introducing circulating tumour cells as a non-invasive biomarker with independent prognostic value. Together, they delivered a clear message: in AL amyloidosis, the future of risk stratification lies at the intersection of refined cardiac imaging and cellular precision.

BACKGROUND

Systemic light chain (AL) amyloidosis is a rare plasma cell dyscrasia characterised by the extracellular deposition of misfolded Ig light chains, most commonly of the lambda (λ) type, as insoluble amyloid fibrils in various organs. Although virtually all organs except the brain may be affected, cardiac and renal involvement are the most frequent. Among these, cardiac involvement is the principal determinant of survival, making preservation and improvement of cardiac function the primary therapeutic goal. Another key prognostic factor is the size of the underlying bone marrow plasma cell clone at diagnosis.1

Despite significant therapeutic advances, including the introduction of daratumumabbased induction regimens and the

increasing use of high-dose melphalan with autologous stem cell transplantation, AL amyloidosis remains incurable. Early mortality continues to pose a major challenge, particularly in those presenting with advanced cardiac dysfunction. Given the strong association between the depth and rate of haematologic response and subsequent organ recovery and survival, precise risk stratification at diagnosis is essential to inform treatment decisions.2,3

The Mayo Clinic staging systems stratify patients into prognostically distinct risk groups based on cardiac biomarkers, namely, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and troponin, and the difference between involved and uninvolved serum free light chains (dFLC). However, in the modern treatment era, where therapies effectively target the

underlying plasma cell clone, the prognostic utility of dFLC appears to be diminishing.4-7 Moreover, these traditional staging models, originally developed before the availability of current anti-plasma cell therapies, may inadequately capture early mortality risk and fail to identify ultra-high-risk patients.

In this feature, the author aims to highlight selected abstracts on AL amyloidosis presented at the 30th Congress of EHA; one of the largest global gatherings of researchers focused on haematologic disorders. This annual meeting provides a platform for investigators to share their latest findings with peers, clinicians, and patient advocates.

A search using the term ‘AL amyloidosis’ on the EHA 2025 Congress website revealed a total of 38 abstracts, including three oral presentations and 18 e-posters. Among these, the author has selected two abstracts that stood out due to their clinical relevance and potential impact on future practice.

REFINING CARDIAC RISK STRATIFICATION: THE MODIFIED MAYO STAGE IIIC MODEL

In the first abstract, a multinational cohort of 325 patients with newly diagnosed systemic AL amyloidosis from the a European collaboration were retrospectively evaluated to assess the applicability of a modified Mayo staging system, incorporating an ultra-poor risk category labelled as ‘Mayo Stage IIIc’ in the daratumumab-treated era.8 This category is defined by the combination of three high-risk features at diagnosis: NT-proBNP ≥8,500 ng/L, high-sensitivity troponin T ≥50 ng/L, and myocardial global longitudinal strain >-9%, the latter reflecting advanced myocardial dysfunction.8

At diagnosis, the median age was 64 years, and the median bone marrow plasma cell infiltration was 15% (range: 0–90%). Cardiac involvement was observed in 81% of the cohort, with a substantial proportion also demonstrating renal (58%) and hepatic (19%) involvement. The cohort was heterogeneous in treatment exposure: 61% received daratumumab-based therapies, while 29% were treated with bortezomib-containing regimens. At a median follow-up of 29 months, the 2year overall survival (OS) rate was 78%.8

However, significant survival stratification was evident when patients were categorised according to the revised staging system.

Median OS for the modified Mayo Stage IIIc patients was only 9 months, compared to 76 months for Stage IIIb (excluding IIIc), while Stages I through IIIa had not yet reached a median survival threshold. The hazard ratio for mortality in Stage IIIc compared to Stage I was 24.33 (95% CI: 5.67–104.00), indicating a profoundly adverse prognosis. This updated model effectively identified an ultra-high-risk subgroup within Stage III and demonstrated improved discriminative capacity (Harrell’s C=0.70). These findings suggest that a combination of global longitudinal strain and cardiac biomarkers provides a valuable tool for early identification of patients at greatest risk of early death, thus supporting more aggressive or tailored interventions in this subgroup.8

Median OS for the modified Mayo Stage IIIc patients was only 9 months, compared to 76 months for Stage IIIb

CIRCULATING TUMOUR CELLS AS A PROGNOSTIC BIOMARKER IN LIGHT CHAIN AMYLOIDOSIS

In the second abstract, Kostopoulos et al.,9 Athens, Greece, prospectively evaluated the prognostic role of circulating tumour cells (CTC) in 218 patients with newly diagnosed, treatment-naïve AL amyloidosis. CTCs were quantified in peripheral blood using highly sensitive next-generation flow cytometry in accordance with EuroFlow guidelines. Detectable CTCs were present in 59% of patients, with a wide range of tumour burden (0.0002–11.4%). The presence of CTCs was significantly associated with higher levels of involved free light chains, elevated NT-proBNP, and increased bone marrow infiltration. Notably, the correlation between CTC levels and bone marrow plasma cell percentage was modest, suggesting that peripheral tumour burden may provide unique prognostic information distinct from marrow involvement.9

The correlation between CTC levels and bone marrow plasma cell percentage was modest

Importantly, baseline CTC levels were not significantly associated with the depth of haematological or organ response. However, a higher CTC burden was independently predictive of inferior eventfree survival (EFS) and OS in multivariate analysis. CTCs retained prognostic significance even after adjusting for Mayo stage, difference in uninvolved free light chains, and daratumumab exposure. The most discriminatory thresholds were identified as ≥10⁻⁴ for OS, and the assay’s limit of detection for EFS. Furthermore, patients without detectable CTCs achieved significantly higher rates of measurable residual disease negativity, implying that the absence of CTCs may serve as a surrogate marker for deeper and more durable treatment responses. These findings position CTC quantification as a promising non-invasive biomarker that could enhance risk stratification and guide therapeutic decision-making in the early stages of AL amyloidosis, prior to the onset of irreversible organ damage.9

CONCLUSION

Systemic AL amyloidosis remains an incurable disease; however, early diagnosis and the advent of novel therapies have significantly improved patient outcomes. All patients require prompt treatment at diagnosis due to the risk of progressive organ dysfunction. As a multisystem disorder, AL amyloidosis necessitates multidisciplinary management, especially in the context of cardiac and renal involvement. Simple, biomarker-based staging systems, using NT-proBNP and cardiac troponin, are widely accessible and clinically useful. Nonetheless, selecting the optimal firstline therapy is critical. The daratumumab, bortezomib, cyclophosphamide, and dexamethasone regimen remains the preferred approach due to its superior haematologic and organ response rates. It is strongly recommended that patients be referred to specialized centers with experience in amyloidosis and autologous hematopoietic stem cell transplantation.

Data presented at the 30th EHA Congress reinforce the importance of refining prognostic stratification in AL amyloidosis. The modified Mayo Stage IIIc model effectively identifies an ultra-high-risk subgroup with poor treatment strategies survival, highlighting the need for tailored or intensified in this population. Additionally, the presence and burden of CTCs emerged as an independent prognostic biomarker, associated with inferior EFS and OS, even after adjusting for established staging criteria.

Taken together, these findings support a paradigm shift toward multimodal risk assessment in AL amyloidosis, incorporating cardiac function, tumour biology, and emerging cellular markers. Continued prospective validation of these tools is essential. Ultimately, a more nuanced understanding of individual patient risk will enable personalised treatment strategies aimed at improving survival while minimising treatment-related toxicity in this complex and heterogeneous disease.

References

1. Sanchorawala V. Systemic light chain amyloidosis. N Engl J Med. 2024;390(24):2295-2307.

2. Kastritis E et al.; ANDROMEDA Trial Investigators. Daratumumab-based treatment for immunoglobulin light chain amyloidosis. N Engl J Med 2021;385:46-58.

3. Gertz MA. Immunoglobulin light chain amyloidosis: 2022 update on diagnosis, prognosis, and treatment. Am J Hematol. 2022;97(6):818-29.

4. Dispenzieri A et al. Serum cardiac troponins and N-terminal pro-brain

natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol. 2004;22(18):3751-7.

5. Kumar S et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol. 2012;30(9):989-95.

6. Wechalekar AD et al. A European collaborative study of treatment outcomes in 346 patients with cardiac stage III AL amyloidosis. Blood. 2013;121(17):3420-7.

7. Khwaja J et al. Limited utility of Mayo 2012 cardiac staging system

for risk stratification of patients with advanced cardiac AL amyloidosisanalysis of a uniformly treated cohort of 1,275 patients. Haematologica. 2024;109(5):1598-1602.

8. Khwaja J et al. Identifying an ultrapoor risk ‘Mayo Stage IIIC’ group in systemic AL amyloidosis in the daratumumab-era: a European collaboration. Abstract S198. EHA Congress. 12-15 June, 2025.

9. Kostopoulos I et al. The evaluation of circulating tumor cells as a prognostic biomarker in newly diagnosed light chain amyloidosis. Abstract S195. EHA Congress. 12-15 June, 2025.

Putting Patients First: Insights from the Specialized Working Group Session on Quality of Life in Haematology

Author: *Deniz Özmen1

1. İstanbul University-Cerrahpaşa, Cerrahpaşa Faculty of Medicine, Türkiye

*Correspondence to deniz.ozmen@iuc.edu.tr

Disclosure: The author has declared no conflicts of interest.

Keywords:

Patient-reported experience measure (PREM), patient-reported outcome measure (PROM), quality of life (QoL).

Citation: EMJ Hematol. 2025;13[1]:24-26. https://doi.org/10.33590/emjhematol/XKXL8810

OVER the past decades, haematology has made great progress in understanding disease mechanisms, developing objective diagnostic criteria, and introducing new treatment options. However, during this period, the ‘subjective’ part of the patient's follow-up, including personal experience such as symptoms, side effects, and perceptions about treatment, has often been overlooked. Clinicians have mainly focused on measurable medical outcomes, and there has been little time or space to address the subjective aspects of care. Today, this situation is beginning to change.

QUALITY OF LIFE AND PATIENTREPORTED OUTCOMES

During the Specialized Working Group session, ‘Quality of Life and Symptoms: Promoting Connection Between Patients and Clinicians’, which took place at the European Hematology Association (EHA) 2025 Congress, Raul Cordoba, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, Madrid, Spain, gave a presentation entitled ‘Assessment of Patients’ Quality of Life (QoL) and Symptoms in Routine Clinical Practice to Aid Treatment Decision Making’. Cordoba began by discussing the concept of value in healthcare, based on the model proposed by Michael E. Porter.1,2 In this model, value is defined as the health outcomes that matter to patients, divided by the cost of achieving those outcomes. Cordoba stressed that, in addition to objective results like survival, patients’ experiences and QoL must also be considered when evaluating healthcare value.

To support this shift, Cordoba emphasised the use of patient-reported outcome measures (PROM) and patient-reported experience measures (PREM) in routine practice. Tools such as the PatientReported Outcomes Version of the Common Terminology Criteria For Adverse Events (PRO-CTCAE®) system, developed by the National Cancer Institute (NCI), are already being used in diseases like chronic myeloid leukaemia and myelofibrosis.3 At Cordoba’s hospital, digital tools like the Casiopea patient portal and electronic medical recordintegrated questionnaires help both patients and healthcare providers monitor care more closely. These tools also allow for analysis of large datasets to improve care processes.

These tools also allow for analysis of large datasets to improve care processes

Although there are no universal PROM/ PREM standards in haematology yet, Cordoba’s team has developed diseasespecific datasets. These include not only traditional outcomes like treatment response and survival, but also QoL indicators such as treatment duration, nutrition, emotional well-being, and social relationships. One interesting innovation is a ‘traffic light’ system based on PROM data, which helps nurses make proactive interventions to prevent worsening of symptoms.

Cordoba also presented results from a 2023 EHA poster. In this study, patients with newly diagnosed aggressive lymphoma receiving intravenous therapy were monitored remotely using the E-Res Salud digital health system. Compared with a control group, these patients had significantly fewer emergency visits and unplanned hospitalisations, and also showed better overall survival.4

Including patient-centred outcomes in clinical decision-making can improve both individual care and system-wide efficiency. In a complex field like haematology, this shift toward value-based, patient-focused care may help raise awareness among clinicians and patients alike, and contribute to better outcomes for all.

In the session ‘Quality of Life in CardioHematology: Lessons from the Horizon 2020 Resilience Trial’, Borja Ibañez, Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain, presented updates from the ongoing RESILIENCE study.5 This trial focuses on one of the key challenges in realworld haematology practice: preventing anthracycline-related cardiotoxicity. It evaluates the potential protective effect of remote ischaemic conditioning in patients with high-risk lymphoma. The primary endpoint is the change in left ventricular ejection fraction, measured by cardiac MRI. The study also includes PROMs and QoL assessments to better understand how cardioprotective strategies affect patient experience.

Although the trial is still in progress, early observations shared at EHA 2025 suggest that combining imaging data with patientreported outcomes is both feasible and valuable. This approach supports a more holistic model of cardio–haematology, one that considers not just survival, but also one of the most important factors affecting patients’ physical and emotional well-being. It is promising to see large-scale studies like this being conducted, with the aim to reduce the cardiac side effects of chemotherapy.

The final presentation of the session, entitled ‘Treatment Outcomes Preferences: What Matters to Patients with Acute Leukemia?’, was delivered by Jan Geissler, Acute Leukemia Advocates Network (ALAN) and Patvocates. His talk focused on the disconnect between traditional clinical endpoints and what patients living with acute leukaemia actually value, particularly in the relapsed/refractory setting.6 As treatment options continue to grow, understanding patient perspectives has become more important than ever.

As treatment options continue to grow, understanding patient perspectives has become more important than ever

Geissler presented the findings from a set of patient-driven studies, which explored treatment goals and priorities using methods such as discrete choice experiments, best–worst scaling, and structured interviews. In these studies, patients were asked to compare hypothetical treatment scenarios involving various trade-offs, such as likelihood of response, side effect burden, treatment duration, and impact on daily functioning. This approach helped quantify what patients are willing to prioritise or sacrifice in different clinical situations.

The results showed that chance of response remains the top priority for most patients. However, QoL during treatment ranked second, and in some cases, patients were willing to accept a lower response rate in exchange for fewer side effects, more convenience, or better overall well-being. Interestingly, two broad groups of patients were identified, one that focuses strongly

References

1. Raul Cordoba. Assessment of patients’ quality of life and symptoms in routine clinical practice to aid treatment decision making. Presentation S245. EHA Congress, 12-15 June, 2025.

2. Porter ME. What is value in health care? N Engl J Med. 2010;363(26):2477-81.

on maximising response, and another that values a more balanced approach between response and QoL. Patients with acute lymphoblastic leukaemia or acute promyelocytic leukaemia, and importantly, newly diagnosed patients, tended to place greater emphasis on response.

Another key aspect of the presentation was the evaluation of standard QoL tools like EuroQol 5-dimensional questionnaire. The studies included two additional dimensions, cognition and tiredness, which patients consistently rated as highly important. Notably, tiredness was given much more weight by patients than by the general public. These findings suggest that existing generic QoL instruments may not fully capture the lived experience of patients with acute leukaemia.

CLOSING REMARKS

In conclusion, these findings highlight the importance of a patient-centred approach that focuses not only on the disease, but on the person experiencing it. The author firmly believes that integrating patient-reported data and treatment preferences into routine care can significantly improve outcome, not just clinically, but also in terms of communication, satisfaction, and empowerment. Tools such as PROMs and preference studies not only help standardise the way patient symptoms and priorities are understood, but also strengthen the dialogue between physicians and patients. Most importantly, they give patients a greater voice in decisions about their own care, which is essential in building a healthcare system that truly reflects what matters to those it serves.

3. Efficace F et al. Patient-reported outcomes in hematology: is it time to focus more on them in clinical trials and hematology practice? Blood. 2017;130(7):859-66.

4. Ramos S et al. P1689: real-world evidence of using telemedicine to capture electronic prom improves quality of life assessment, healthcare resources management and overall survival in patients with lymphoma. Hemasphere. 2023;7(Suppl):e3331772.

5. Borja Ibañez. Quality of life in cardiohematology: lessons from the horizon 2020 resilience trial. Presentation. EHA Congress, 12-15 June, 2025.

6. Jan Geissler. Treatment outcomes preferences: what matters to patients with acute leukemia? Presentation. EHA Congress, 12-15 June, 2025.

Highlights in Acute Lymphoblastic Leukaemia: European Hematology Association (EHA) 2025

Author: *Josep-María Ribera1

1. Clinical Hematology Department, ICO-Hospital Germans Trias i Pujol, Josep Carreras Research Institute, Badalona, Spain *Correspondence to jribera@iconcologia.net

Disclosure:

Ribera has received consulting fees from Incyte, Pfizer, Bristol Myers Squibb, Novartis, and Takeda; payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events from Incyte, Pfizer, Bristol Myers Squibb, Novartis, and Takeda; and grants or contracts from Amgen, Incyte, and Pfizer.

Keywords: Acute lymphoblastic leukaemia (ALL), immunotherapy, Philadelphia chromosome, tyrosine kinase inhibitors (TKI).

Citation: EMJ Hematol. 2025;13[1]:27-30. https://doi.org/10.33590/emjhematol/OOJT7345

IN RECENT YEARS, significant improvements have been achieved in the management of children and adults with either Philadelphia (Ph) chromosome-positive or negative acute lymphoblastic leukaemia (ALL). The most important have been the incorporation of immunotherapy in newly diagnosed patients and the incorporation of new monoclonal antibodies and CAR-T constructs in the treatment of relapsed or refractory (R/R) patients. In Ph-positive ALL, new tyrosine kinase inhibitors (TKI) are being incorporated in first-line treatment, and the role of haematopoietic transplantation is being redefined. On the other hand, advances in T-ALL are still modest, the most promising being the CAR-T use in R/R patients.

PHILADELPHIA CHROMOSOMENEGATIVE ACUTE LYMPHOBLASTIC LEUKAEMIA

The most important advances in Phnegative ALL come from the incorporation of immunotherapy into first-line ALL. In this sense, Dinner et al.1 analysed the outcomes of the addition of blinatumomab to consolidation therapy in 132 younger adults (30–54 years) with BCR::ABL1-negative B-acute lymphoblastic leukaemia enrolled in the ECOG-ACRIN E1910 Phase III trial. For the 66 patients randomised to receive blinatumomab during consolidation, the overall survival (OS) was better than that of the control group (92% for blinatumomab versus 67% for chemotherapy [hazard ratio (HR): 0.20; 95% CI: 0.08–0.54; p=0.002]).1

This significant advantage was also observed in the following patients’ subgroups: those aged 30–39 years and those with a Ph-like phenotype.1 These results reinforce the need to include blinatumomab in the consolidation regimen in young adults with newly diagnosed Ph-negative ALL.

Single-agent subcutaneous blinatumomab is a new compound that has promising efficacy in ALL. It was proven to be welltolerated and effective in the Phase I study in adult patients with R/R Ph-negative ALL.2 Jabbour et al.3 presented the results of a Phase I/II extension study consisting of 88 patients who were separated into two dose level cohorts: 1) 250 μg once-daily (QD) for Week 1 of cycle 1 and 500 μg thrice-weekly (TIW) thereafter (250/500), or 2) 500 μg

QD and 1,000 μg TIW (500/1,000). The drug was shown to be effective in both cohorts: CR (complete remission)/CRh (CR with partial haematologic recovery)/CRi (CR with with incomplete haematologic recovery) rate was 89% and 92% with measurable residual disease (MRD) negativity in 91% and 90% of responders in cohort 1 and cohort 2, respectively.3 The estimated 12-month OS rate was 62.7% and 69.7% in 250/500 and 500/1000, respectively.3 The rates of Grade ≥3 cytokine release syndrome were 17% and 23% and those of neurologic events (including ICANS) were 28% and 27%, for 250/550 and 500/1000 cohorts, respectively.3 No fatal treatmentrelated adverse events were observed, and adverse events were managed with blinatumomab interruption and/or supportive care measures, without the need for SC blinatumomab discontinuation.3 Notably, the FDA has selected the 250/500 dose for further trials. In summary, singleagent SC blinatumomab resulted in high efficacy, with a high MRD-negativity rate, and an acceptable safety profile, and will be investigated in Phase II and Phase III studies.3

Stock et al.4 retrospectively analysed outcomes in patients with R/R B-cell ALL receiving inotuzumab ozogamicin (InO), stratified by cumulative dose received (≤3.3 mg/m2; 161 patients versus >3.3 mg/m2; 177 patients). Among responders, improved progression-free survival (PFS)/

OS outcomes were observed in patients from the ≤3.3 mg/m2 group, a feature attributed to a greater number of patients who proceeded to haematopoietic stem cell transplantation (HSCT).4 The risk of post-HSCT sinusoidal obstruction syndrome between dose groups appeared similar, but the incidence of post-HSCT mortality and non-relapse mortality was lower in the ≤3.3 mg/m2 group.4 Less myelosuppression was also observed in the ≤3.3 mg/m2 group.4

The 10-year survival following the CALGB 10403 (ALLIANCE) trial, an intensive paediatric regimen for adolescents and young adults with ALL, showed OS and event-free survival (EFS) rates of 56% and 44%, respectively.5 Of note, late events beyond 3 years were observed in 25% of patients of B-ALL versus none in T-ALL, and early eradication of MRD was highly predictive of better 10-year survival.4 Patients with Ph-like phenotype, BMI >30, and those who did not complete maintenance did poorly. The results of this study highlight the importance of long-term follow-up of ALL studies. Several questions like 1) Will the addition of blinatumomab consolidation change the outcome? 2) Will the addition of blinatumomab improve outcomes in patients with Ph-like and those with high BMI? 3) Can the addition of blinatumomab replace some of the chemotherapy for patients with non-high genetic risk? should be answered in future studies.

PHILADELPHIA CHROMOSOME POSITIVE ACUTE LYMPHOBLASTIC LEUKAEMIA

A post-hoc analysis of patients from the Phase III PhALLCON trial (randomly comparing ponatinib versus imatinib combined with attenuated chemotherapy) not achieving complete molecular response (CMR) after 4 weeks (the main objective of the trial), but continuing in the trial, showed higher rates of deep molecular response after the end of induction in patients treated with ponatinib (48% versus 33%).6 This was translated into lower use of allogeneic HSCT and better PFS survival in patients in the ponatinib group.

Two Phase II trials from China showed the results of the combination of olverembatinib (a third generation TKI active against T315I mutations) or flumatinib (a second generation TKI) with standard induction chemotherapy in newly diagnosed patients with Ph+ ALL.7,8 Olverembatinib combined with vindesine and prednisone (37 patients) showed a CR rate of 97%, with CMR of 89% after 3 cycles, resulting in 2-year OS and 96% EFS.7 The safety profile was good, notably without cardiovascular toxicity. This compound should be investigated in combination with blinatumomab in future trials. In turn, flumatinib combined with vincristine, idarubicin, and prednisone (140 patients) showed promising efficacy (CR/ Cri: 98.6%; CMR at 3 months 48%), with 2-year OS of 79%. IKZF1plus, MRD at 3 months, and allo-HSCT were independent prognostic factors of PFS and OS.8

Mauro et al.9 presented the results of the first-in-human Phase I study of asciminib monotherapy in 28 heavily pretreated adults with R/R Ph+ ALL. After a starting dose of 40 mg twice daily (BID) with dose escalation to 280 mg BID, no maximum tolerated dose was reached, and 200 mg BID was selected for an expansion cohort study.9 The most common Grade ≥3 adverse events were cytopaenias, infections, and alanine aminotransferase, gamma-glutamyl transferase, and lipase elevations. Molecular response by Week 4 was observed in 33% of patients.

CAR-T CELL THERAPY

Obecabtagene Autoleucel (obe-cel) is the third autologous anti-CD19 CAR-T construct approved for use in R/R ALL. Park J et al.10 showed the long-term findings (median follow-up of 3 years) and the predictors of sustained remission for 127 patients included in the Phase II FELIX trial, where the medians of EFS and OS were 11.9 and 17.1 months, respectively. The 24-month probability of remaining in remission was 54.1%, with 38.4% of responders being in long-term remission without consolidative SCT or other therapies.9 Ph+ ALL, earlier obe-cel use, and less refractory disease correlated with achieving higher remission rates, whereas lower disease burden at lymphodepletion and ongoing CAR-T cell persistence were independent factors associated with long-term remission and survival.9 In sum, these results suggest that a proportion (40%) of patients treated with obe-cel may not need further therapy.

Shah et al.11 analysed the efficacy and safety outcomes of obe-cel stratified by age (<55 years, n=79 versus ≥55 years, n=48) in patients with R/R B-ALL included in the FELIX trial. No differences were observed in terms of efficacy (overall response rate: 72% versus 85% and median EFS 14.3 versus 11.7 months for patients <55 years and ≥55 years, respectively) and safety (Grade ≥3

CRS: 2.5% versus 2.1% and Grade ≥3 ICANS: 5.1% versus 10.4% for patients <55 years and ≥55 years, respectively).10 The frequencies of cytopaenias and infections were not significantly different among the age groups.11 From this, obe-cel appears to be welltolerated and effective in both older and younger patients, thus providing an attractive option for older patients with R/R ALL.

References

1. Shira Dinner et al. Addition of blinatumomab to consolidation therapy for younger adults (BCR:ABL1-negative B-acute lymphoblastic leukemia) on the ECOG-ACRIN E1910 Phase III Trial. Presentation S110. EHA Congress, 12-15 June 2025.

2. Jabbour E et al. Single agent subcutaneous blinatumomab for advanced acute lymphoblastic leukemia. Am J Hematol. 2024;99(4):586-95.

3. Elias Jabbour et al. Safety and efficacy of single-agent subcutaneous blinatumomab in adults with relapsed/ refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL): results from a phase 1/2 dose expansion study. Presentation S112. EHA Congress, 12-15 June 2025.

4. Wendy Stock et al. Outcomes in patients with B-cell precursor acute lymphoblastic leukemia receiving inotuzumab ozogamicin stratified by cumulative dose. Presentation S111. EHA Congress, 12-15 June 2025.

CONCLUDING REMARKS

The incorporation of blinatumomab in first-line therapy in Ph-negative B cell ALL opens new questions, for example, the substitution of chemotherapy rather than the mere addition of immunotherapy, and the use of monotherapy in earlier phases of the treatment, among others. In Ph-positive ALL, immunotherapy is not yet approved. Meanwhile, new TKIs are emerging, with olverembatinib and asciminib being the most promising. New bispecific monoclonal antibodies and safer CAR-T constructs show promising results for R/R patients. There is no doubt that further improvements will be presented in future EHA Congresses.

5. Wendy Stock et al. Long-term followup of an intensive pediatric regimen for adolescents/young adults (AYA) with acute lymphoblastic leukemia (ALL): 10-year survival following CALGB 10403 (ALLIANCE). Presentation S118. EHA Congress, 12-15 June 2025.

6. Gambacorti-Passerini C et al. Achievement of MRD negativity after end of induction with ponatinib and imatinib in the phase 3 PhALLCON trial: a post hoc analysis. Presentation S116. EHA Congress, 12-15 June 2025.

7. Xu G et al. Combination of olverembatinib and VP regimen as first-line therapy for adult patients with philadelphia chromosomepositive acute lymphoblastic leukemia: a single-arm, multicentre, phase 2 trial. Poster PS1372. EHA Congress, 12-15 June 2025.

8. Liu W et al. A Prospective study of flumatinib with chemotherapy for newly diagnosed BCR::ABL1-positive acute lymphoblastic leukemia in adults: RJ-ALL2020.2A trial. Poster PF386. EHA Congress, 12-15 June 2025.

9. Mauro M et al. First-in-human study of asciminib (ASC) monotherapy in adults with relapsed/refractory (R/R) philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Presentation S119. EHA Congress, 12-15 June 2025.

10. Park J et al. Can CAR T-cell therapy be a definitive treatment for adult r/R B-ALL without transplant? longterm findings and predictors of sustained remission for obecabtagene autoleucel. Presentation S113. EHA Congress, 12-15 June 2025.

11. Shah B et al. efficacy and safety outcomes of obecabtagene autoleucel (obe-cel) stratified by age in patients with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL). Presentation S114. EHA Congress, 12-15 June 2025.

Advancing Frontiers in Myeloproliferative Neoplasms

Author: *Erika Morsia1

1. Hematology Unit, Department of Clinical and Molecular Sciences, Università Politecnica delle Marche, Ancona, Italy

*Correspondence to erika.morsia@ospedaliriuniti.marche.it

Disclosure: The author has declared no conflicts of interest.

Keywords: Disease biology, myeloproliferative neoplasms (MPN), new drugs.

Citation: EMJ Hematol. 2025;13[1]:31-35. https://doi.org/10.33590/emjhematol/MJUD9157

THE 30th EUROPEAN Hematology Association (EHA) Congress marked a pivotal year in advancing the treatment and understanding of myeloproliferative neoplasms (MPN). Breakthroughs in novel therapies, disease biology, and molecular risk stratification highlighted EHA 2025 Congress as a key event shaping the future of MPN care. Herein are the main takeaways from pivotal presentations.

NEW THERAPEUTIC HOPE IN MYELOFIBROSIS

Two major studies presented at EHA 2025 brought promising news for patients with myelofibrosis (MF).

RESTORE Trial1

Timothy Devos, University Hospitals Leuven, Belgium, presented data showing that elritercept, an activin receptor ligand trap, provided both haematological and clinical benefits in patients with MF. Treatment led to reductions in splenomegaly and improved symptom control. Notably, elritercept significantly improved anaemia, demonstrating efficacy both as a standalone therapy and in combination with ruxolitinib, suggesting its potential as a disease-modifying agent.

MANIFEST-2 72-Week Update2

Alessandro Vannucchi, University of Florence and AOU Careggi, Florence, Italy, presented updated results from the MANIFEST-2 trial, which assessed pelabresib, a bromodomain and

extraterminal domain (BET) inhibitor, in combination with ruxolitinib in patients with JAK inhibitor-naïve MF. The regimen demonstrated sustained improvements in spleen volume and symptom burden at 72 weeks, alongside a favourable safety profile, supporting its role as a potential first-line treatment. Although an early imbalance in leukaemic transformation was noted in the pelabresib arm compared to placebo, the incidence over time aligned with expected rates for the MF population.

NOVEL AGENTS TARGETING CALR MUTATIONS AND T CELL REDIRECTION

A strong focus was placed on targeted therapies for CALR-mutant MPNs, a historically underserved subgroup.

A strong focus was placed on targeted therapies for CALR-mutant MPNs, a historically underserved subgroup

INCA0357843

Beth Psaila, Imperial College London, UK, introduced a T cell-redirecting bispecific antibody that targets CALR mutations, showing early signs of immune activation and tumour targeting in preclinical and earlyphase clinical testing. This approach opens a new chapter for immunotherapy in MPNs.

INCA339894

John Mascarenhas, Icahn School of Medicine at Mount Sinai, New York, USA, presented first-in-human data on INCA33989, a monoclonal antibody specifically targeting mutant CALR. In patients with essential thrombocythaemia (ET), the therapy demonstrated a favourable safety profile and encouraging early clinical activity. Most patients experienced rapid and sustained normalisation of blood counts, along with a reduction in mutant CALR variant allele frequency. Notably, 25% of patients achieved early partial molecular remission, suggesting the potential for true disease modification and supporting a new precision medicine approach in CALR-mutant ET.

of patients achieved early partial molecular remission, suggesting the potential for true disease modification and supporting a new precision medicine approach in CALR-mutant ET

INTERFERON INNOVATION: ROPEGINTERFERON ALFA-2B STANDS OUT

Ropeginterferon alfa-2b, a long-acting interferon, took centre stage with several abstracts presented across the Congress.

SURPASS-ET Trial5

Harry Gill, The University of Hong Kong, Hong Kong SAR of China, delivered a presentation that compared ropeginterferon alfa-2b versus anagrelide in second-line ET. Ropeginterferon alfa-2b demonstrated superior haematologic and molecular responses, alongside a better safety profile.

Pre-Fibrotic Myelofibrosis Use6

In lower-risk and early-stage MF, ropeginterferon alfa-2b showed disease control and JAK2V617F allele burden reduction, suggesting utility in early intervention.

Low-Polycythaemia Vera Rollover Cohort7

Data showed deep molecular responses even at fixed low doses in polycythaemia vera (PV), indicating sustained disease modulation with less toxicity.

Resistance Mechanisms

Jihyun Song, University of Utah, USA, revealed molecular pathways linked to resistance, paving the way for personalised treatment optimisation.

MYELOFIBROSIS BEYOND JAK INHIBITION

Several abstracts presented at EHA2025 emphasised the requirement to address unmet needs such as anaemia and post-JAK failure.

Nuvisertib9

Lindsay Rein, Duke University Medical Center, Durham, North Carolina, USA, presented early-phase results of nuvisertib, a selective proviral integration site for Moloney murine leukemia virus 1 (PIM1) inhibitor, demonstrating clinical activity across spleen volume reduction, symptom improvement, and haematological response. The treatment also modulated inflammatory cytokines, indicating a potential mechanism of action. These findings offer a promising therapeutic option for patients with MF who are refractory to JAK inhibitor therapy.

Momelotinib Studies10,11

Francesca Palandri, IRCCS S. OrsolaMalpighi Hospital, Bologna, Italy, explored momelotinib, which uniquely targets anaemia through activin A receptor type I (ACVR1) inhibition. Post hoc analyses of SIMPLIFY-1 and MOMENTUM trials showed improved survival in patients achieving dual spleen and transfusion responses, reinforcing its disease-modifying potential.12,13

Anaemia-Related Outcomes14

Pankit Vachhani, University of Alabama at Birmingham, USA, emphasised the benefits of combining erythropoiesisstimulating agent or danazol with ruxolitinib in patients with MF who are anaemic. This approach maintained spleen and symptom responses comparable to the broader JUMP cohort and allowed most patients to tolerate higher ruxolitinib doses while keeping haemoglobin levels stable.15 The findings support integrated anaemia management to sustain treatment intensity and improve outcomes.

GENOMIC RISK STRATIFICATION AND BIOMARKERS

Precision medicine was also a recurring theme throughout the Congress, highlighted by two key presentations delivered by Barbara Mora, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy, and Elisa Rumi, University of Pavia, Italy.

Genomic Profiling in PostPolycythaemia Vera and Post-Essential Thrombocythaemia Myelofibrosis16

Mora highlighted the role of nextgeneration sequencing in guiding treatment transitions in secondary MF, particularly in determining transplant eligibility and identifying high-risk clones.

Germline Genetics17

Rumi’s work on familial and early-onset MPNs revealed the germline variants contributing to pathogenesis, suggesting a need for genetic counselling and earlier screening.

Does clone size matter? Debate

There was a lively discussion led by Harrison regarding the allelic burden of driver mutations in MPNs, how this impacts thrombotic risk and event-free survival in MPNs, but also how it is still not included in the tools currently used for risk stratification and therapeutic decision-making.

EMERGING MECHANISTIC INSIGHTS AND TARGETS

Tyrosine Kinase 2 Activation in CALR-Mutant MPNs18

Nicolas Chatain, University Hospital RWTH Aachen, Germany, showed that tyrosine kinase 2 (TYK2), not JAK2, is a key downstream effector in CALR-mutant disease, challenging traditional assumptions and pointing to new druggable targets.

Bone Marrow Microenvironment19

Martina Crysandt, University Hospital RWTH Aachen, Germany, presented a study that mapped stromal and immune

cell interactions in the myelofibrotic niche, suggesting the potential for combination strategies targeting the tumour microenvironment.

Neutrophil-to-Lymphocyte Ratio20

Tiziano Barbui, Fondazione per la Ricerca Ospedale di Bergamo ETS, Bergamo, Italy, proposed the neutrophil-to-lymphocyte ratio as a simple surrogate marker for JAK2V617F suppression, closely reflecting variant allele frequency dynamics and correlating with event-free survival in PV.

POLYCYTHAEMIA VERA AND ESSENTIAL THROMBOCYTHAEMIA: NEW INSIGHTS

Divesiran21

Marina Kremyanskaya, Icahn School of Medicine at Mount Sinai, New York, USA, discussed early-phase results of divesiran, a small interfering RNA targeting ALAS2, which showed potential in reducing haematocrit and controlling disease activity in PV.

EHA2025 represented a significant milestone in MPN research

MPL-Mutant Essential Thrombocythaemia22

Steffen Koschmieder, RWTH Aachen University, Germany, led an international study of 312 patients with MPL-mutant ET, revealing distinct thrombotic risk and survival patterns compared to JAK2or CALR-mutated cases. The findings highlight the need for tailored risk scores and management strategies for this unique MPN subgroup.

CONCLUSION: A TRANSFORMATIVE YEAR FOR MYELOPROLIFERATIVE NEOPLASMS

EHA2025 represented a significant milestone in MPN research. Novel therapies, including calreticulin (CALR)targeted immunotherapies, momelotinib, and elritercept, are expanding the treatment landscape beyond JAK inhibitors. Advances in genomic profiling, interferon therapy, and biomarker development are bringing the field closer to personalised medicine. Collectively, these developments are not only broadening therapeutic options, but also prompting a re-evaluation of disease mechanisms and treatment strategies, signalling a future of greater precision and hope for patients with MPN.

References

1. Devos T et al. Hematological improvement and other clinical benefits of elritercept as monotherapy and in combination with ruxolitinib in participants with myelofibrosis (MF) from the ongoing phase 2 RESTORE trial. Abstract S220. EHA Congress, 12-15 June, 2025.

2. Vannucchi A et al. Pelabresib in combination with ruxolitinib for Janus kinase inhibitor-naive patients with myelofibrosis: 72-week follow-up with long-term efficacy outcomes of the phase III MANIFEST-2 study. Abstract S223. EHA Congress, 12-15 June, 2025.

3. Pandey V et al. INCA035784, a novel, equipotent T cell–redirecting antibody for patients with myeloproliferative neoplasms carrying different types of calreticulin mutations. Abstract S212. EHA Congress, 12-15 June, 2025.

4. Mascarenhas J et al. INCA33989 is a novel, first in class, mutant calreticulin-specific monoclonal antibody that demonstrates safety and efficacy in patients with essential thrombocythemia (ET). Abstract LB4002. EHA Congress, 12-15 June, 2025.

5. Gill H et al. Better safety and efficacy with ropeginterferon alfa-2b over anagrelide as second-line treatment of essential thrombocythemia in the topline results of the randomized phase 3 surpass-ET trial. Abstract S102. EHA Congress, 12-15 June, 2025.

6. Gill H et al. Ropeginterferon alfa-2b for pre-fibrotic primary myelofibrosis and DIPSS low/intermediate-risk myelofibrosis. Abstract S222. EHA Congress, 12-15 June, 2025.

7. Barbui T et al. Deep molecular responses with low-fixed dose of ropeginterferon alfa-2b in a rollover cohort of the LOW-PV trial. Abstract PS1847. EHA Congress, 12-15 June, 2025.

8. Song J et al. Molecular determinants of resistance to ropeginterferon alfa2b in PV and ET. Abstract PS1818. EHA Congress, 12-15 June, 2025.

9. Rein L et al. Preliminary data from Phase I/II study of nuvisertib, an oral investigational selective PIM1 inhibitor, showed clinical response correlating with cytokine modulation in patients with myelofibrosis. Abstract S221. EHA Congress, 12-15 June, 2025.

10. Palandri F et al. Survival impact and kinetics of hemoglobin improvement with momelotinib in patients with myelofibrosis and moderate to severe anemia: post hoc analyses of SIMPLIFY-1 and MOMENTUM. Abstract PF828. EHA Congress, 12-15 June, 2025.

11. Palandri F et al. Impact of dual spleen response and transfusion independence on survival in JAK inhibitor–naive patients with myelofibrosis and anemia treated with momelotinib: a subgroup analysis of SIMPLIFY-1. Abstract PS1829. EHA Congress, 12-15 June, 2025.

12. Mesa RA et al. SIMPLIFY-1: a phase III randomized trial of momelotinib versus ruxolitinib in Janus kinase inhibitornaïve patients with myelofibrosis. J Clin Oncol. 2017;35(34):3844-50.

13. Verstovsek S et al. Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study. Lancet. 2023;401(10373):269-80.

14. Vachhani P et al. Clinical outcomes in patients with myelofibrosis treated with ruxolitinib and anemia-supporting medications. Blood. 2024;144(Suppl 1):634.

15. Al-Ali HK et al. Primary analysis of JUMP, a phase 3b, expanded-access study evaluating the safety and

efficacy of ruxolitinib in patients with myelofibrosis, including those with low platelet counts. Br J Haematol. (2020): 189(5):888-903.

16. Mora B et al. Genomic profiling for clinical decision making in postpolycythemia vera and post-essential thrombocythemia myelofibrosis. Abstract S219. EHA Congress, 12-15 June, 2025.

17. Rumi E et al. Germline variants in myeloproliferative neoplasms with early onset or familial history. Abstract PS1802. EHA Congress, 12-15 June, 2025.

18. Kalmer M et al. TYK2 is specifically activated in CALR-mutant myeloproliferative neoplasms and JAK2 expression determines its druggability. Abstract PF825. EHA Congress, 12-15 June, 2025.

19. Crysandt M et al. Unraveling the myelofibrotic bone marrow niche: stromal and immune interactions as potential therapeutic targets. Abstract PS1794. EHA Congress, 12-15 June, 2025.

20. Barbui T et al. Neutrophil-tolymphocyte ratio as a surrogate inflammatory biomarker for JAK2V617F suppression and event-free survival in polycythemia vera. Abstract S217. EHA Congress, 12-15 June, 2025.

21. Kremyanskaya M et al. SANRECO, an on-going Phase 1/2 study evaluating divesiran, a novel GalNAcconjugated siRNA, in patients with polycythemia vera. Abstract S224. EHA Congress, 12-15 June, 2025.

22. Koschmieder S et al. Clinical characteristics and survival of 312 patients with MPL-mutant essential thrombocythemia: an international European LeukemiaNet collaborative study. Abstract S215. EHA Congress, 12-15 June, 2025.

Measurable Residual Disease in Clinical and Regulatory Decision Making

Author: Helena Bradbury, EMJ, London, UK

Citation: EMJ Hematol. 2025;13[1]:36-39. https://doi.org/10.33590/emjhematol/FWYZ3638

THE EUROPEAN Hematology Association-European Medicines Agency (EHA2025-EMA) Joint Symposium on minimal residual disease (MRD), which took place at the EHA2025 Congress in Milan, Italy, explored its critical role in clinical and regulatory decision-making across various haematologic malignancies. Experts and patient advocates discussed advances in MRD detection, its impact on treatment strategies, and the challenges of standardisation and acceptance in both clinical practice and regulatory frameworks. While this article refers to ‘minimal residual disease’, the term ‘measurable residual disease’ is increasingly being used instead.

PATIENT PERSPECTIVES ON MEASURABLE RESIDUAL DISEASE

Opening the session, Anne-Pierre Pickaert, a patient in remission from Philadelphia chromosome-positive acute lymphoblastic lymphoma (ALL), gave a powerful insight into the patient perspective of this disease. Pickaert is also actively engaged in patient advocacy through multiple roles, including volunteering with the leukaemia and bone marrow transplant patient organisations EGMOS and the Association Laurette Fugain, contributing to the research endowment fund HTC Project focused on posttransplant complications, and serving as a board member of Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) as well as an advisor for Acute Leukaemia Advocates Networkb (ALAN).

So, how was MRD explained to her at treatment initiation? To quote, her first explanation was as follows: “It is using advanced tools to look for a tiny number of cancer cells still present in the body after treatment, even in the absence of signs of ALL on standard tests.” The concept of thresholds was subsequently introduced as: “If that number of cancer cells goes beyond a certain threshold, it means the disease might come back.” Finally, touching on the definition of ‘MRD-negative’, she was told

that it refers to when cancer cells stay below the stated threshold. In summary, MRD is predictive of remission and relapse, as well as access to bone marrow transplant.

If that number of cancer cells goes beyond a certain threshold, it means the disease might come back

Importantly, she addressed how terminology influences patient understanding and emotional response. For instance, she states that the term ‘minimal residual disease’ was historically used in clinical and research settings, but it has now been termed ‘measurable residual disease’. From a patient advocate perspective, this change is meaningful. The term ‘minimal’ can be misleading and falsely reassuring, understating the risk and severity of the disease. Conversely, the word ‘measurable’ is more objective, highlighting the importance of sensitivity in detecting the disease accurately and helping patients better grasp the value of MRD monitoring in guiding care. Pickaert stressed the significant impact language can have on patients and how they perceive their disease journey. Additionally, the application of MRD as a tool varies across different blood

cancers. For instance, in ALL, acute myeloid leukaemia (AML), chronic myeloid leukaemia, and multiple myeloma (MM), MRD is seen as a reliable prognostic tool and regularly used to inform treatment decisions. However, this is not the case for other conditions, such as chronic lymphocytic leukaemia (CLL) and lymphoma, where it instead has limited use in clinical practice and remains largely confined to the research setting.

She also introduced the term ‘MRDanxiety’ used in cancer care to describe the emotional distress patients may experience after an indication that some cancer cells remain after treatment. Finally, she highlighted the heterogeneity in testing methods, time points in testing, and inconsistent definitions across various institutions and countries. “This is making comparability difficult and challenging, and from a European level, when we advocate, there is definitely heterogeneity in access.”

To conclude, Pickaert recognised the potential of MRD as an early indicator of treatment efficacy, but only on the following conditions: firstly, if MRD thresholds and assessment guidelines are agreed upon globally; secondly, if MRD is validated as a surrogate endpoint based on robust correlation with survival; and finally, if overall survival is collected as a co-primary endpoint.

A CASE STUDY FROM ACUTE LYMPHOBLASTIC LEUKAEMIA: A CLINICIAN’S PERSPECTIVE

Following this, Nicola Gökbuget, Department of Medicine II, Goethe University Hospital, Frankfurt, Germany, offered a clinical perspective. MRD refers to the small population of cancer cells remaining in the body that are not detectable by conventional cytomorphology, thus requiring more sensitive cytometric methods and thresholds.

She began by presenting an example case of a 28-year-old male experiencing symptoms of bruising and fatigue. He was subsequently diagnosed with common B-lineage ALL and treated with an intensive regimen comprising induction, consolidation, re-induction, and maintenance therapy. Despite achieving complete haematological remission, molecular failure was detected following the first two rounds of induction chemotherapy and the first round of consolidation.

This is making comparability difficult and challenging, and from a European level, when we advocate, there is definitely heterogeneity in access

Historically, in the absence of MRD testing, decisions were guided solely by haematologic response, and salvage treatment was the only option when firstline treatment failed. With the introduction of MRD testing, the traditional approach would recommend stem cell transplantation (SCT) based on MRD. In contrast, the current standard approach advises targeted therapy based on MRD, followed by SCT. This shift showcases the progress made from generalised treatment to more targeted approaches, enhancing patient outcomes.

How should MRD be incorporated in the clinical trial landscape? Traditionally, new drug compounds were tested only after haematologic relapse or treatment failure. However, a more forward-looking strategy proposes evaluating new drug compounds at the molecular level. This approach benefits patients by enabling earlier detection and intervention. It also supports clinical care, since the condition worsens significantly once a full haematologic relapse occurs, compared to a molecular relapse. For instance, the blood count deteriorates, leukaemia burden is higher, the risk of organ infiltration and biologic resistance is higher, and the time window for SCT is shorter compared to during molecular relapse, as the disease is less advanced. Gökbuget stated: “I want to make the point that MRD is not only an endpoint, but it’s an indication to treat with new compounds.”

To conclude, she highlighted the prerequisites needed for MRD-directed treatment, including historical data showing a correlation between MRD response and outcome; established, standardised MRD testing in reference laboratories; reimbursement of MRD testing; MRDbased indication for new compounds; and MRD-based response criteria.

ATTITUDES ON MINIMAL RESIDUAL DISEASE IN FRONTLINE MULTIPLE MYELOMA

Subsequently Anna Smit, Erasmus Medical Center Cancer Institute, Rotterdam, the Netherlands, presented the results of an interesting study that evaluated the attitudes of healthcare professionals and regulators towards MRD as an efficacy endpoint in transplant-eligible MM.

It can often take many years for a significant impact to be observed in progressionfree survival and overall survival for novel drugs in first-line randomised trials in MM. Therefore, earlier endpoints, such as MRD, have been suggested to inform clinical and regulatory decisions. However, the question has been raised regarding whether MRDnegative response may serve as a primary endpoint from both a clinical and regulatory standpoint. In 2024, the FDA endorsed MRD as a surrogate endpoint for accelerated drug approval in MM; however, this has not yet been translated in Europe.

To better understand the attitudes towards MRD as an efficacy endpoint in frontline treatment of transplant-eligible MM, Smit and her team conducted a global survey. Participants comprised of healthcare professionals from the International Myeloma Society (IMS), national myeloma working parties, and the EHA, as well as regulators from EMA and other international

I want to make the point that MRD is not only an endpoint, but it’s an indication to treat with new compounds

regulatory agencies. In total, 389 healthcare professionals and 40 regulators participated. Results showed that healthcare professionals were more willing to accept a 20% increase in toxicity when the MRD negativity difference was 30% (45–75%). Acceptance declined as MRD differences narrowed and toxicity increased. Regulators showed a similar trend, but placed greater emphasis on toxicity than on MRD negativity. Overall, the majority of participants agreed that treatments with an MRD negativity increase of >20% and toxicity increase from 40% to a maximum of 60% were clinically useful.

The second component of the survey assessed the attitudes of both cohorts towards the use of MRD as an early endpoint in MM. The majority of healthcare professionals agreed or strongly agreed that MRD-negative status is the preferred endpoint in clinical trials for newly diagnosed MM. In contrast, the majority of the regulators disagreed with this statement. In addition, most healthcare professionals felt that requiring progression-free survival benefit delays access to innovative treatment for patients in MM, while only some regulators agreed and the majority disagreed. Despite these differences, there was broad consensus among all participants on the need to establish a globally consistent approach to MRD testing.

WHAT DOES MINIMAL RESIDUAL DISEASE MEAN FOR THE REGULATORS?

Finally, Pierre Démolis took the stage to give an insight into the regulators’ side. He discussed the evolving role of MRD as a parameter in drug evaluation, emphasising that while MRD may not yet serve as a standalone endpoint for drug registration, it remains valuable for guiding treatment decisions and assessing prognosis. In certain late-stage or limited-treatmentoption cases, MRD could support early or conditional approval, much like overall response rates have in haematology. However, true surrogacy for efficacy endpoints, such as progression-free or overall survival, is unlikely in the near future. Still, MRD is already used as a supportive endpoint, and its role may expand under specific regulatory frameworks without requiring a paradigm shift.

CONCLUSION

The symposium highlighted MRD’s growing significance as both a prognostic tool and a potential early efficacy endpoint, while also highlighting the need for global standardisation in testing and interpretation. Despite differing perspectives among clinicians, regulators, and patients, there is a shared commitment to advancing MRD integration to improve patient outcomes and accelerate access to innovative therapies.

Evolving Endpoint Strategies: Navigating New Therapies and Regulatory Acceptance

Author: Helena Bradbury, EMJ, London, UK

Citation: EMJ Hematol. 2025;13[1]:40-43. https://doi.org/10.33590/emjhematol/NKEV2865

SINGLE clinical trial endpoints often fall short in capturing the full scope of patient experience, particularly in complex conditions like sickle cell disease and haematologic malignancies. A European Hematology Association (EHA)Patient Joint Symposium presented at the EHA2025 Congress, held in Milan, Italy, created space for multistakeholder discussions on topics with policy and regulatory implications. These topics are valuable to, and chosen by, patients. This particular session brought together perspectives from patient advocates, clinicians, regulators, industry, and health technology assessment (HTA) bodies to examine the limitations of single endpoints and explore how integrating patient-reported outcomes (PRO), demographic-specific measures, and multiple sources, including real-world data, can lead to more comprehensive and informative patient-centred evaluation frameworks.

LIMITATIONS OF TRADITIONAL ENDPOINTS AND THE NEED FOR EVOLUTION

Jenica Leah, President of the European Sickle Cell Federation (ESCF), opened the discussion by highlighting the current limitations of traditional clinical trial endpoints. Endpoints, by definition, are the specific metrics that researchers measure in a clinical trial to see if a treatment works. In the context of sickle cell disease, these typically include vasoocclusive crisis frequency, healthcare utilisation, haemoglobin levels, and quality of life. However, Leah highlighted that such endpoints are not typically reflective of the majority of patients with sickle cell disease. For example, vaso-occlusive crises are self-reported and can be inconsistent, as many patients experiencing symptoms may not seek clinical care. Moreover, high haemoglobin does not always equate to fewer symptoms. Leah also flagged that quality of life does not always take into consideration the patient’s mental health, fatigue, and social burden of disease.

How should endpoints evolve? Leah proposed an alternative approach, using mixed models that utilise both biomarkers and PROs. She also highlighted the possibility of demographic-specific endpoints and the importance of incorporating mental health, life-function, and fatigue at the forefront of the definition of clinical trial success and endpoint design.

To close, Leah highlighted several areas for improvement in addressing research gaps. Noting the increasing life expectancy of individuals with sickle cell disease, she stressed the importance of developing endpoints that reflect the needs and challenges faced by patients in later stages of life. She also emphasised the importance of raising awareness around clinical study failures, not just successes.

She concluded: “Going forward, patients should be asked what we want improved, and trials should be designed with the patients, not just for the patients, because sometimes what is looked for in a clinical setting as a positive endpoint may not necessarily be what a patient sees a good endpoint for their future.”

HOW TO ALIGN CLINICAL RELEVANCE WITH THE LIVED PATIENT EXPERIENCE

Lorenzo Brunetti, Hematology and Bone Marrow Transplant Unit, Ancona University Hospital, Italy, took the stage next to discuss the limitations of surrogate endpoints. Defined as measures used in clinical trials to substitute for direct, clinically meaningful outcomes, surrogate endpoints can help accelerate the development and approval of new therapies. However, as highlighted by Brunetti, surrogate endpoints are often tumour-centred rather than patientcentred, which can overlook toxicity and patient experience, and not always correlate with overall survival.

He spoke on the ALFA0701 study,1 in which patients with acute myeloid leukaemia received either conventional front-line induction chemotherapy or chemotherapy in combination with a targeted immunotherapy, called gemtuzumab ozogamicin. The primary endpoint was a surrogate endpoint, event-free survival, which refers to the length of time after treatment begins that a patient remains free of certain defined events, such as disease progression, reoccurrence, or death. Secondary endpoints included overall survival and quality of life. Notably, although the event-free survival was improved in the treatment versus control arm, there was no significant difference

in overall survival, and immunotherapy was associated with significant toxicities, including prolonged thrombocytopaenia.1

Brunetti also discussed the MAIA study,2 which evaluated the effectiveness of adding daratumumab to the standard regimen of lenalidomide plus dexamethasone (D-Rd) for patients with multiple myeloma. The primary endpoint was again a surrogate endpoint; progression-free survival. After 28 months of follow-up, the test arm showed improved progression-free survival; however, no benefit in overall survival was observed.2 In contrast to the ALFA0701 study, Brunetti highlighted how this study incorporated PROs which made the surrogate endpoint more meaningful. The D-Rd arm demonstrated faster and more sustained improvements in PROs compared to the standard treatment arm.2

To conclude, Brunetti advocated for a holistic approach to be taken in clinical research and trial design. Surrogate endpoints should be always coupled with patient-centred outcomes, as this integrated approach provides a more accurate and meaningful assessment of treatment benefit.

Surrogate endpoints should be always coupled with patient-centred outcomes

CHOICE OF ENDPOINTS FROM THE PERSPECTIVE OF REGULATORS

Although speaking personally, Francesco Pignatti, Scientific Advisor for Oncology, European Medicines Agency (EMA), followed with a powerful opening statement: “I cannot remember any other topic in my long life as a regulator that would attract so much controversy and discussion.” When deciding which endpoint to prioritise in a trial, you assess it against certain characteristics such as its relevance, validity, sensitivity, specificity, and precision. It is always a matter of balancing these various characteristics, and since individuals often have differing goals and preferences, clear-cut definitions are rarely possible. He stressed that in conversations regarding trial endpoints, the narrative should not be: ‘What is the superior endpoint?’; but rather: ‘How can we most comprehensively describe the effects of a drug, so that patients and others can make informed decisions?’

He highlighted the importance of patient preference studies, which aim to describe which endpoints and treatments patients favour, including the level of risk patients are willing to accept for certain benefits. A notable example was a study evaluating the preferences of adults and adolescents with alopecia areata undergoing treatment with JAK inhibitors. In this study, adults were willing to accept a mean 3-year risk of serious infection (7.4%; 95% CI: 5.5–9.3%), cancer (2.5%; 95% CI: 1.9–3.1%), and blood clots (9.3%; 95% CI: 6.4–12.2%) for a 20% increase in the likelihood of achieving 80–100% scalp hair regrowth.3

To conclude, he reinforced that we should move away from the quest for a single perfect endpoint and focus on the goal of communicating all the different effects and uncertainties we know about a drug, to help inform treatment decisions. If in doubt about what endpoints matter to patients, patient preference studies should be used to inform development and evaluation. Moreover, he recommended complementing conventional efficacy and safety summaries with an evaluation of health over time to better assess patients’ experience.

ENDPOINTS: AN INDUSTRY PERSPECTIVE

James Ryan, Director HTA Policy, Oncology Business Unit, AstraZeneca, on behalf of the European Federation of Pharmaceutical Industries and Associations (EFPIA), then provided an industry perspective. He began by summarising data from 130 ongoing industry-sponsored Phase III haematology trials, highlighting the use of more patientcentric endpoints, such as overall survival, cognitive function, and quality of life. However, Ryan also noted the challenges in capturing overall survival within a defined time frame, especially given the heterogeneous experiences of patients. Quoting a patient who said: “It all depends on what you’re looking for in your treatment, and what your goal is,” he emphasised the importance of individual perspectives. Ryan then outlined key considerations in appraising endpoints, including how the sensitivity of a test affects interpretation, the magnitude of change required to alter

its perceived utility, how the direction of change in other endpoints should be evaluated, whether the absence of statistical evidence negates surrogate validity, and how to effectively incorporate patient experience data and patient preference studies.

To close, his key takeaways spotlighted the four main themes at play: how relevant are the endpoints to the different needs at play, the importance of continued validation of surrogate endpoints, maintaining a focus on patients and keeping them at the heart of all decisions, and finally, fostering collaboration between all stakeholders involved, whether that be clinicians, HTA bodies, industry, or patients.

HOW CAN ENDPOINTS BE IMPROVED TO SUPPORT HEALTH TECHNOLOGY ASSESSMENT DECISION MAKING

Finally, Beate Wieseler, Head of the Department of Drug Assessment at Germany’s Institute for Quality and Efficiency in Health Care (IQWiG), provided an insightful look at the role of HTAs. Whilst regulators often look at the safety and efficacy of health technologies, ensuring they meet minimum standards for market authorisation, HTA bodies assess the value of health technologies, considering the clinical and cost-effectiveness. As highlighted by Wieseler, this is incredibly important, on an individual level for informing treatment decisions, on a population level with the deliverance of new clinical guidelines, and on a healthcare system level to inform pricing and reimbursement decisions.

She commented: “To answer the question if something is better than what we

References

1. Lambert J et al. Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haematologica. 2019;104(1):113-9.

already have is important, because we usually would only like to pay higher prices if we have added benefit from this new drug, to keep our healthcare systems sustainable, and to allow for universal care for each and every patient.”

Wieseler explained that the three main endpoints in HTAs are mortality, morbidity, and health-related quality of life. For the latter two, this can incorporate PROs, as the patient can report on any symptoms of complications from the treatment, as well as the impact of the disease and its treatment on physical, emotional, and social wellbeing. With these factors in mind, she urged for study programmes to be designed that consider all decision-makers from the start, including regulators, HTA bodies, and the patient. When studies do not address the questions for these parties, as explained, there are delays for the drug to enter the market and to achieve evidence-based care, as the uncertainty is so high.

CONCLUSION

The panel highlighted the need to move beyond ‘one-size-fits-all’ endpoints toward a more nuanced and inclusive approach to clinical trial design. Aligning regulatory, clinical, and patient perspectives will be key to defining endpoints that not only demonstrate efficacy, but also reflect true patient benefit, inform decisionmaking, and support the delivery of equitable and effective care. Importantly, all panellists expressed a strong willingness to hear from patients and understand what is meaningful to them. The challenge now lies in determining how to consistently and effectively incorporate the oftendiverse patient perspective at every step of the process.

2. Perrot A et al. Health-related quality of life in transplant-ineligible patients with newly diagnosed multiple myeloma: findings from the phase III MAIA trial. J Clin Oncol. 2021;39(3):227-37.

3. Tervonen T et al. Treatment preferences of adults and adolescents with alopecia areata: a discrete choice experiment. J Dermatol. 2024;51(2):243-52.

CLL Highlights from EHA 2025: Expert Perspectives and Clinical Developments

The European Hematology Association (EHA) Annual Congress was held in Milan, Italy, between 12th–15th June 2025.

Support: This publication was supported by BeOne Medicines, who has had no control or influence over the content.

Chairperson: Clemens Wendtner1

1. Professor and Medical Director of Munich Clinic Schwabing, Germany

Disclosure: Wendtner has served on advisory boards for AbbVie, Amgen, Astrazeneca, BeOne Medicines, BIONTech, Cllag-Janssen, F. Hoffmann-La Roche, Genentech, Gilead, GSK, Moderna, and Morphosys; has received honoraria from AbbVie, Amgen, AstraZeneca, BeOne Medicines, BioNTech, Cilag-Janssen, F. Hoffmann-La Roche, Genentech, Gilead, GSK, Moderna, and MorphoSys; and research funding from AbbVie, AstraZeneca, BeOne Medicines, Cilag-Janssen, F. Hoffmann-La Roche, Genentech, Gilead, GSK, and MorphoSys.

Acknowledgements: Writing assistance was provided by Helen Boreham, HB Medical UK Ltd, Wetherby, UK.

Keywords:

B cell lymphoma 2 (BCL2) inhibitor, Bruton’s tyrosine kinase inhibitor (BTKi), CAR-T cell therapy, chronic lymphocytic leukaemia (CLL), continuous therapy, first-line, fixed duration (FD), minimal residual disease (MRD).

Citation: EMJ Hematol. 2025;13[1]:44-52. https://doi.org/10.33590/emjhematol/XKNG8205 PHARMA PARTNERSHIP

Meeting Summary

This article captures key research highlights and new clinical evidence on chronic lymphocytic leukaemia (CLL) presented at the European Hematology Association (EHA) 2025, with a focus on first-line disease management.

Navigating Treatment Selection In CLL

Over the past decade, therapeutic advances in CLL have led to a seismic shift in the treatment landscape. A vast range of novel agents and different combination regimens are now available for the treatment of CLL, each with unique clinical profiles and offering the choice between continuous and fixed-duration (FD) therapy. Several sessions at EHA 2025 were focused on

helping clinicians navigate this increasingly complex therapeutic landscape in CLL, using patient and disease-specific factors, plus the latest clinical and real-world evidence to guide treatment decision-making.

Some of the latest strategies and evidence-based approaches to managing CLL were discussed by experts in the BeOne-sponsored satellite symposium chaired by Clemens Wendtner, Professor and Medical Director of Munich Clinic

1: Predictive biomarkers in chronic lymphocytic leukaemia.1-8

IGHV status

abnormality

Complex karyotype

BTKi

monotherapy1-5

Obi-ven6-7

Ibr-ven8-9

Predictive in multivariate analysis

Predictive in univariate analysis or real-world data

Not predictive No mature data TP53

BTKi: Bruton’s tyrosine kinase inhibitor; Ibr-Ven: ibrutinib/venetoclax; IGHV: Ig heavy chain variable; Ven-Obi: venetoclax-obinutuzumab.

Schwabing in Germany. Most patients with previously untreated CLL will have multiple viable treatment options, encompassing chemoimmunotherapy (CIT) and targeted therapies such as covalent Bruton’s tyrosine kinase inhibitors (BTKi) and B cell lymphoma 2 (BCL2) inhibitors. Treatment strategies can be broadly categorised into FD therapies and continuous BTKi-based regimens. The process of selecting treatment for first-line CLL is multidimensional and must consider numerous variables, including patient profile and preferences, disease- and treatmentrelated factors, treatment sequencing and resistance, and cost.

Predictive Biomarkers

In terms of disease biology, Ig heavy chain variable (IGHV) status, del(17p)/TP53 mutations, and complex karyotype are key predictive biomarkers. However, to date, there have been no dedicated clinical trials of these prognostic biomarkers, meaning that only post hoc analyses are available to guide treatment decision-making (Figure 1).1-8

The 2025 French Innovative Leukaemia Organisation (FILO) first-line treatment algorithm positions continuous BTKis before venetoclax-obinutuzumab (Ven-Obi) for patients with TP53 mutation and/or complex

karyotype based on poorer outcomes with the latter in the CLL14 study.6,9

In contrast, the next-generation BTKi, zanubrutinib, has shown consistent efficacy across low- and high-risk CLL, while maintaining a favourable safety profile.1,10,11 Estimated 5-year progression-free survival (PFS) rates in the pivotal SEQUOIA study were 76% and 72% in del(17p) negative versus positive zanubrutinib-treated patients, respectively.1

Looking at the impact of karyotype, increasing complexity has been shown to be an independent predictor of inferior PFS and overall survival (OS) with ibrutinib in retrospective analysis.12 However, in the pooled venetoclax arms of the GAIA/CLL13 study and the SEQUOIA trial of zanubrutinib, ≥3 cytogenetic abnormalities (CA) did not significantly influence PFS versus ≤2 CAs (although ≥5 CAs was found to be an independent prognostic factor for inferior PFS with venetoclax).13,14

IGHV status can be another key factor influencing treatment choice in front-line CLL. The latest FILO guidelines position Ven-Obi as the first choice for mutated IGHV (mIGHV) and recommend FD targeted therapy with either Ven-Obi or ibrutinib/ venetoclax (Ibr-Ven), or continuous BTKi for unmutated IGHV (uIGHV).9 In the SEQUOIA

Figure

study, no significant difference was seen in PFS for mIGHV versus uIGHV patients treated with zanubrutinib, and similar PFS outcomes independent of IGHV status have also been reported for ibrutinib and acalabrutinib.1-3 In contrast, 5-year follow up of the GLOW and CAPTIVATE trials revealed shorter PFS in patients with uIGHV treated with Ibr-Ven as compared to mIGHV patients.7,8,15

Beyond Biomarkers

Beyond biomarkers, bulky disease and patient fitness can also help to guide front-line treatment selection. Bulky disease affected PFS outcomes with VenObi in the CLL14 study, while consistent PFS benefit versus CIT was retained with zanubrutinib and Ibr-Ven, with or without ≥5 cm lymph node size, in the SEQUOIA and GLOW trials, respectively.1,6,15 Fitness also had no impact on PFS in patients treated with Ven-Obi in pooled analysis of the CLL13/14 studies, while Ibr-Ven was better tolerated by fit versus unfit patients in cross-trial comparison.15-17

Patient profile, comorbidities, and risk factors must also be considered during treatment decision-making in CLL. Based on outcomes from head-to-head studies, the second-generation BTKis acalabrutinib and zanubrutinib are generally recommended over ibrutinib for patients with CV risk.18,19 In the ALPINE trial comparing zanubrutinib to ibrutinib, atrial fibrillation/flutter occurred in 7.1% versus 17% of patients, while the rate of fatal cardiac adverse events was 0% versus 2%, respectively.20,21 A recent Bayesian network meta-analysis to assess the relative safety profile of first-line targeted therapies in patients with CLL with advanced age and/ or comorbidities found that monotherapy was better tolerated than combinations, next-generation BTKis had the most favourable safety profile, and zanubrutinib was associated with the lowest risk of adverse events leading to discontinuation.22

Another key challenge facing clinicians involved in modern-day CLL management is the choice between continuous and FD therapies. This involves balancing factors such as safety and tolerability

against efficacy and disease control, as well as practicality and convenience. Continuous therapies such as BTKis deliver sustained disease control in lowand high-risk disease, have a generally favourable safety profile suitable for use in elderly, unfit, or frail patients, and also benefit from convenient administration and monitoring.1-3,10,22 FD regimens, on the other hand, deliver more intense initial therapy with the aim of affording patients a treatment-free interval without continuous medication. This approach may be preferable for fitter, younger patients better able to tolerate higher toxicity, but comes with logistically more complex administration and monitoring schedules.6,8,15

Treatment After First Line

Looking beyond the front-line setting, treatment at first symptomatic relapse in CLL is dependent on both prior treatment sequencing and the type of relapse. In patients with relapsed/refractory disease (R/R) post-CIT or after continuous BTKi, FILO preference is for venetoclax-rituximab (Ven-R) based on results of the MURANO study, which showed a median PFS of 53.6 months for Ven-R versus 17.0 months for bendamustine-rituximab (BR).9,23

Where BTKis are recommended in the R/R setting, preference is for secondgeneration agents over ibrutinib based on head-to-head study results. In the ALPINE trial, zanubrutinib showed sustained PFS benefit over ibrutinib that was consistent across sensitivity analyses (36-month PFS rate: 64.5% versus 54.4%, respectively),20 while acalabrutinib proved non-inferior to ibrutinib for PFS in the ELEVATE-RR study, but with better CV tolerability.24

New Directions in CLL Therapy

New avenues under active exploration in CLL were discussed in an expert-led educational session, chaired by Martina Seiffert, Group Leader at the German Cancer Research Center. CAR-T cell therapy, notably lisocabtagene maraleucel (liso-cel), has demonstrated good longterm remissions in R/R CLL, but is not yet

approved for this indication in Europe.25 Efforts to improve the efficacy of CAR-T cell therapy for CLL include: combination therapy with BTKis (which may enhance T cell performance and reduce exhaustion); use at earlier lines of therapy when the burden of disease is less; and exploration of novel targets like the B cell activating factor receptor. In the TRANSCENDCLL 004 study, liso-cel plus ibrutinib produced higher complete remission rates compared to monotherapy (~20% versus 45%), with median duration of response and PFS not yet reached for patients in complete remission.26 Initial safety signals also revealed lower Grade 3 cytokine release syndrome and neurotoxicity with combination therapy, potentially due to ibrutinib’s anti-inflammatory effects.26 Currently, CAR-T cells are a very personalised therapy that take resources and money to produce but, in the future, ‘off the shelf’ options may become available. A ground-breaking trial (open to patients with CLL) is also ongoing, evaluating in vivo CAR-T cell therapy where the vector is administered directly to patients, allowing cancer-targeting T cells to be manufactured inside their own body.27

Long-term disease control is now achievable in CLL, with patients treated with continuous BTKis showing similar OS to an age-matched population.28 FD strategies have also been added to the armoury that aim to improve patient quality of life and reduce the risk of clonal evolution by offering protracted treatment-free intervals. However, a definitive disease cure remains elusive. New avenues under exploration in CLL include the use of MRD-guided strategies to determine optimal duration and number of therapies in a personalised approach to treatment. For example, the multicentre Phase II BOVen study of zanubrutinib with obinutuzumab and venetoclax used speed of MRD (MRD4+) to tailor therapy duration. This study met its primary endpoint, with 89% of previously untreated patients with CLL reaching undetectable MRD (uMRD) in both blood and bone marrow, despite median treatment of only 10 months.29

In terms of new drug development, more potent options targeting known disease pathways in CLL may help to transform long-term disease control into cure. The second-generation BCL2 inhibitor sonrotoclax, in combination with zanubrutinib, achieved 96% ORR and high uMRD rates in the ongoing global Phase I/Ib study (BGB-11417-101) in R/R CLL, and recruitment is now underway for the Phase III CELESTIAL trial.30,31 Another BCL2 inhibitor, lisaftoclax, has also shown efficacy in combination with acalabrutinib in patients progressed on venetoclax, using an accelerated daily ramp-up dosing schedule. A global Phase III registrational study (GLORA) is currently recruiting.32

BTK degraders aim to overcome treatmentemergent BTKi resistance mutations which can compromise efficacy.33 The BTK degrader BGB-16673 is a bivalent small molecule that binds specifically to BTK and the E3 ligase, marking it for destruction by the proteasome.34 At the 200 mg dose, BGB-16673 demonstrated an ORR of 94% in the ongoing open-label Phase I/II CaDAnCE-101 study in patients with double/ triple refractory CLL. In all 49 responseevaluable patients, the ORR was 78% and the CR/CRi with incomplete hematologic recovery rate was 4%.35 Another BTK degrader, NX-5948, is at a slightly earlier stage of clinical development.33

Bridging the gap between malignant B and T cells in CLL, epcoritamab is a bispecific CD20-directed CD3 T cell engager that has shown early evidence of single-agent efficacy.36 Finally, inhibitors targeting the ERK/MEK pathway are under investigation as potential future therapeutic candidates for CLL.37

Insights From New Data in FrontLine CLL

A plethora of new clinical data and real-world evidence on front-line CLL management was presented at EHA 2025, providing further insights that will help to shape patient care moving forward.

Figure 2: First-line zanubrutinib maintained progression-free survival benefits in patients with del(17p) over a 5-year follow-up in the SEQUOIA trial.

No. at risk, n

PFS events, n (%) – Zanubrutinib 33(30.0)

Months

aKaplan-Meier plot of PFS in patients with del(17p), confirmed by central laboratory (N=110)

PFS: progression-free survival.

Clinical Trials

The sustained efficacy of zanubrutinib in treatment-naïve, higher-risk patients with del(17p) was confirmed in 5-year follow-up data from the SEQUOIA trial, with patients continuing to demonstrate PFS benefits consistent with the randomised cohort of patients without del(17p) (Figure 2). A total of 111 treatment-naïve patients with CLL and del(17p) (median age: 71 years), were treated with zanubrutinib monotherapy in arm C of SEQUOIA. At median follow-up of 65.8 months, median PFS and OS were not reached. The estimated 60-month PFS and OS rates were 72.2% and 85.1%, respectively, with an ORR of 97.3%. No new safety signals were identified with longer-term followup, and zanubrutinib treatment remained ongoing in 62% of del(17p) carriers.38

In the R/R setting, the randomised Phase III ALPINE study was the first trial to demonstrate PFS superiority in a global head-to-head comparison of BTKis,

establishing the superiority of zanubrutinib over ibrutinib for both PFS and ORR.39

Final efficacy results from this trial at a 3.5 year follow-up using independent review committee-assessed responses were reported at EHA 2025. PFS rates at 36 months were 67.4% with zanubrutinib and 56.3% with ibrutinib, with PFS benefits in zanubrutinib-treated patients observed across major subgroups, including carriers of the del(17p)/TP53 mutation.39

The Role of MRD

A key theme at this year’s EHA was the current and future role of MRD, in particular its utility in informing decisions about stopping or restarting treatment. The ongoing Phase III FLAIR trial has become the first to confirm that Ibr-Ven with MRDguided duration of treatment is superior to both continuous ibrutinib monotherapy and fludarabine, cyclophosphamide, and rituximab (FCR) for previously untreated

PFSa

CLL. Ibr-Ven significantly improved time to uMRD, PFS, and OS rates at 5-year followup. This trial supports the role of MRD in personalising treatment duration with BTKibased combination therapy for first-line CLL in order to optimise patient outcomes.40

The relationship between MRD status and PFS was also evaluated in patients with CLL treated with first-line FD acalabrutinibvenetoclax combinations versus CIT in the ongoing AMPLIFY Phase III trial. The triple combination of acalabrutinib-venetoclaxobinuzumab (AVO) achieved the highest uMRD rates regardless of methodology or IGHV status and demonstrated uMRD durability up to 36 months after end of treatment (EOT). For both the acalabrutinibvenetoclax and AVO arms, achieving uMRD by EOT was associated with a significantly lower risk of disease progression or death versus FCR/bendamustine-rituximab for patients with uIGHV, with a similar trend seen among patients with mIGHV.41

The CAPTIVATE trial of first-line Ibr-Ven included FD and MRD-guided randomisation cohorts. In a final analysis of this trial, presented at EHA 2025, Ibr-Ven continued to provide durable PFS and OS with longterm follow-up, achieving 5.5-year PFS and OS rates of 66% and 97%, respectively. At EOT, 69% of patients were MRD negative in the peripheral blood. Around one-third (n=64) of patients experienced disease progression after completion of FD Ibr-Ven, with ibrutinib-based retreatment providing durable responses in patients needing subsequent therapy.42

Indirect Analyses

In the absence of prospective headto-head trials investigating different BTKi and BCL2 FD treatment strategies, indirect comparisons afford a useful means of assessing comparative efficacy. However, these results should always be interpreted with some degree of caution given the limitations of indirect modelling methodology and potential sources of bias.

Indirect comparison of the AMPLIFY and CAPTIVATE trials has suggested that FD Ibr-Ven may offer a PFS advantage over

acalabrutinib-venetoclax (Acala-Ven) in treatment-naïve, fit patients with CLL and without TP53 aberrations. This comparative analysis, which included 450 patients, found a 3-year restricted mean survival time difference of 2.7 months in favour of Ibr-Ven when high-risk patients were excluded.43

Similar findings were obtained in a crossstudy comparison which compared pooled data from the CAPTIVATE FD cohort and Ibr-Ven arm of GLOW to the Acala-Ven arm of AMPLIFY. This analysis found that patients treated with Ibr-Ven achieved statistically significantly improved PFS outcomes and were significantly more likely to achieve uMRD at EOT+3 compared to patients treated with Acala-Ven.44

FD Acala-Ven also appeared inferior to continuous zanubrutinib treatment in a matching adjusted indirect comparison of the SEQUOIA and AMPLIFY trials. PFS was significantly superior for patients treated with zanubrutinib and 36-month PFS rates for zanubrutinib versus Acala-Ven were 88.5% and 76.5%, respectively. Collectively, these results suggest a significant PFS advantage of continuous zanubrutinib therapy over FD Acala-Ven in the first-line treatment of CLL.45

Real-World Evidence

Next-generation BTKi monotherapy is now the standard of care for treatment-naïve CLL, and recommended in guidelines.9 Real-world evidence is helping to reinforce the efficacy and safety results from BTKi clinical trials and establish optimised strategies for use of these agents in everyday clinical practice.

Results from a retrospective observational study of 2,515 patients from the USA Flatiron Health database treated with BTKi as their first-line monotherapy were presented at EHA 2025. First-line ibrutinib use was shown to decrease over time, with zanubrutinib being most commonly used by 2024 (49% versus 44% acalabrutinib, and 7% ibrutinib). Similarly, more patients treated with zanubrutinib in the real-world setting had a del(17p)/TP53 mutation: 16% versus 12% acalabrutinib, and 11% ibrutinib.

Table 1: Landmark probabilities of key real-world outcomes for patients on Bruton’s tyrosine kinase inhibitors.

rwTTNT, % (95% CI)

6 months

12 months

18 months

rwTTD, % (95% CI)

6 months

12 months

18 months

Zanubrutinib n=310

91 (87, 94)

83 (77, 87)

78 (72, 84)

85 (80, 88)

76 (70, 81)

70 (63, 76)

88 (86, 90)

81 (78, 83)

74 (71, 77)

81 (78, 83)

72 (69, 75)

66 (63, 69)

85 (83, 87)

75 (72, 78)

67 (64, 69)

75 (72, 77)

62 (59, 65)

53 (50, 56)

rwTTD: real-world time to treatment discontinuation or death; rwTTNT: real-world time to next treatment or death.

In terms of efficacy, patients on zanubrutinib had a significantly longer real-world time to next treatment or death, time to treatment discontinuation or death, and overall survival compared to those on ibrutinib. Patients on zanubrutinib also showed longer trends compared with those on acalabrutinib (Table 1).46

A further real-world comparative effectiveness analysis conducted in USA community oncology practices looked at the likelihood of patients with CLL remaining on their initial first-line BTKi treatment and requiring subsequent therapy. Patients who received zanubrutinib were significantly more likely to remain on treatment compared with those who received acalabrutinib, and less likely to require the next line of therapy. At 2 years, there was a 53% probability of ongoing treatment with acalabrutinib compared to 76% with zanubrutinib, and 67% versus 72% probabilities, respectively, of not advancing to the next line of treatment.47

Safety is also a key consideration in the real-world setting, particularly given the association between BTKis and CV events.

A real-world study of 837 patients who received first-line BTKi captured data on new-onset of worsening hypertension over 12-months follow-up. Rates of new-onset hypertension were lower with zanubrutinib (13.9%) and acalabrutinib (12.4%) compared to ibrutinib (18.0%), with similar trends also observed for worsening hypertension.48

Conclusion

Several presentations at this year’s EHA Congress were aimed at helping clinicians map the evolving therapeutic landscape in CLL and make treatment decisions that enhance patient outcomes. Notable highlights in terms of new clinical evidence included updates from the ALPINE and SEQUOIA trials of zanubrutinib, and groundbreaking data from the FLAIR study showing the successful application of MRD-guided duration of treatment. Important evidence from real-world studies and indirect analyses were also presented, helping to further define optimal treatment strategies in CLL management.

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15 June, 2025.

43. Molica S et al. Fixed-Duration BTKiVenetoclax combinations In CLL: an indirect comparison of AMPLIFY and CAPTIVATE Trials. Poster PS1580. EHA Congress, 12-15 June, 2025.

44. Munir T et al. Cross-Study comparison of ibrutinib in combination with venetoclax (I+V) Vs acalabrutinib in combination with venetoclax (A+V) In subjects with previously untreated chronic lymphocytic leukemia (CLL). Poster PF587. EHA Congress, 12-15 June, 2025.

45. Munir T et al. Comparative efficacy of zanubrutinib versus fixed-duration acalabrutinib plus venetoclax for firstline treatment of chronic lymphocytic leukemia (Cll): a matching-adjusted indirect comparison (MAIC). Poster PS1581. EHA Congress, 12-15 June, 2025.

46. Jacobs R et al. Real-world comparative effectiveness of first-line Bruton tyrosine kinase inhibitors in patients with chronic lymphocytic leukemia. Poster PS1578. EHA Congress, 12-15 June, 2025.

47. Hou J-Z et al. Real-World Bruton Tyrosine Kinase Inhibitor Use And Clinical Outcomes Among Patients With Chronic Lymphocytic Leukemia/ Small Lymphocytic Lymphoma. Abstract PB2663. EHA Congress, 1215 June, 2025.

48. Lamanna N et al. Risk of hypertension in patients newly diagnosed with chronic lymphocytic leukemia/small lymphocytic lymphoma (Cll/Sll) and treated with covalent bruton tyrosine kinase inhibitors (Cbtki): a real-world study. Poster PF588. EHA Congress, 12-15 June, 2025.

EHA2025

Abstract Reviews

Drawing on insights from the European Hematology Association (EHA) 2025 Congress, these abstract reviews highlight significant new research developments in the field of haematology.

Spectrum, Prevalence, and Clinical Correlates of PPM1D Mutations in Patients with Clonal Haematopoiesis and Clonal Cytopenias

Authors: *Talha Badar,1 Ludovica Marando,2 Terra Lasho,2 Francyess Denis Oliva,3 Chenyu Lin,3 Benjamin J. McCormick,1,4 Mobachir El Kettani,1 Kashish J. Shah,1 Yael Kusne,5 Omer Jamy,4 Kendall Diebold,4 Alexander Coltoff,6 Christy Finke,2 James Foran,1 Mohamed Kharfan-Dabaja,1 Yao-Shan Fan,1 Liuyan Jiang,1 Rong He,7 Miles Thomas,8 Anand Patel,8 David Viswanatha,7 Mithun Vinod Shah,7 Antoine Saliba,2 Abhishek Mangaonkar,2 Kristina Kirschner,2 Aref Al-Kali,2 Naseema Gangat,2 Mark Litzow,2 Mrinal M. Patnaik2

1. Division of Hematology-Oncology and Bone Marrow Transplant Program, Mayo Clinic, Jacksonville, Florida, USA

2. Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA

3. Division of Hematologic Malignancies and Cellular Therapy, Duke University School of Medicine, Durham, North Carolina, USA

4. Division of Hematology and Oncology, University of Alabama at Birmingham, USA.

5. Department of Hematology Oncology, Mayo Clinic, Phoenix, Arizona, USA

6. Division of Hematology and Oncology, Medical University of South Carolina, Charleston, USA.

7. Division of Hematopathology, Mayo Clinic, Rochester, Minnesota, USA

8. Division of Hematology and Oncology, University of Chicago, Illinois, USA

*Correspondence to badar.talha@mayo.edu

Disclosure: Badar has received research funding from Takeda; and served on an advisory board for Takeda, Morphosys, Pfizer, Syndax, and Amgen. Jamy has served on an advisory board for Ascentage, Sobi, Maat, and TERN. Patel has received research funding from Kronos Bio, Sumitomo, Servier, Incyte, Pfizer; and honoraria for advisory boards from Sobi and AbbVie. Finke has served on an advisory board for Stemline; and received honoraria from the Binaytara foundation. Lin has served on an advisory board for ADC therapeutics and Autolus; and provided consulting for Rigel. The other authors have declared no conflicts of interest.

Acknowledgements: The authors would like to thank the patients and families for contributing to this study. Badar, Marando, and Patnaik designed the study, performed analysis, and co-wrote the paper. El Kettani, McCormick, and Shah helped in collecting data. Lasho, Oliva, Lin, Kusne, Jamy, Diebold, Coltoff, Finke, Foran, Kharfan-Dabaja, Fan, Jiang, He, Thomas, Patel,

Viswanatha, Shah, Saliba, Mangaonkar, Al-Kali, Gangat, and Litzow contributed patients. All authors reviewed and approved the final draft of the paper.

Keywords: Clonal haematopoiesis (CH), PPM1D, therapy-related myeloid neoplasm, TP53

Citation: EMJ Hematol. 2025;13[1]:54-57. https://doi.org/10.33590/emjhematol/ZUPR7395

BACKGROUND

TP53 and PPM1D are key regulators of DNA damage response and repair, and somatic mutations in these genes often co-occur in haematopoietic cells, expanding under genotoxic stress. Unlike with TP53 mutations, where mechanisms of progression are defined,1 the pathways underlying clonal fitness and transformation in mutant PPM1D remain poorly defined.2,3

METHODS

In collaboration with five academic institutions, the authors analysed the clinical and molecular landscape of 337 patients with clonal haematopoiesis (CH) and clonal cytopenia of undetermined significance (CCUS) across four genotypes: PPM1D mutations (mt)/TP53-wild type (wt) (n=170 [50%]), PPM1Dmt/TP53mt (n=25 [7%]), TP53mt/PPM1Dwt (n=17 [5%]), and TP53wt/PPM1Dwt (n=125 [38%]).4

RESULTS

All PPM1D variants were truncating, located in exon 6 of the gene, with a median variant allele frequency (VAF) of 6% (0.3–64%). Patients with PPM1Dmt/ TP53wt were the oldest (median: 72 years; range: 31–94 years) followed by PPM1Dmt/ TP53mt (median: 71 years; range: 52–89 years), PPM1Dwt/TP53wt (median: 69 years; range: 20–99 years), and PPM1Dwt/

1: Variant allele frequency-based clonal analysis.

Figure

Figure 1: Variant allele frequency-based clonal analysis (Continued).

A–B) Heatmaps showing VAFs of somatic mutations in patients with (A) CH (n=58) and (B) CCUS (n=137), categorised by clonal hierarchy: dominant (red), co-dominant (yellow), and sub-clonal (grey).

C) Bar chart comparing the proportion of dominant, co-dominant, and sub-clonal mutations across four groups: t-CH, CH, t-CCUS, and CCUS.

D) Table summarising the percentage of patients within each group who carried dominant, co-dominant, or sub-clonal mutations.

CCUS: clonal cytopenia of undetermined significance; CH: clonal haematopoiesis; t: therapy-related; VAF: variant allele frequency.

TP53mt (median: 65 years; range: 52–75 years) groups (p=0.004). Consistent with the notion that DNA damage response gene mutations are preferentially selected under the pressure of anticancer therapy,3 the PPM1Dmt/TP53wt genotype group were most frequent in therapy-related (t) CH/CCUS (80%, 66.5%, 76.5%, and 19%; p<0.001) and had a shorter time interval from last therapy to diagnosis (6.2, 5.9, 11.25, and 24.5 months; p<0.001) compared to PPM1Dmt/TP53wt, TP53mt/ PPM1Dwt, and TP53wt/PPM1Dwt, respectively. A significantly higher proportion of patients in the PPM1Dmt/ TP53wt (6%/26%) and PPM1Dmt/TP53mt (24%/24%) groups, in comparison to the PPM1Dwt/TP53mt (0%/0%) and PPM1Dwt/ TP53wt (0%/3%) groups, received poly ADP-ribose polymerase inhibitors and radioisotope-based cytotoxic therapy, respectively (p=0.01; p<0.001). To describe the position of PPM1D mutations within the clonal architecture, the authors performed a VAF-based analysis to infer clonal hierarchy.5 For this analysis, the authors compared individuals according to disease category and included 58 patients with CH and 137 patients with CCUS. Dominant PPM1D mutations were observed in 32 (53%) patients with CH, and 66 (50%) patients with CCUS (Figure 1A–B).

To further assess whether prior cytotoxic therapy influences the clonal position of PPM1D mutations, the authors stratified each disease group by therapy-related versus sporadic cases, and compared the distribution of dominant, co-dominant, and sub-clonal PPM1D mutations (Figure 1C–D). In the CH subgroup, prior therapy

was associated with a higher likelihood of having a dominant PPM1D mutation (56%) than for sporadic cases (28%). The overall distribution of clonal categories differed significantly between therapyrelated and sporadic CH (χ²=6.83; degrees of freedom=2; p=0.033; Figure 1C–D).

In CCUS, there was no significant difference in clonal status distribution by therapy exposure. Dominant mutations were seen in 44 (48%) therapy-related cases and 22 (53%) sporadic cases, co-dominant in 18 (20%) and five (12%), and sub clonal in 30 (32%) and 14 (34%), respectively (χ²=1.11; degrees of freedom=2; p=0.58).

CONCLUSION

The authors acknowledge the limitations of their study, including shorter follow-up in the PPM1Dmt/TP53wt and PPM1Dmt/ TP53mt groups, as well as heterogeneity in genomic sequencing techniques between the five academic institutions that participated in this study. However, to the best of their knowledge, this work represents the largest series reporting on the spectrum of precancerous PPM1D mutations in the context of evolving cancer therapies. In conclusion, while PPM1D mutations were frequently identified in t-CH/CCUS and associated with unexplained cytopenias in the context of low VAF, within limitations of a short followup in our cohort, they were associated with a low rate of myeloid clonal evolution, even in the presence of TP53mt. Longerterm follow-up is planned to better assess impacts on progression free survival and overall survival.

References

1. Badar T et al. Prognostic impact of 'multi-hit' <i>versus</ i> 'single-hit' <i>TP53</i> alteration in patients with acute myeloid leukemia: results from the Consortium on Myeloid Malignancies and Neoplastic Diseases. Haematologica. 2024;109(11):3533-42.

2. Badar T et al. PPM1D somatic mutations in myeloid neoplasms: clinical profile, clonal characteristics and impact of concurrent somatic TP53 mutations. Blood. 2024;144(Suppl 1):3218.

3. Hsu JI et al. PPM1D mutations drive clonal hematopoiesis in response to cytotoxic chemotherapy. Cell Stem Cell. 2018;23(5):700-13.e6.

4. Badar T et al. Spectrum, prevalence and clinical correlates of PPM1D mutations in patients with therapy related clonal hematopoiesis and clonal cytopenias. Poster PS1635. EHA Congress, 12-15 June, 2025.

5. Awada H et al. Clonal hematopoiesis-derived therapyrelated myeloid neoplasms after autologous hematopoietic stem cell transplant for lymphoid and non-lymphoid disorders. Leukemia. 2024;38(6):1266-74.

Hydroxyurea Improves Mesenteric Blood Flow and Reduces Gut Permeability in Sickle Cell Disease Mice

Authors: *Érica M. F. Gotardo Azevedo,1 Pâmela L. de Brito,1 Lucas F. S. Gushiken,1 Flávia Costa Leonardo,1 John Brewin,2 Andrey Santos,3 Daniéla Oliveira Magro,3 Fernando Ferreira Costa,1 Nicola Conran1

1. Hematology and Transfusion Center, University of Campinas-UNICAMP, São Paulo, Brazil

2. Red Cell Biology Group, Faculty of Life Sciences and Medicine, King’s College London, UK

3. Faculty of Medical Sciences, University of Campinas-UNICAMP, São Paulo, Brazil

*Correspondence to erikinha_gotardo@yahoo.com.br

Disclosure: Gotardo has received funding from FAPESP (São Paulo Research Foundation; Project Number 2023/01379-5); a post-doctoral fellowship (2023/10650-4); and support for attending meetings and/or travel. Brewin has participated in the Genomics England Advisory Board of Diverse Data. Costa has received grants or contracts from FAPESP and CNPq; consulting fees from Novartis and Pfizer; and payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing, or educational events from Novo Nordisk. Conran has received funding from FAPESP (São Paulo Research Foundation; Project Number 2023/01379-5); grants or contracts from Novartis AG; consulting fees from Novo Nordisk; support for attending meetings and/or travel from FAPESP (São Paulo Research Foundation); and has participated in the Sickle Cell Disease Patient Equity Advisory Board from Novo Nordisk. The other authors have declared no conflicts of interest.

Acknowledgements: This work was supported by the São Paulo Research Foundation (FAPESP), grant numbers 2023/10650-4 and 2023/09206-2.

Keywords: Hydroxyurea (HU), intestinal permeability, mesenteric blood flow, sickle cell disease (SCD).

Citation: EMJ Hematol. 2025;13[1]:58-60. https://doi.org/10.33590/emjhematol/IDNH6330

BACKGROUND AND AIMS

Sickle cell disease (SCD) is a genetic disorder characterised by chronic inflammation, vaso-occlusion, and endothelial dysfunction, leading to

ischaemic injury and progressive organ damage,1,2 including in the gut.3 Intestinal blood flow impairment in SCD may disrupt gut homeostasis, contributing to dysbiosis, increased permeability, microbial translocation, and systemic inflammation.3-5 This creates a vicious cycle that exacerbates vascular and immune complications.5 Based on the known vascular and anti-inflammatory effects of hydroxyurea (HU), it is hypothesised that this therapy may help preserve intestinal barrier integrity in SCD.6,7

This study aimed to investigate intestinal perfusion and permeability in mice with SCD, and the effects of HU treatment (the standard treatment for SCD).

METHODS

For this, male and female hemizygous (AS) and homozygous (SS) Townes mice (4 months old) were fasted for 4 hours and 60 mg/100 g body weight of fluorescein isothiocyanate (FITC)-dextran was administered orally (4 kDa). After 3 hours, plasma fluorescence was measured by spectrometry.

To assess mesenteric blood perfusion, mice were anesthetised, and the mesentery was exposed. Real-time laser speckle contrast imaging (PeriCam PSI System®, Perimed, Järfälla, Sweden) was used to measure perfusion levels in intestinal loops and mesenteric vessels. A subset of SS Townes mice was treated with HU (50 mg/kg/day for 6 weeks), or not (control-water) to evaluate its effects on intestinal permeability, mesenteric perfusion, and systemic inflammatory markers.

RESULTS

Plasma FITC-dextran levels were significantly higher in SS mice compared to AS controls, indicating increased intestinal

A) Concentration of FITC-dextran in the plasma of AS and SS Townes mice. B) P.U generated from real-time blood perfusion analysis images by laser speckle contrast imaging (PeriCam PSI System®, Perimed, Järfälla, Sweden) in control AS and SS Townes mice. Levels of LBP (C), calp (D), IFABP (E), and IL-17 (F) measured in the serum of Townes mice treated with or without HU. SS Townes mice were treated orally with HU (50 mg/kg/day for 6 weeks) or not (control-water).

The p values represent data from statistical analysis (ANOVA).

Representative images of murine intestinal loops and mesentery circulation were taken during laser speckle contrast imaging to enable real-time assessment of tissue blood perfusion; red colour represents regions with higher blood perfusion. AS: hemizygous; Calp: calprotectin; FITC: fluorescein isothiocyanate; HU: hydroxyurea; IFABP: intestinal fatty-acid binding protein; LBP: lipopolysaccharide binding protein; P.U: perfusion units; SS: homozygous.

permeability (Figure 1A). Additionally, mesenteric perfusion was significantly reduced in SS mice relative to AS mice (Figure 1B), as shown by laser imaging analysis, suggesting altered intestinal vascular function. Notably, HU treatment led to a marked reduction in intestinal permeability, with plasma FITC-dextran levels in HU-treated SS mice approaching those observed in AS controls (Figure 1A). Furthermore, HU significantly improved mesenteric blood perfusion (Figure 1B), with increased perfusion signals in intestinal loops and mesenteric vessels.

SCD mice showed higher serum levels of lipopolysaccharide-binding protein (LBP, Figure 1C), calprotectin (CALP, Figure 1D), intestinal fatty-acid binding protein (IFABP, Figure 1E), and IL-17 (Figure 1F) compared with controls. HU significantly reduced calprotectin and IFABP levels, suggesting decreased microbial translocation, improved gut barrier function, and inflammation. Interestingly, IL-17 levels increased with HU treatment. Although classically proinflammatory, IL-17 also contributes to epithelial barrier maintenance and the regulation of gut microbiota composition.6

Figure 1: Markers of gut barrier integrity, inflammation, and mesenteric blood perfusion in sickle cell disease mice.

Hemizygous (AS) SS - Water SS - HU

CONCLUSION

In conclusion, the results of this study confirm intestinal dysregulation in SCD mice and indicate that HU contributes to the preservation of gut health. The beneficial effects of HU include reducing systemic

References

1. Conran N, Belcher JD. Inflammation in sickle cell disease. Clin Hemorheol Microcirc. 2018;68(2-3) 263-99.

2. Kato GJ et al. Sickle cell disease. Nat Rev Dis Primers. 2018;4:18010.

3. Brim H et al. The gut microbiome in sickle cell disease: characterization and potential implications. PloS One. 2021;16(8):e0255956.

4. Lewis CV et al. Intestinal barrier dysfunction in murine sickle cell disease is associated with small intestine neutrophilic inflammation, oxidative stress, and dysbiosis. FASEB BioAdv. 2023;5(5):199-210.

inflammation and restoring intestinal barrier integrity, resulting in improved mesenteric and intestinal blood perfusion. These findings suggest that HU, a drug already used in patients with SCD, may also offer a therapeutic strategy for targeting intestinal health management in this population.

5. Gupta CL et al. Microbiome in sickle cell disease: pathophysiology and therapeutic insights. Br J Haematol. 2024;205(4):1279-87.

6. Gotardo Azevedo EMF et al. Hydroxyurea improves mesenteric blood flow and reduces gut permeability in sickle cell disease mice. Abstract S289. EHA Congress, 12-15 June, 2025.

7. Delgadinho M et al. How hydroxyurea alters the gut microbiome: a longitudinal study involving angolan children with sickle cell anemia. Int J Mol Sci. 2022; 23(16):9061.

Long-Term Follow-Up after Allogeneic Haematopoietic Stem Cell Transplantation for Acute Lymphoblastic Leukaemia

Authors: Mounira Baazizi,1,2 Farih Mehdid,1,2 Nadia Rahmoune,1,2 Dina Ait Ouali,1,2 Sabrina Akhrouf,1,2 Hanane Bouarab,1,2 Sara Zerkout,1 Fouzia Louar,1 Farida Harieche,1,2 Rose-Marie Hamladji,1,2 Redhouane Ahmed Nacer,1,2 *Malek Benakli1,2

1. Centre Pierre et Marie Curie, Algiers, Algeria

2. University of Health Sciences, Algiers, Algeria

*Correspondence to malekbenakli@gmail.com

Disclosure: The authors have declared no conflicts of interest.

Keywords: Allogeneic stem cell transplantation (allo-HSCT), acute lymphoblastic leukaemia (ALL), total body irradiation.

Citation: EMJ Hematol. 2025;13[1]:61-62. https://doi.org/10.33590/emjhematol/DFMH8771

BACKGROUND

Patients (pts) with acute lymphoblastic leukaemia (ALL) in difficult first complete remission (CR) or in second CR, and those with Philadelphia chromosome-positive ALL, are at risk because chemotherapy alone does not allow for long-term survival. Allogeneic haematopoietic stem cell transplantation (allo-HSCT) offers a curative therapeutic alternative in these cases.1,2 The authors report the results of this procedure in a series of 342 pts. 3

MATERIALS AND METHODS

From February 1999–December 2023, 342 allo-HSCTs were performed, including 259 genoidentical, 77 haploidentical, five phenoidentical, and one mismatched (3/6) unrelated transplant from cord blood. At the time of transplant, 115 pts (33.6%) were in first CR, 202 pts (59%) were in second CR, nine pts were in ≥third CR, and 16 pts had active disease. The median age of the pts was 17 years (range: 4–61), with 179 pts (52.3%) <18 years of age. The sex ratio (male/female) was 1.87. The average time from diagnosis to transplant was 27 months (range: 3–144). Molecular testing for the

BCR-ABL fusion transcript was performed in 124 pts, identifying 76 Philadelphia chromosome-positive cases (22.2%). Various conditioning regimens without total body irradiation were used, including busulfan-cytarabine-melphalan in 158 pts (46.1%), busulfan-cyclophosphamide in 38 pts (11.1%), busulfan-cyclophosphamidethymoglobulin (5 mg/kg) in 10 pts (2.9%), and busulfan-cyclophosphamide-etoposide in 59 pts (17.2%). For haploidentical alloHSCTs, conditioning regimens included cytarabine-busulfan-cyclophosphamidethymoglobulin (10 mg/kg) in 21 pts (6.1%), and busulfan-thiotepa-fludarabine in 56 pts (16.3%). Graft-versus-host disease (GVHD) prophylaxis consisted of ciclosporine-methotrexate (human leukocyte antigen [HLA]-identical sibling), ciclosporine-methotrexate-mycophenolate mofetil (Beijing Protocol), ciclosporinemycophenolate mofetil-post-transplant cyclophosphamide, and ciclosporine alone for cord blood transplantation. Peripheral blood stem cells were used as the graft source in 303 pts (88.6%), bone marrow graft in 16 pts (4.6%), umbilical cord blood in two pts, and a combination of bone marrow and peripheral blood stem cells in 21 pts (Beijing Protocol). As of the 30th of June 2024, the minimum follow-up was 6 months, and the maximum follow-up was 304 months.4,5

RESULTS

Aplasia was observed in all pts, with a median duration of 15 days (range: 6–66). The median day of neutrophil engraftment was 15 days (range: 10–67). Two pts experienced graft rejection. Veno-occlusive disease occurred in 14 pts (4%), including eight severe cases. Acute GVHD occurred in 137 pts (42.6%), including 52 pts with Grade IV disease (38% of the entire patient population). Chronic GVHD was seen in 93 pts (39.7%), with the extensive form in 70 pts (29.9%). Cytomegalovirus reactivation was noted in 63 pts (19%).

Relapse prevention with tyrosine kinase inhibitors after transplantation was used in 44 pts. Relapse was observed in 101 pts (30.1%) after a median time of 11 months (range: 1–60), including 16 pts who had received tyrosine kinase inhibitors. After a median follow-up of 40 months (range: 6–304), 117 pts (34.2%) were alive in CR, and 225 pts (65.7%) had died, including 135 pts (39.4%) from transplant-related mortality (early infection: n=17; acute GVHD: n=56; chronic GVHD: n=11; veno-occlusive disease: n=8; visceral haemorrhage: n=7; late infection: n=10; others: n=26), and 90 pts from relapse. The overall survival and disease-free survival at 25 years are 27.4% and 27.3%, respectively.

CONCLUSION

Allo-HSCT with conditioning regimens without total body irradiation in high-risk ALL allows about one-quarter of pts to achieve long-term remission, as shown in this series, although the rates of transplant-related mortality and relapse remain relatively high.

References

1. Kantarjian H, Jabbour E. Adult acute lymphoblastic leukemia: 2025 update on diagnosis, therapy, and monitoring. Am J Hematol. 2025;100(7):1205-31.

2. Agrawal V et al. The role of transplant for Philadelphia-positive B-cell acute lymphoblastic leukemia in 2025. Curr Oncol Rep. 2025;27(6):748-60.

3. Mounira B et al. Long-term follow-up after allogeneic hematopoietic stem cell transplantation for acute lymphoblastic leukemia (ALL). EHA Congress, 12-15 June, 2025.

4. Benakli M et al. Two decades of experience in a combined adult/pediatric allogeneic hematopoietic stem cell transplantation center in Algiers, Algeria. Ann Hematol. 2020;99(3):619-25.

5. Lv M et al. Total body irradiation versus chemotherapy myeloablative conditioning in B-cell acute lymphoblastic leukaemia patients with first complete remission. Sci Rep. 2025;15(1):10079.

Microfluidic Testing in Patients with Bleeding Disorder of Unknown Cause

Authors: Amaury Monard,1,2 Lori Moonen,1 Dave Hellenbrand,3 Paul Verhezen,3 Inge Merry,1 Floor Derikx,1 Erik Beckers,1 Paola van der Meijden,4 Judith Cosemans,4 Yvonne Henskens,2,3 *Floor Heubel-Moenen1

1. Department of Hematology, Maastricht University Medical Center+, the Netherlands

2. Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands

3. Central Diagnostic Laboratory, Maastricht University Medical Center+, the Netherlands

4. Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, the Netherlands

*Correspondence to floor.moenen@mumc.nl

Disclosure: Monard has received support for attending meetings and/or travel from Sobi, for WFH 2024, and Roche, for EAHAD 2025. Verhezen holds an unpaid role as a steering committee member of the Working Group for Hemostasis Diagnostics, which is part of the Dutch Society for Thrombosis and Hemostasis. Cosemans has received a BHF-DZHK-DHF International Cardiovascular Research Partnership Award (02001-2022-0124); and is the Chair of the Scientific Theme Committee on Arterial Thromboembolism at ISTH 2026. Henskens is an advisor for Promicol; and has collaborated with and tested reagents and equipment from IVD companies in the field of haemostasis (Werfen, Siemens, Roche, Nodia, and Stago). Heubel-Moenen has received support for the present manuscript through an Octapharma unrestricted research grant, with payment to the institution. The other authors have declared no conflicts of interest.

Keywords: Bleeding disorder of unknown cause (BDUC), diagnostics, microfluidics.

Citation: EMJ Hematol. 2025;13[1]:63-65. https://doi.org/10.33590/emjhematol/YSTY6819

BACKGROUND

In 40–70% of patients referred to a haematologist for the evaluation of an increased bleeding tendency, no diagnosis can be found after extensive laboratory testing.1 These patients are classified as having a bleeding disorder of unknown

cause (BDUC). Their bleeding phenotype resembles that of patients with known (mild) bleeding disorders, including platelet function disorders.2 Currently available laboratory haemostasis tests are unable to diagnose these patients.3 Therefore, the aim of this study was to investigate the underlying pathophysiological bleeding mechanism in patients with BDUC by using a microfluidic assay to identify sheardependent primary haemostasis defects.4

METHODS

Data from the ProBe-AHP cohort were analysed. In this cohort, patients referred to the haematologist for the analysis of an increased bleeding tendency were included. This study was previously described in more detail.5 Patients with BDUC who had an increased International Society on Thrombosis and Haemostasis - Bleeding Assessment Tool (ISTH-BAT) score, as well as normal von Willebrand factor levels, light transmission aggregometry, and ATP release, were selected from this cohort. Shear-dependent platelet adhesion, activation, and aggregation were assessed using microfluidic analysis of shear-dependent collagen only, and/or collagen with tissue factor induced whole blood thrombus formation at 37°C.6,7

RESULTS

In 26/48 (54%) selected patients with BDUC, who had a mean ISTH-BAT score of 10, abnormal shear-dependent platelet function was observed compared to reference ranges based on measurements in 49 healthy controls. A combination of lower platelet adhesion, lower integrin activation, lower phosphatidylserine exposure, and/or lower P-selectin expression was seen in these patients (Table 1). Additionally, the visually assessed morphology, contraction, and multilayer scores were impaired in 5/48 patients with BDUC. Fibrin formation on

Table 1: Overview of the abnormalities found per parameter* in patients with bleeding disorder of unknown cause (N=48).

*Number of abnormalities in platelet SAC: 11; platelet deposition: 12; morphology score: 5; contraction score: 4; and multilayer score: 4. Number of abnormalities on collagen Type I: BF: 5; Fibr: 3; PS exposure: 6; and P-selectin: 8. Number of abnormalities on collagen Type III: BF: 9; Fibr: 0; PS exposure: 0; and P-selectin: 2. No abnormalities found in 22 patients with BDUC.

BDUC: a bleeding disorder of unknown cause; BF: brightfield; Fibr: fibrinogen; P-sel: P-selectin; PS exp: phosphatidylserine exposure; SAC: surface area coverage.

a collagen Type I spot co-coated with tissue factor showed no statistically significant difference between patients with BDUC and healthy volunteers.

CONCLUSION

Results from this study show that microfluidic analysis of whole blood thrombus formation under shear can identify shear-dependent platelet function defects in 54% of patients with BDUC, in whom light transmission aggregometry, ATP-release, von Willebrand factor activity, and antigen levels are normal.

References

1. Thomas W et al. Bleeding of unknown cause and unclassified bleeding disorders; diagnosis, pathophysiology and management. Haemophilia.

2020;26(6):946-57.

2. Quiroga T et al. High prevalence of bleeders of unknown cause among patients with inherited mucocutaneous bleeding. A prospective study of 280 patients and 299 controls. Haematologica. 2007;92(3):357-65.

3. Baker RI et al. Standardization of definition and management for bleeding disorder of unknown cause: communication from the SSC of the ISTH. J Thromb Haemost. 2024;22(7):2059-70.

4. Monard A et al. Microfluidic testing using the maastricht flowchamber in patients with bleeding disorder of unknown cause (BDUC). Abstract S317. EHA Congress, 12-15 June, 2025.

5. Moenen F et al. Screening for platelet function disorders with Multiplate and platelet function analyzer. Platelets. 2019;30(1):81-7.

6. Heubel-Moenen F et al. Multiparameter platelet function analysis of bleeding patients with a prolonged platelet function analyser closure time. Br J Haematol. 2022;196(6):1388-400.

7. Brouns SLN et al. Platelet-primed interactions of coagulation and anticoagulation pathways in flow-dependent thrombus formation. Sci Rep. 2020;10(1):11910.

Durable Responses to Lenzilumab: Azacitidine

Combination Therapy in High Risk Proliferative Chronic Myelomonocytic Leukaemia with Suppression of CBL and RAS Mutant Subclones

Authors: *Daniel Thomas,1,2 David Ross,1-4

Timothy Hughes,1 David Yeung,1,2 Monika Kutyna,1 Kelly Lim,1 Steven Lane,5,6 Agnes Yong,1,7 John Reynolds,8 Devendra Hiwase1,2

1. South Australian Health and Medical Research Institute, Adelaide, Australia

2. Central Adelaide Local Health Network, Australia

3. Centre for Cancer Biology, University of South Australia, Adelaide, Australia

4. SA Pathology, Adelaide, Australia

5. Cancer Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia

6. Royal Brisbane and Women’s Hospital, Herston, Australia

7. Royal Perth Hospital, Australia

8. Australian Centre for Blood Diseases, Monash University, Melbourne, Australia

*Correspondence to Daniel.thomas@adelaide.edu.au

Disclosure: Thomas has received support for the present manuscript from the Australian Medical Research Future Fund (1201012, 2024427, 2008972), the National Health and Medical Research Council (2023/GNT2029809), the Leukemia & Lymphoma Society with support from the Mike and Sofia Segal Foundation (LLS 6619-21, LLS 6650-23; CMML Special Initiative), the Snowdome Foundation (co-funder LLS 661921, LLS 6650-23), and the Leukaemia Foundation (co-funder LLS 6619-21, LLS 6650-23). Ross has received payment or honoraria from Novartis, Merck, Keros, Takeda, and Menarini. Hughes has received payment or honoraria from Novartis, Bristol Myers Squibb, and Ariad. Yeung has received payment or honoraria from Novartis, Amgen, BMS, Takeda, Pfizer, and Ascentage. Lane has received payment or honoraria from Abbvie, GSK, and BMS. Yong has received payment or honoraria from Novartis, BMS, and Celgene. Reynolds has received payment or honoraria from Abbvie, Janssen, Novartis AG, Novartis Australia, and Sandoz AG; and holds a leadership or fiduciary role in the Australasian Leukaemia and Lymphoma Group, Australasian Myeloma Research Consortium, HaemaLogiX, Monash University, MRFF, NHMRC, and Telethon Kids Institute (Australia). Hiwase has received payment or honoraria from Abbvie, Otsuka, and Astella Pharma. The other authors have declared no conflicts of interest.

Acknowledgements: The authors thank all patients and their families for their participation in the trial. This work has been carried out with funding support from the Australian Medical Research Future Fund (1201012, 2024427, 2008972), the National Health and Medical Research Council (2023/GNT2029809), the Leukemia & Lymphoma Society (LLS 6619-21, LLS 6650-23; CMML Special Initiative) with support from Mike and Sofia from the Segal Foundation, the Snowdome Foundation (co-funder LLS 661921, LLS 6650-23), and the Leukaemia Foundation (co-funder LLS 6619-21, LLS 6650-23).

Keywords: Antibody targeting, chronic myelomonocytic leukaemia (CMML), granulocyte-macrophage colony-stimulating factor (GM-CSF), monocyte.

Citation: EMJ Hematol. 2025;13[1]:66-67. https://doi.org/10.33590/emjhematol/WVMU7856

BACKGROUND AND AIMS

Chronic myelomonocytic leukaemia (CMML) is a rare cancer orchestrated by granulocyte-macrophage colonystimulating factor (GM-CSF), a proinflammatory cytokine that drives leukaemic monocyte proliferation. The authors’ laboratory research has shown that TET2 mutations increase the production of GM-CSF in human monocytes after innate immune stimulation, and CBL mutations amplify the proliferative response to low dose GM-CSF. Standard of care for CMML treatment includes azacitidine (AZA), with a complete response (CR) rate of 16–21%. The PREACH-M (ACTRN12621000223831)1 trial investigates novel CMML therapies directed by molecular profiling. Lenzilumab (LENZ; Taran Therapeutics, Short Hills, New Jersey, USA) is a monoclonal antibody that neutralises GM-CSF. This report details the objective clinical responses from an interim analysis of the first 20 subjects who completed at least 3 months of LENZ/AZA treatment.2

The aim of this study was to investigate if a molecularly driven protocol, based on pre-clinical science, could improve outcomes for patients with CMML.

METHODS

PREACH-M is a Phase II/III non-randomised, uncontrolled, open-label trial involving 54 adults aged at least 18 years, newly diagnosed with the WHO 2016 criteria for CMML and stratified according to mutation status. Subjects exhibiting RASpathway mutations (NRAS, KRAS, CBL) receive 24 cycles (every 28 days) of AZA (subcutaneous: 75 mg/m2 for 7 days) and LENZ (intravenous: 552 mg; Day 1 and Day 15 for Cycle 1, and Day 1 only for all subsequent cycles). Those with only TET2 mutations receive the same AZA regimen along with sodium ascorbate (intravenous: 30 g for 7 days [15 g for first dose only, 30 g thereafter if no evidence of tumour lysis syndrome]; per os: 1.1 g on all other days). Subjects who complete 24 cycles of treatment are followed every 6 months for an additional 24 months. The primary endpoint is the frequency of CR or partial response during the first 12 cycles according to Savona Criteria.

RESULTS

As of the last 2024 database lock, 27 subjects were enrolled overall (18 receiving >12 months of treatment) and 20 subjects were enrolled in the LENZ/AZA arm (nine females and 11 males; mean age: 69 years; mean white cell count: 37.8x109 /L; mean haemoglobin: 108 g/L; mean platelet count: 72x109 /L; mean blast count: 9%). Mutations included CBL (65% of subjects), NRAS (20%), KRAS (50%), ASXL1 (55%), and TET2 (70%). Subjects exhibited CMML-specific

prognostic scoring system-molecular (CPSS-MOL) scores of intermediate risk 1 (n=2), intermediate risk 2–3 (n=12), and high risk 4–6 (n=6). Overall, subjects had completed a median number of 13.5 cycles of LENZ/AZA at the time of reporting. Of the patients, 85% attained a complete remission or a marrow complete remission within the first 12 months on study, according to International Working Group (IWG) 2006 criteria. According to Savona criteria, 85% of patients achieved a CR or an optimal marrow response within the first 12 months on treatment. Importantly, 64% of patients achieving a CR or a marrow CR had detectable CBL mutations at baseline. Of the 10 subjects with dominant CBL mutations (variant allele frequency >10%), 90% achieved a CR or marrow complete remission in the first 12 months with durable suppression of CBL clones.

CONCLUSION

Interim analysis of the PREACH-M trial shows promising results: LENZ/AZA resulted in durable CRs beyond 12 months, with 85% of subjects achieving a complete remission or a marrow complete remission without significant LENZ related toxicity.

References

1. South Australian Health & Medical Research Institute Ltd. Efficacy of assigning treatment for participants with Chronic Myelomonocytic Leukaemia based on their individual molecular results (lenzilumab plus azacitidine versus sodium ascorbate plus azacitidine). ACTRN12621000223831. https://www. anzctr.org.au/Trial/Registration/TrialReview. aspx?ACTRN=12621000223831

2. Hiwase D et al. Durable responses to lenzilumab - azacitidine combination therapy in high risk proliferative CMML with suppression of CBL and RAS mutant subclones. Abstract S179. EHA Congress, 12-15 June, 2025.

Congress Interviews

This year we had the privilege of speaking with Konstanze Döhner and Martin Dreyling, two leading voices in European haematology. Döhner outlined her vision for a more inclusive, innovative, and borderless EHA, while Dreyling, speaking in person at the Congress, reflected on the shift toward targeted therapies and the collaborative spirit behind this year’s scientific programme.

Featuring: Konstanze Döhner and Martin Dreyling

Konstanze Döhner

President Elect, European Hematology Association (EHA); Assistant Professor and Head of the Myeloid Neoplasms Section, Department of Internal Medicine III, University Hospital of Ulm, Germany

Citation: EMJ Hematol. 2025;13[1]: 68-71. https://doi.org/10.33590/emjhematol/EBSJ8988

Q1

As the incoming President of the European Hematology Association (EHA), what are your top priorities for the coming term?

My top priorities as EHA President align closely with the association’s strategic roadmap, which we have developed and begun to implement over the past 2 years. At the core of this roadmap are five key ambitions that will guide our work.

The first ambition is nurturing knowledge and professional growth. To give an example of what that means, we are expanding our EHA Campus with new interactive content and personalised learning tools, making high-quality haematology education accessible globally, anytime, anywhere. This supports continuous professional development across all career stages.

The second ambition is fostering innovation, and here we have a lot of activities to offer, for example, the EHA Kick-off Grant and the EHA Innovation Grant. We are encouraging cutting-edge ideas

with these grants, whether in diagnostics, digital health, or new therapeutic approaches. Moreover, we strongly promote collaboration between academic partners from different countries.

Another ambition is advancing research for real breakthroughs. This means that we support investigator-driven studies through our large and intensive collaborations with scientific networks and joint research initiatives, such as our three Research Training Programs: the EHA-ASH (American Society of Hematology) Translational Research programme, the EHA Clinical Research Training in Hematology programme, and the EHA-EMBL/EBI (European Molecular Biology Laboratory’s European Bioinformatics Institute) Computational Biology Training in Hematology programme. These programmes help to accelerate impactful haematology research.

Ensuring equitable access to care is another ambition, and here we advocate for better access to drugs and diagnostics across Europe, especially in the under-

resourced regions and countries. EHA plays a very important role in European-level policy discussions to reduce inequalities in patient care.

The last ambition is empowering a strong, connected haematology community, particularly we are building a stronger network with our national societies. We are also strengthening many collaborations and advancing Diversity, Equity, and Inclusion through our DEI programme. This is done within our leadership, events, and outreach. The Young EHA committee is vital in supporting the next generation of haematologists.

In addition to supporting these collective goals, I’m personally committed to strengthening EHA’s role in supporting haematologists from underrepresented countries, particularly in terms of access to education, research, career development, clinical trials, and treatment. I’m also committed to maintaining financial sustainability so that EHA remains a robust and forward-looking organisation.

Another important priority is staying connected to our members, listening to their needs, and ensuring that EHA is an inclusive, responsive, and supportive community for

haematologists across all career stages and areas of specialisation.

Ultimately, my goal is to ensure that EHA continues to be a modern, impactful organisation that advances haematology across Europe and beyond.

Q2What are the most pressing challenges facing haematology research and patient care across Europe today? How do you envision EHA playing a proactive role in addressing these, from regulatory hurdles to funding gaps and disparities in access to care?

One of the most urgent challenges today is the growing disparity in access to care across Europe. While some countries have access to cutting-edge diagnostics, clinical trials, and novel therapies, others

still struggle with the availability of basic treatments and medication. This inequity not only affects patient outcomes but also slows down the collective progress in the field.

Another pressing issue is sustainable research funding, particularly for basic and translational research. Early career researchers often face difficulties in securing stable support and funding, and this risks us losing the next generation of haematology innovators.

The first ambition is nurturing knowledge and professional growth

In addition, the regulatory environment remains very complex and fragmented, especially when it comes to data sharing, cross-border clinical trials, and the implementation of new technologies like cell and gene therapies. This slows down innovation and patient access. EHA is actively working to address these challenges at multiple levels. We are advocating at the European Union level for harmonised rules (for example, in the European Health Data Space and the upcoming Biotech Act) and for greater investment in haematology research. Through our work on these various initiatives and in collaboration with the ASH, we help to support data-driven research and cross-border projects.

We also continue to expand our educational support, including grants, fellowships, and training programmes. Importantly, we are committed to supporting underserved regions, including through EHA memberships, targeted capacity building, and partnerships with our national societies. Our goal is to ensure that all haematology professionals and patients, regardless of where they are in Europe, can benefit from the latest scientific advances and standards of care.

Q3

EHA often speaks of 'Borderless Hematology'. How is the association actively removing barriers for haematologists across Europe and beyond?

'Borderless Hematology' is much more than a slogan. It reflects EHA’s deep commitment to ensuring that geography, resources, or politics do not limit access to knowledge, collaboration, or care. We are actively removing barriers in several key ways.

To give an example, ‘education without borders’. Through our

anytime, anywhere, free or at minimal costs. EHA also supports mobility grants, as well as research through fellowships and collaborative grants. This includes specific programmes to help colleagues in underrepresented regions and countries have access to training or pursue international projects.

We also take care of our global partnerships. We work very closely with ASH and our national societies around the world, including those in Africa, Asia, and Latin America. Here, we aim to harmonise training, exchange expertise, and strengthen haematology globally.

EU (ACT EU) initiative, aimed at improving the design, efficiency, and effectiveness of clinical trials in Europe. We’re also leading a multistakeholder coalition and campaign to reduce bureaucracy in clinical trials (RBinCT).

My goal is to ensure that EHA continues to be a modern, impactful organisation that advances haematology across Europe and beyond

EHA Campus, our digital learning platform, haematologists around the world can access high-quality, up-to-date educational resources,

Now we come to policy and advocacy, which is another very important element of EHA’s work. EHA is very active in Brussels, working to remove regulatory barriers that hinder collaborative research and cross-border clinical trials in Europe.

For example, EHA is actively engaged with the European Union institutions as well as the European Medicines Agency (EMA) to address the complex regulations that make it difficult to run multinational clinical trials across Europe. We’re an active stakeholder with nominated representatives in the Accelerating Clinical Trials in the

Regarding patient access and health equity, we work to ensure that regulatory reforms prioritise affordability and equity in patient access to diagnostics and treatment across all European member states. This involves contributing to discussions on the SoHO (Substances of Human Origin) and pharmaceutical legislation, EU Health Technology Assessment (HTA), and pricing and reimbursement, for example, through our participation in the EU-funded ASCERTAIN project. EHA is also involved in shaping the European Health Data Space (EHDS), pushing for legislation that enables the seamless, secure, and privacy-preserving sharing of health data for research purposes across borders. This is critical for leveraging real-world evidence and AI, as well as for biomarker discovery.

EHA is also an active and leading member of the BioMed Alliance, where we jointly advocate for better EU policies and funding schemes, such as Horizon Europe. Finally, we implement diversity, equity, and inclusion,

our DEI programme, in all of our activities. We are committed to supporting a diverse and inclusive haematology community, and this includes creating opportunities for professionals from various backgrounds, regardless of their location.

Ultimately, 'Borderless Hematology' means that no matter where a haematologist lives or works, they should be part of a connected, empowered, and well-supported global community.

Q4 Reflecting on EHA2025, what key scientific trends, breakthroughs, or innovations have emerged from this year’s Congress, and how do you see them shaping the future of haematology?

A very positive development is that we can increasingly offer tailored therapies for many haematological diseases. This is a clear trend towards precision haematology. In addition, there were many presentations clearly demonstrating promising oral combinations, as well as intensive combination therapies and combination therapies. One novel drug, a menin inhibitor, has been shown to be very active in the treatment of acute leukaemia. These achievements suggest a kind of paradigm shift towards more accessible outpatient-based targeted therapies that significantly improve tolerability and the outcomes of patients; this is particularly true for older or frailer patients.

Our Congress also included novel aspects regarding CAR-T cell therapy and presented cutting-

Haematology is evolving rapidly, scientifically, clinically, and socially, and EHA must continue to grow with it

edge data on upfront treatment strategies. These insights highlight a new era, where cell therapies are not just a salvage option, but are being increasingly integrated into standard treatment algorithms. We then had multiple sessions addressing the integration of AI and big data in diagnostics, prediction, prognosis, and personalised treatment planning.

One other important part of our Congress is bridging the gap between clinical topics and the policy and regulatory domain, as

well as deepening our stakeholder engagement. Our European Affairs track featured joint symposia in collaboration with the EMA and patient organisations, with multistakeholder sessions, focusing on quality of life and patient-reported outcomes, safety reporting, and measurable residual disease as a regulatory endpoint.

In summary, the EHA2025 Congress exemplified how haematology is rapidly evolving, driven by patient-centred outcomes, cellular advancements, and advancements in treatment, digital tools, and inclusive care models.

Q5

Finally, is there anything else you would like to share with the haematology community as you begin your term as EHA President?

Above all, I want to say that this is a shared journey. As EHA President, I will serve a community that is passionate, diverse, and committed to advancing the lives of people with blood disorders. Haematology is evolving rapidly, scientifically, clinically, and socially, and EHA must continue to grow with it. That means staying close to our members, listening to their needs, and creating opportunities for all of them, from young scientists to senior experts, whether they are from well-resourced or underrepresented regions. EHA has changed significantly in recent years, and we are now a truly European, or even global, inclusive and dynamic Association. As President, I want to build on that momentum. My message is very simple and very short: EHA is our association, and together, we can shape its future.

Martin

Dreyling

Professor

of Medicine and Head of Lymphoma Programme, Ludwig Maximilian University, Munich, Germany; Scientific Program Committee Chair, European Hematology Association (EHA)

Citation: EMJ Hematol. 2025;13[1]:72-74.

https://doi.org/10.33590/ emjhematol/GFPQ3502

Q1

Firstly, thank you for taking the time to speak with us today. To begin, could you briefly walk us through your educational and professional journey, and what initially inspired your focus on haematology and clinical research?

Well, I’m probably a bit of an exception, and I have a good reason for that. As a young student, I was set on becoming a cardiologist. I did everything to pursue that path, but in the end, things worked out differently.

By chance, during my clinical training, I did a rotation in the oncology ward. In Germany, haematology and oncology are combined, and the attending physician that day turned out to be one of my role models. That experience opened my eyes.

I realised how deeply meaningful it is to connect directly with patients. I had a strong feeling that what I was doing made sense, and I thought, “If I want to do medicine, I want to do it like this.” I loved the idea of shared decisionmaking, a strong patient–physician connection, and working in an interprofessional environment. That’s ultimately what brought me to haematology.

Q2

We are fortunate to have an excellent Programme Committee, with experts from all over Europe and beyond, including the USA and other regions

As the Scientific Program Committee Chair for the European Hematology Association (EHA) Congress 2025, what were the key considerations that guided the development of this year’s Congress programme? How has the committee worked to ensure that the content is relevant and engaging for such a diverse audience?

EHA offers an incredible wealth of opportunities; it’s actually quite difficult to choose which highlights to include. We are fortunate to have an excellent Programme Committee, with experts from all over Europe and beyond, including the USA and other regions.

At the beginning, the task feels almost overwhelming. You think, how can we possibly select just a few topics? But we begin by working in small expert groups, and very quickly we begin to see patterns, what’s trending, what’s advancing, and where we need to provide clinical education.

Once the small groups align on their recommendations, I’m always impressed at how efficiently it begins to come together. Because we all bring different perspectives, different specialties, backgrounds, and areas of focus, the final result is more than the sum of its parts.

EHA has become the epicentre for scientific updates in haematology

I’d encourage anyone to get involved with the Programme Committee. You start from scratch, asking, What’s new? What will be hot a year from now? You have to look ahead.

We are deeply reliant on the expertise within our diseasespecific working groups. They begin by preparing detailed proposals, and then we all come together in a consensus meeting.

For me, it feels almost miraculous. After a few very intense days, we emerge with a solid first draft of the programme. It still needs some refinement, of course, but it already reflects a rich, diverse,

and well-balanced offering, from clinical training to basic research, from scientific breakthroughs to policy discussions.

That breadth is what makes EHA truly unique.

What can attendees expect from participating in an EHA Congress, and why do you believe it plays such a critical role in staying at the forefront of haematology research and innovation?

EHA has become the epicentre for scientific updates in haematology. It’s where you’ll

find cutting-edge developments presented alongside high-quality educational sessions and vibrant networking opportunities.

You will see people everywhere engaging in conversations, discussing new strategies, and exchanging ideas, and that’s exactly what EHA is all about. That’s our mission: to connect people and bring them together around haematology.

Q4 Looking ahead, what emerging research areas or therapeutic strategies in haematology are you most excited about, and how do you see them influencing future EHA congresses?

This is truly an exciting time in haematology. We are witnessing a shift away from traditional chemotherapy, which, while effective, often takes a toll on patients, towards more targeted therapies.

This evolution brings major implications. It means we must tailor treatment based on the genomic makeup of the malignant cells. If we get this right, we are close to what was once called the “magic bullet”, therapies that precisely target cancer cells without harming healthy ones.

That’s the vision. The holy grail in haematology is long-term remission, what I like to call a functional cure. And I believe we are on the brink of achieving it, with treatments that are not only more effective but also much better tolerated by patients.

Interviews

This year, we spoke with three leading haematology experts: Elena Zamagni, Joshua Richter, and Lydia Scarfò. Zamagni discussed integrating real-world data with biobanking and establishing minimal residual disease as a standard endpoint in multiple myeloma. Richter explored multifunctional antibodies and advances in precision medicine for myeloma. Scarfò reflected on American Society of Hematology (ASH) Annual Meeting 2025, highlighting key insights on chronic lymphocytic leukaemia and her ongoing research.

Featuring: Elena Zamagni, Joshua Richter, and Lydia Scarfò

Elena Zamagni

Associate Professor of Haematology, University of Bologna, Italy

At that time, in the late 90s, not many options existed for multiple myeloma, so I joined the field without knowing what might happen in the next 10 years

Citation: EMJ Hematol. 2025;13[1]:75-78. https://doi.org/10.33590/emjhematol/LWSA4002

You have dedicated your career to advancing our understanding and treatment of multiple myeloma. What first inspired you to pursue this specific area of haematology?

In the beginning, when I was very young, I was more interested in acute leukaemia and the suffering of young people. When I got to university, I was enthusiastic about my lessons and about the clerkship in haematology that I did while I was there. However, my former boss and university professor, Cavo, was the one who asked me to join the myeloma field. At that time, in the late 90s, not many options existed for multiple myeloma, so I joined the field without knowing what might happen in the next 10 years. Although it might not have been a choice I made alone, I consider myself lucky that it happened.

Q2 At the 2024 American Society of Hematology (ASH) Annual Meeting, you discussed an ambitious project combining real-world data with large-scale biobanking. Can you walk us through the initiative and the kind of insights you hope it will generate for future treatment strategies?

It is a very ambitious Italian project involving real-life biobanking. When patients agree to take part in clinical trials, they are lucky because 1) the treatment they receive may be the most modern, innovative, and advanced one available, particularly when taking the approval and regulatory status of the drugs into account, and 2) within clinical trials, they receive prognostic factors and response assessments in the best, most sensitive, and most up-to-date way, using the most modern techniques. That's not the case in everyday life because the resources are not there for everyone, and not all centres have the necessary expertise.

There could also be clinical or timing reasons for being unable to perform these tasks or provide this treatment.

With biobanking, we would like to ensure that it is available for the whole patient population. This is a project that enrolled consecutive patients, without using specific inclusion criteria such as performance, status, age, phase of the disease, etc. Their bone marrow and peripheral blood will be biobanked, and in the future, when we want to look for a progressive factor or search for a biomarker of response, we will have samples we can use. I think this will ensure high-quality management of the whole patient population without prioritising those who might be younger or more physically fit.

This is ongoing, as it isn’t easy to collect samples outside of clinical trials since patients might have more urgent clinical issues. In this context, sampling may not be the top priority, but we try to keep the endpoint in mind. Not every centre is involved, but perhaps two-thirds of haematological centres in Italy are participating. I think it’s a very worthy effort.

One of the pitfalls of real-life analysis is that you're often lacking biomarkers, fluorescent in situ hybridisation (FISH) analysis, or minimal residual disease (MRD) testing, because you might have the clinical data, but you don't have other data for support. We would like to try to fill this gap and have biological data available for patients.

Q3

MRD remains a major focus in your research. How close are we to establishing MRD as a standard endpoint in multiple myeloma treatment?

I think we are very close to this goal. In the USA, we may be even closer, because the FDA formally approved it as an early endpoint. The European Medicines Agency (EMA) hasn’t reached this point, but it seems like we are heading in the right direction.

In principle, no matter what stage the authorities are at in the decision-making process, without their approval, we are going nowhere. However, I think it is accepted in the scientific community and by physicians, and I can see in my routine practice

that it is now accepted by patients, who are starting to ask about their results. Thus, we are getting closer and closer to the objective.

The opportunity to receive MRD testing and results should be available to all patients and centres. Wherever you are in the country, you should be treated in the same way

What is likely not yet at the right point is the homogeneity in countries all over the world. For example, not all centres in Italy can perform MRD testing. Although we are in the process of creating a network, until the network is complete, this will always be the case. It is, in my opinion, a gap in multiple myeloma treatment. The opportunity to receive MRD testing and results should be available to all patients and centres. Wherever you are in the country, you should be treated in the same way.

In 2024, you co-authored international guidelines on T cell-engaging bispecific antibodies with the International Myeloma Working Group. What are the key takeaways clinicians should be aware of?

I think that was a very important paper, because perhaps half of the physicians in Italy, as well as in other countries, are not used to the management of patients with bispecific antibodies. In many countries, it has only received approval outside of clinical trials for a few months now. Those who could not get and do not have access to clinical trials are not familiar with this management.

Bispecific T cell engagers are excellent, very potent drugs that induce a high rate of highquality responses. As there are no age barriers and no specific organisational issues, in theory, every physician and patient could use this treatment. While it is a broader option, it's not an easy treatment to perform. The major issues with T cell engagers are infections, issues such as hypogammaglobulinemia, and patient management outside of treatment units. All these topics are touched on and explained in the paper, but we also tried to provide practical guidelines and recommendations, as it's necessary for physicians to learn how to manage this. It could also be a resource for patients and local medical authorities, particularly those who are less used to this treatment, to turn to.

Q5 Looking back on your career so far, which achievement or contribution are you most proud of, and why?

My first love was imaging techniques, so that was my first approach to clinical research. The

first time I gave a talk was in 2005, and it was about a prospective study that we ran in Bologna comparing functional imaging techniques with wholebody X-rays. This focus on imaging followed me throughout my career. I achieved many things with the International Myeloma Working Group, the International Myeloma Society, and nuclear medicine physicians with whom I collaborate in Bologna. Many improvements were offered to patients: the use of functional techniques, the use of imaging techniques to evaluate responses after therapies and establish MRD imaging categories, and the standardisation of imaging techniques. We also have a paper outlining recommendations for the use of imaging techniques in multiple myeloma, particularly in the early phases. I think that I was able to contribute to all of this, which will always remain a part of me.

Looking to the future, where do you see your research heading next, and which emerging areas in myeloma science excite you most?

The first thing I’d like to mention is the potential for a cure, which we should start systematically aiming for. For example, in the annual response criteria that will be provided either this year or early next year, the word ‘cure’ will appear for the first time, because we are starting to think about it. We need to look at which patients can currently be cured with the prognostic stratification and treatments that we have now. Moreover, we need to consider who the patients with huge unmet clinical needs are.

Systematically applying MRDtailored treatment over the next few years will also be important,

and I think it's time to have some recommendation guidelines. Several trials have been run regarding MRD tailoring, and a majority did not answer the relevant clinical questions. These questions still exist, so there are more ongoing trials, some of which will be presented for the first time in future congresses.

Lastly, we should focus on reshaping the treatment of multiple myeloma. Rather than using continuous treatments, we should try to find out who can receive fixed-duration treatments, how they can receive them, and in which contexts. We need to use the potent immunotherapies that we have, such as CAR-T cells and bispecific antibodies, and consider fixed-duration treatment as another endpoint.

Q7As both a clinician and an educator, how are you preparing the next generation of haematologists to navigate the evolving landscape of precision medicine in multiple myeloma?

There are many enthusiastic and well-prepared young people who possess a great deal of knowledge, but I think it's important to teach them to integrate everything they know. It's also important in the first year to see what others are doing and understand that a vital part of research groups is the discussion. We are responsible, as older and more experienced physicians, for teaching them that teamwork is essential. The idea of the lone genius doesn’t exist anymore. We need to have discussions because that is how we generate ideas.

We should focus on reshaping the treatment of multiple myeloma. Rather than using continuous treatments, we should try to find out who can receive fixed-duration treatments

We also need to teach them to ask for help if they need it. There might be a point in life where you’re juggling kids and a career, and asking for help might be necessary. You should ask, because in my opinion, it all comes back around. There might be a time when you're asking and a time when you're giving. This is what I'm trying to teach my fellows and PhD students. It's important to exchange and witness support for each other.

Lastly, I'm always telling these young people that they are very lucky, because with multiple myeloma, we have gone through a true revolution in the last 10–15 years. They are seeing incredible things, such as new treatments, endpoints, and biomarkers, as well as MRD and demonstrations of mechanisms of resistance (for those more interested in biological research). There are so many different directions they could go in, and although competition is an inherent part of our job, there is enough room for everyone.

Joshua Richter

Associate Professor, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York,

USA

We can all work together to provide patients with every possible option and reduce the negative impact on their quality of life

Citation: EMJ Hematol. 2025;13[1]:79-81. https://doi.org/10.33590/emjhematol/GGDY7274

Q1

What initially inspired your journey into medicine, and what motivated your specialisation in haematology and oncology, particularly within the plasma cell disorders field?

I knew from a very young age that I was interested in medicine and science. As an undergraduate, I ended up majoring in psychology and minoring in philosophy, where I became fascinated by not just medicine, but also by ethics and end-of-life care ethics. We can really help people live full and complete lives. We can help them through the good and the bad and develop important relationships with them and for some we can “functionally cure”. It is wonderful to visit a doctor with a problem, have them evaluate you and give you a therapy that they did not discover, invent, or optimise, and then become cured.

There's also something wonderful about helping people even when there is no cure, going through the good times and the bad times and trying to help them live normal lives despite the disease. When I was training, this was a major inflexion point for myeloma. If you look at the therapies and the outcomes before I started practising, it was dismal. Now, however, it's amazing. Some of my early mentors, people like Madhav Dhodapkar, Fred Hutchinson Cancer Center, Washington, USA, and Sundar Jagannath, Mount Sinai, New York, USA, were trying to cure patients when everyone was saying that it wasn’t possible. There’s a common expression, “hold my beer”, that in this instance boils down to: we don't care about

what you're saying, and we're going to find a way to cure it, understand it, and get inside of it.

In my opinion, one of the greatest things you can do is be part of a global effort to take a disease from being fatal and incurable to one that people can recover from and live their lives without. I'm hoping that by the time I retire, we’ll be able to cure everyone. It’s an amazing thing to be part of.

Q2

With your focus on multifunctional antibodies, what are the primary challenges you face in applying these therapies to multiple myeloma, and how is your team addressing them?

Medicine is like the story of Goldilocks and the Three Bears You never want things too hot, too cold, or too extreme one way or the other. It’s the same idea for bispecific and trispecific antibodies. We don't want your immune system to be too weak, where it's not fighting the cancer, but we also don't want it to be so active to the point where you're having side effects.

When you first administer these drugs, they can cause the immune system to become overactive. At academic centres, we have a lot of expertise in that, but community doctors don't, and 80% of myeloma in the USA is treated in the community. The reality is that this doesn't have to be an all or none situation. We can share responsibility; we can work together. You might ask why a patient should travel two hours to see me if they only

need to travel for five minutes to see their primary oncologist. The answer is that, if you are being treated by a doctor in the community that doesn't have the inpatient facilities or the expertise to administer the initial dose with those toxicities, then I can and will take care of the patient for a fixed period of time and get them over that initial issue. Once things have settled down, the patient can go back to their local physician, and the primary oncologist and I can work together. Patients don’t have to only be treated locally or only be treated by me; instead, we can all work together to provide patients with every possible option and reduce the negative impact on their quality of life.

Precision medicine is central to your work in myeloma. How do you envision its evolution over the next five years, particularly regarding patient stratification and tailoring treatment approaches?

In many ways, lymphoma is quite far ahead of us. There are so many different types of lymphoma, such as diffuse large B cell lymphoma and chronic lymphocytic leukaemia. We joked in the past, when the primary treatment for lymphoma was R-CHOP

(a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), that lymphoma was 100 diseases with one treatment and myeloma was one disease with 100 treatments. This isn’t true anymore, because they administer different treatments for lymphoma. When we diagnose patients, we take a snapshot of how we think it will behave, but we don’t fully know how it will act until we start treating it. We give them all the same therapy, and sometimes it works better than expected, while other times it doesn’t.

I'm hoping that, with the evolution of precision medicine, myeloma becomes more like a urinary tract infection. If someone has a urinary tract infection, they pee in a cup, they place the urine on agar disks and then put little tablets of antibiotics so as the bacteria grows we know which antibiotic kills it I want the future of myeloma to be like this: the patient is sequenced, we know what drugs they need, and they don't need a transplant. Instead of feeling our way around in the dark, we can turn the light on and tell them exactly what type of myeloma they have and what treatment is needed. The future is about personalised treatment.

Q4

Resistance to bispecific antibodies remains a challenge. What mechanisms are you focusing on, and what strategies are you exploring to overcome them?

Checkpoint inhibitors have had a very interesting role in the history of myeloma. This work was originally done in the KEYNOTE-183 and KEYNOTE-185 trials, when we combined pembrolizumab with lenalidomide and pomalidomide, but the studies were negative. The questions were: are PD-1 and PD-L1 the right checkpoint inhibitors, and is that the right combination? Now that we're looking at T cell redirection therapy, including CAR-T cells and bispecific antibodies, we're starting to ask these questions again. Should checkpoint inhibitors be part of this, now that we're actually using T cell therapy?

Our translational partners in the lab are analysing patients who are progressing on bispecific antibody and CAR-T cell therapies. We're discovering that checkpoints are overexpressed, and it's not PD-1 or PD-L1, but other checkpoints like LAG-3, TIGIT, and TIM3. What we're trying to figure out is, if we're going to bring in checkpoint inhibitors, which ones

are we bringing in and when. It's not enough to just identify what the checkpoints are. If you bring them in too early, there will be too many side effects. If you bring them in too late, when the T cells are exhausted and the antigen is gone, they won’t be useful. We have to work out what the right checkpoints are and what the right timing is to optimise the response. Do we wait until slow progression occurs? Do we wait for the suboptimal deepest response? We're working with our translational partners to answer this.

Q5 You’ve spoken about toxicity concerns with targeted bispecific antibodies. What are your key recommendations for clinicians managing these adverse effects in practice?

I think that it is better to be proactive than reactive. One of the biggest issues with bispecific antibodies and T cell redirection is the high rate of associated infections. Prophylaxis is key. Ensure that patients are up to date on all recommended vaccinations, including those for pneumococcus, COVID-19, respiratory syncytial virus, and influenza. Measures such as antimicrobial administration, Pneumocystis jirovecii pneumonia prophylaxis, and herpes simplex virus prophylaxis should also be taken. Furthermore, we know that giving intravenous immunoglobulin as a primary prophylaxis reduces the risk of infections tenfold.

While playing the character of Harry Callahan in ‘Magnum Force’, Clint Eastwood (actor, USA) said: “A man's got to know his limitations.” The average haematology-oncology doctor in this country sees zero to 10 cases of myeloma per year. I see 60 to 100 a week. If you're administering

a drug and you’re unsure about any aspect of the situation, reach out to someone who sees a lot of myeloma cases. Myeloma specialists might understand what’s going on even if another doctor might consider it strange or confusing. When in doubt, there is a whole community of myeloma nurse practitioners, physician assistants, registered nurses, and doctors. We're all happy to help and we all have the same goal in mind. It's a tug of war, but we're all pulling on the same side.

Q6

Based on your career, what advice would you offer to medical students interested in pursuing haematology-oncology?

I think that the early phase of a medical career is quite difficult. The people you are exposed to the most are other medical students, residents, and fellows, and it’s important to recognise that this is a small portion of your career. You need to try to get some insight from attendings about what their day-to-day life is like; med students might see a resident and assume that their work represents what medicine is going to be like, but that has nothing to do with the reality of day-to-day life.

For example, when I was in residency, I loved cardiology. I loved reading ECGs. Then I asked myself: do I want to be the person who gets a call at midnight about a patient having chest pains? Do I want to have to go in and open up a catheterisation laboratory? The answer was no; I don't want to be that guy.

Try to take a step back and look at what it’s going to be like in the long term. Embrace and understand what your strengths and weaknesses are. Be introspective. I was interested

in surgical oncology at one point, but I knew I wouldn’t be the right person for it. Take the time and effort to ask yourself what you want your career to be like. Although, in my opinion, working in the cancer field is amazing.

Lydia Scarfò

Assistant Professor, Università Vita-Salute San Raffaele, Milan, Italy Physician Scientist, B-cell Neoplasia Unit, IRCCS Ospedale San Raffaele, Milan, Italy

Citation: EMJ Hematol. 2025;13[1]:82-84. https://doi.org/10.33590/emjhematol/GGDY7274

Q1Reflecting on the recent European Hematology Association (EHA) Congress, what do you consider the most impactful takeaways for the chronic lymphocytic leukaemia (CLL) community this year?

We can also see that using the three-drug combination, especially in patients at high risk, such as those carrying an unmutated IGHV genes, can prolong PFS

This year, the EHA Congress provided us with long-term follow-up of some very interesting study, including the GAIA/CLL13 trial, where they updated the progression-free survival (PFS) of different cohorts. It seems that, especially in patients carrying unmutated IGHV genes, the triplet combination of ibrutinib, venetoclax, and obinutuzumab, is associated with a prolonged PFS. As a reminder, the GAIA/ CLL13 trial was focused on young, fit patients without TP53 aberrations, who were randomised 1:1:1:1 to: venetoclax plus obinutuzumab; or venetoclax plus obinutuzumab plus ibrutinib; or venetoclax plus rituximab; or FCR/BR. In general, chemofree combinations proved to be superior to chemoimmunotherapy. Now, with prolonged follow-up, we can also see that using the threedrug combination, especially in patients at high risk, such as those carrying an unmutated IGHV genes, can prolong PFS.

Along similar lines, in patients treated with a fixed-duration combination of ibrutinib plus venetoclax in the CAPTIVATE study, we now have long-term data suggesting that at 5.5 years of follow-up, 60% have not relapsed, which is very reassuring. Among those who did relapse and were retreated with either ibrutinib alone or the combination of ibrutinib plus venetoclax, the overwhelming majority responded. Now, with longer follow-up data on retreatment (more than 2 years in those who were retreated with ibrutinib), we see >90% PFS at 2 years, and >96% overall survival (OS) at 2 years after restarting treatment with ibrutinib. This is highly encouraging and helps us to better manage our patients in clinical practice.

Importantly, we also received updated follow-up results of the FLAIR study, which was designed by UK colleagues using an adaptive design. At this meeting, they presented the comparison data on PFS and OS across three cohorts: patients treated with fludarabine, cyclophosphamide, and rituximab; patients treated with ibrutinib; and patients treated with ibrutinib plus venetoclax, based on a minimal residual

disease-driven approach. With prolonged follow up, the UK team confirmed a PFS benefit for ibrutinib plus venetoclax, not only in comparison to chemoimmunotherapy, but also versus ibrutinib monotherapy. This benefit also translated into improved OS, which is a very impressive for the CLL community.

We are actually improving the management of patients with CLL starting from first-line treatment

Q2You recently presented these findings at EHA 2025. Could you walk us through the updated efficacy and safety findings of BGB-16673 in patients with relapsed or refractory CLL/small lymphocytic lymphoma, from the ongoing Phase I CaDAnCe-101 study?

We are actually improving the management of patients with CLL starting from first-line treatment, but we still have to face the issue of patients relapsing after initial treatment. In particular, there is an unmet need in patients who relapse on covalent Bruton tyrosine kinase (BTK) inhibitors or shortly after receiving combination treatment. And in the CaDAnCe-101

study, we enrolled patients with relapsed/refractory CLL. The vast majority had previously been exposed to a covalent BTK inhibitor. A relevant proportion, more than 80%, had also received venetoclax treatment, and about 18% had additionally been exposed to a non-covalent BTK inhibitor, generally pirtobrutinib. This represents a very heavily pretreated patient population. The median number of prior lines of therapy was four, and these patients were enriched for unfavourable disease features, like TP53 aberrations, unmutated IGHV genes, and complex karyotype (defined as three or more abnormalities). Almost 40% of patients carried BTK mutations. Thus, in this very difficult-to-treat population, BGB-16673 achieved a very high response rate. The study design is a Phase I/II, and the aim was to identify the recommended dose for expansion, which was established at 200 mg daily. If we analyse the whole cohort, the overall response rate (ORR) was more than 85%, with a complete response rate of 4.5%. Focusing on patients receiving the recommended dose for expansion of 200 mg daily, we observed an ORR of more than 93%. This response rate was consistent across different patient subgroups, including so-called triple-exposed patients, who have received a covalent BTK inhibitor, a B-cell lymphoma 2 (BCL-2) inhibitor, and non-covalent BTK inhibitor.

In terms of safety, since this is a Phase I study, the main focus was on tolerability. The study was the drug was very well tolerated, with no unexpected toxicities. The most frequent adverse events were fatigue, contusion, diarrhoea, and neutropenia, but these were all manageable. Regarding cardiovascular toxicity, given that the main target is BTK, we identified only two cases of atrial fibrillation and two major haemorrhages. Notably, no new major haemorrhages have been reported since the previous analysis presented in 2024. BGB-16673 acts via a completely different mechanism compared to other available drugs, since it does not inhibit BTK directly but instead tags BTK for degradation via the proteasomal pathway. This is showing very promising efficacy and is now being studied in Phase II and III trials.

Q3 Can you describe the methodology behind your qualitative study exploring the patient experience with continuous covalent BTK inhibitors in CLL?

So, in this study, we wanted to learn more about the patient experience with continuous covalent BTK inhibitors, because the information we currently have is derived from the physician assessment in clinical trials. We wanted to understand how patients tolerate these therapies

and what impact they have on quality of life in everyday clinical practice. We focused not only on patient perceptions, but also on care partner perspectives, because this is also relevant in the CLL patient journey, as well as physician perspective. We wanted to compare the different viewpoints to better understand whether continuous BTK inhibitor treatment is associated with impaired quality of life, or if some covalent BTK inhibitors are better tolerated in everyday life and are compatible with continuous treatment, in line with the current prescribing schedules. So far, we are still recruiting patients. We did not achieve yet our recruitment goal, but we hope to present the results of the cumulative analysis at upcoming meetings.

Q4In your view, what are the biggest challenges and opportunities currently facing clinicians and researchers working in the CLL field?

We have greatly improved the management of our patients, because we have shifted from a chemotherapy-based approach to a chemo-free approach. At the same time, we are now not only improving the symptoms and the quality of life of our patients with treatment, but we are actually

improving their survival. Recently, the results of a cumulative analysis confirmed that patients treated with either ibrutinib as a single agent or in combination with venetoclax in the first line, have the same OS as the general population matched according to sex and age. This is a very relevant achievement in the CLL field, even though CLL remains incurable.

In the next future, I would say that our main focus will probably be on achieving a cure for CLL. We are not there yet, and to achieve this goal, we may need to go back to the bench. The greatest achievements of the last few years have been associated with a better understanding of the mechanisms leading to CLL onset, progression, and resistance to treatment. We now need to delve deeper to identify other potential targets that we can exploit in order to achieve deeper responses, and long-term disease control, and hopefully a cure.

Nowadays, in everyday clinical practice, the main issue concerns patients who have been previously exposed to both a covalent BTK inhibitor and a BCL-2 inhibitor, particularly those who are not only double-exposed but also double-refractory. In such cases, we have limited treatment options.

We have recently acquired pirtobrutinib in Europe for patients previously exposed to a covalent BTK inhibitor but we still need to identify other targets and strategies, especially for young, fit patients, that will allow us to achieve long-term disease control.

Q5 Looking ahead to EHA 2025, what emerging themes or developments in CLL research are you most excited to see discussed?

I would say that we will learn more about BTK degraders. There are two BTK degraders in clinical development, BGB16673 and NX-5948, and they are both very promising agents may be approved and used in clinical practice soon. For CLL, there are also novel BCL-2 inhibitors in development, such as lisaftoclax and sonrotoclax. In the next future, we will learn more about the results of these novel BCL-2 inhibitors. At the last EHA meeting, bispecifics and CAR-T cells were not the main topics of discussion. Thus, I hope that at the next EHA meeting, we will have updated results from larger cohorts on the use of bispecifics and CAR-T cells, both alone or in combination, in the treatment of patients with CLL.

A MULTI-CRITERIA DECISION FRAMEWORK TO GUIDE TREATMENT

IN PATIENTS WITH LENALIDOMIDE-REFRACTORY MULTIPLE

This publication was supported by Stemline Therapeutics Switzerland GmbH. It is based on a abstract presented at the European Hematology Association (EHA) Congress, held from the 12th–15th June 2025. EMJ Hematol. 2025;13[1]:86-87. https://doi.org/10.33590/emjhematol/WUYT2786

INTRODUCTION

Multiple myeloma is the second most common haematological malignancy, with an increasing global incidence.2

A study presented at the EHA Congress elicited treatment preferences from 20 haematologists from the European Myeloma Research Network Research Italy Working Group and other stakeholders to identify decision criteria to support physicians in choosing second-line treatment for patients who relapse after DRd.1

STUDY STAGES

1. Decision criteria were identified through a literature review

2. Decision criteria were discussed during a workshop, (20 haematologists, one methodologist, two decision makers, one patient representative)

3. A subsequent, focused literature review assessed data availability for each treatment alternative

4. Each treatment option was allocated a performance level for each criterion

5. Stakeholders weighted the different criteria and scored performance levels for each treatment option via a questionnaire

6. Questionnaire results were analysed in a final stakeholder workshop

References

1. Bocadoro M et al. Abstract PB2976. EHA, 12-15 June, 2025.

2. Malard F et al. Nat Rev Dis Primers. 2024;10:45.

3. Dimopoulos MA et al. Ann Oncol. 2021;32(3):309-22.

4. Kastritis et al. Blood. 2023;142(Suppl 1):7424.

5. Richardson P et al. Eur J Haematol. 2025;114(5):822-31.

6. Dimopoulos MA et al. Lancet Oncol. 2017;18(10):1327-37.

Abbreviations

aBCMA: anti-B-cell maturation antigen; DRd: daratumumab, lenalidomide and dexamethasone; EPAR: European Public Assessment Report; HR: hazard ratio; IV: intravenous; Kd: carfilzomib and dexamethasone; PFS: progression-free survival; PVd: pomalidomide, bortezomib and dexamethasone; RCT: randomised clinical trial; SC: subcutaneous; SVd: selinexor, bortezomib and dexamethasone.

MULTI-CRITERIA DECISION

The final Multi-Criteria Decision Analysis comprised five main criteria: administration, organisational impact and acquisition cost. Efficacy was rated the most relevant criterion by 83.3% of participants and safety was ranked second-most relevant by 75% (with a median Three non-aBCMA EMA-approved therapeutic options are recommended for lenalidomide-refractory patients who relapse post-DRd:3

Each treatment option was scored for its performance levels against sub criteria.1

The main criteria and sources of information for informing the for each treatment option.

in relation to Vd-derived lenalidomide-refractory

Kd PVd SVd

TREATMENT DECISION-MAKING

MULTIPLE MYELOMA POST-DRd

Vd-derived

criteria: efficacy, safety, route of participants (with a median weight of 38.1%), median weight of 26.8%).1 recommended in the 2025 EHA guidelines against the five main criteria and safety

performance matrix

DISTRIBUTION OF AGGREGATE SCORES OF ALTERNATIVES2

Based on the group’s elicited preferences, SVd was ranked as the most valuable therapy with a global score of 72, followed by PVd (44) and Kd (26).

100% of participants ranked SVd first

100% of clinicians had preferences compatible with the ranking of SVd>PVd>Kd

Distribution of aggregate scores of alternatives.

Based on 24 stakeholders’ preferences. Median aggregate scores are reported beside each box.

The study identified key decision criteria and their relevance for assessing second-line therapeutic options for lenalidomide-refractory MM post DRd from an Italian multi-stakeholder perspective.1

SVd emerged as a preferred alternative over PVd and Kd for patients who relapse after first-line DRd and are ineligible for autologous stem cell transplantation.1

The results provide new insights for physicians to support treatment decision-making.

The Immunotherapy Landscape for Multiple

EMJ Hematol. 2025;13[1]:88-89. https://doi.org/10.33590/emjhematol/LIXI1048

Introduction to Multiple Myeloma1,2

Multiple myeloma is the second most common haematologic malignancy after non-Hodgkin lymphoma.

It arises from the uncontrolled proliferation of abnormal plasma cells, which produce excessive immunoglobulins.

Multiple myeloma exists on a spectrum of plasma cell disorders, ranging from monoclonal gammopathy of undetermined significance (MGUS), to smouldering myeloma, multiple myeloma, and plasma cell leukaemia. The risk of progression from multiple myeloma to plasma cell leukaemia however is low.

It can lead to...

Recent Developments and Future Outlooks13-16

In vivo CAR delivery approaches, such as ESO-T01, are showing promise and reducing manufacturing restrictions.

At ASH 2024, Anitocabtagene autoleucel (antio-cel), a novel CAR-T cell therapy showed a 95% overall response rate in relapsed/refractory multiple myeloma.

Trispecific antibodies like JNJ-79635322, which target BCMA, GPRC5D, and CD3, are designed to enhance efficacy and reduce the risk of antigen escape.

Bispecific Antibodies

These bind to two the antigen of the antigen of the myeloma

E.g. There are currently teclistamab, elranatamab,

+ Prove to be highly

- Can lead to severe regular intravenous prevent infections.

Abbreviations

Antibody-Drug

Conjugates:

This is a monoclonal agent, delivering chemotherapy

To note, there are multiple myeloma.

+ Targeted approach surrounding healthy

- Common toxicities neutropenia, and anaemia.

- Keratopathy is also requiring patients while on treatment.

A: advantage; D: disadvantage; MGUS: monoclonal gammopathy of undetermined significance; NK: natural killer.

References

1. Memorial Sloan Kettering Cancer Center. Available at: https://www.mskcc.org/cancer-care/types/ multiple-myeloma/multiple-myeloma-treatment/ immunotherapy-car-cell-therapy-for-multiplemyeloma. Last accessed: 02 June 2025

Perforin granzymes

CD3+ T cell

CD3

Multiple Myeloma

Antibodies3-6

different proteins simultaneously; one on patient’s T cell, called CD3, and one on the myeloma cell, such as BCMA, GPRC5D, or FcHR5. currently three anti-BCMA BiTEs approved: elranatamab, and linvoseltamab. highly effective with response rates of over 60%. severe hypogammaglobulinemia, necessitating intravenous immunoglobulin (IVIG) replacement to infections.

Cellular Immunotherapy7-9

CAR-T Cell Therapy:

Patient T cells are genetically modified to express a chimeric antigen receptor targeting myeloma antigens such as BCMA. E.g. ciltacabtagene autoleucel (Cilta-cel) and idecabtagene vicleucel (ide-cel).

+ One time treatment requiring no maintenance therapy.

- Acute toxicities can include immunological effector cell-associated neurotoxicity syndrome (ICANs), cytokine release syndrome (CRS). Delayed toxicities can include parkinsonism, and enterocolitis

Conjugates:10

monoclonal antibody linked to acytotoxic chemotherapy directly to cancer cells. currently no approved ADCs for approach means there is less damage to healthy cells. toxicities include neuropathy, anaemia.

also a toxicity with belantamab, to have ophthalmologic evaluation treatment.

2. Multiple Myeloma Research Foundation. Available at: https://themmrf.org/multiple-myeloma/. Last accessed: 2 June 2025.

3. International Myeloma Foundation. Available at: https://www.myeloma.org/videos/immunotherapymultiple-myeloma-understanding-its-roletreatment. Last accessed: 2 June 2025.

4. Hsin-Ti Lin C et al. Cur Int J Mol Sci. 2024;25(11):6192.

5. Xu L et al. Cell Death Discov. 2024;10(1):55.

6. Lancman G et al. Blood. 2022;140(Supplement 1):10073-4.

Immunotherapeutic Approaches for Multiple Myeloma

3-12

Monoclonal Antibodies:12

These are complimentary and specific to one antigen protein on the myeloma cells, once bound they trigger an immune response. E.g. daratumumab, isatuximab, or elotuzumab.

+ High specificity targets myeloma cells with fewer side effects.

- Side effects can include allergic reactions and immunosuppression.

7. Sheykhhasan M et al. CAR T therapies in multiple myeloma: unleashing the future. Cancer Gene Ther. 2024;31(5):667-86.

8. Shah UA et al. CAR T and CAR NK cells in multiple myeloma: expanding the targets. Best Pract Res Clin Haematol. 2020;33(1):101141.

9. VJHemOnc -Video Journal for Hematology & HemOnc. Available at: https://www.youtube.com/ watch?v=gM6cwDih2O0. Last accessed: 03 June 2025.

10. Rodríguez-Nava C et al. Biomedicines. 2023;11(6):1610.

11. Dimopoulos MA et al. Blood. 2024;144 (Suppl 1):773.

12. Xu J et al. Lancet. 2025:S0140-6736(25)01030-X

13. International Myeloma Foundation. Available at: https://www.youtube.com/ watch?v=HavpCF6wWQ4. Last accessed: 3 June 2025.

14. Pillarisetti R et al. Blood. 2023;142(Supplement 1):456.

Antibody

Myeloma cell

Bispecific antibody

MM target

T Cell Fights off foreign invaders dangerous to the body

CAR Receptor engineered to target specific proteins

CAR-T Cell

Enhanced and ready to find and destroy cancer cells

Gene Therapy: Living With(out) Haemophilia?

Author: *Lieke Baas1

1. Section of Medical Ethics, Philosophy, and History of Medicine, Erasmus University Medical Centre, Rotterdam, the Netherlands *Correspondence to L.Baas@erasmusmc.nl

Disclosure: The author has declared no conflicts of interest.

Received: 08.04.25

Accepted: 04.06.25

Keywords: Cure, ethics, gene therapy, haemophilia.

Citation: EMJ Hematol. 2025;13[1]:90-93. https://doi.org/10.33590/emjhematol/QMQG5189

INTRODUCTION

Since research on human gene therapy began, the expectations regarding its potential in treating haemophilia have been high. Haemophilia is a heritable bleeding disorder, characterised by a lack of clotting factor VIII (in the case of haemophilia A) or IX (in the case of haemophilia B). As a result of this deficiency, people living with haemophilia experience spontaneous and trauma-induced bleeding into muscles and joints, which can lead to pain, arthropathy, and loss of function. At this moment, multiple treatment options for haemophilia are available, which allow people living with the condition to have an increasingly normal lifespan and quality of life.1

However, none of these treatment options have led to a definitive cure for haemophilia. Therefore, the field has focused on gene therapy to bridge this gap. At the time of writing, three gene therapy products for haemophilia have received market authorisation by the European Medicines Agency (EMA), and more products are under development. Results from trials indicate that these gene therapies are effective and increase clotting factor levels, thereby decreasing the number of bleeding episodes and foregoing the need for prophylactic treatment.2 However, some studies indicate that these effects decrease over time, and it is unknown how long clotting factor

levels will remain elevated, as there is still a scarcity of long-term follow-up data.2 As a result, there is no consensus on whether gene therapy has already led to a cure, or if it will be capable of producing a cure.3

Due to these uncertainties, people who have received gene therapy may not be described best as living with haemophilia, nor as being cured from haemophilia.

IN BETWEEN HEALTH AND DISEASE

The state of being in between health and disease has already been described in the literature, both for people who no longer have a disease and for people who do not yet have a disease. The first group is said to be ‘in remission’ after active medical treatment.4 The second group is described as being ‘in waiting’ after receiving a diagnosis, but before the onset of symptoms.5 Paradoxically, gene therapy can lead to a state in which people living with haemophilia simultaneously find themselves both ‘in remission’ and ‘in waiting’.

To begin, the term ‘remission society’ has been used to describe all people who have had a disease and are effectively well, but who still experience consequences of the disease.4 According to Arthur Frank (VID Specialized University, Oslo, Norway), a sociologist and cancer survivor who

introduced the term ‘remission society’, this includes all those with a history of illness. This group consists of, but is not limited to, cancer survivors who are not declared ‘cured’ because the cancer might return at some point in time, all people who have to return to the doctor for a check-up, or people with a pacemaker that offsets the metal detector at airports.4

When gene therapy for haemophilia achieves the effects that are aimed for in trials (i.e., long-term increase in coagulation factor levels, thereby foregoing the need for clotting factor replacements) people will no longer have any symptoms of haemophilia. However, they will continue to live with the consequences of haemophilia. This may include joint damage that will continue to progress, potential psychological burdens, and any other consequences that have resulted from haemophilia, such as career opportunities that were lost earlier in life. Furthermore, as haemophilia is a congenital disorder, it will remain a factor to take into account when making reproductive choices for people who have been ‘cured’. As a result, haemophilia will continue to have an impact on their lives, and they may not be able to live with a completely “haemophilia-free mind”.6

Meanwhile, the notion of “patients-inwaiting” is used to describe people who are already diagnosed with a disease, but do not (yet) experience symptoms. This includes, for instance, infants who receive a genetic diagnosis or people who receive a biomarker-based diagnosis, such as for Alzheimer’s disease, before the disorder becomes symptomatic.5,7 The term is also used to describe people who are at risk of developing a disease, such as people with high cholesterol.5 These people are described as being in a diagnostic ‘limbo’, wherein they have received a disease label, but it might be years before they start experiencing the first symptoms, if ever.

Results of gene therapy trials for haemophilia seem to indicate that, for many individuals, gene therapy is effective in reducing, and in some cases fully

eliminating, symptoms. This allows people to live a life free of bleeding risk after gene therapy. At the same time, these effects appear to decrease over time.2 However, the likelihood and timing of this decrease remains hard to predict, as there is still a scarcity of long-term follow-up data, and the data that does exist indicates that there is much variation between individuals.2 As a result, it is hard to predict if and when people may need to return to prophylactic treatment after gene therapy. This puts people who have been treated with gene therapy in a position similar to that of “patients-in-waiting”; there is a chance that the disorder might return in their lifetime, but it is uncertain if this will happen and, if it does, when symptoms will reoccur.5,7

People living with haemophilia differ from the groups traditionally described as ‘in waiting’. Not only have they been diagnosed with haemophilia at a young age, but they have also experienced symptoms and needed continuous treatment from the moment they learned to crawl. Nonetheless, because of the promise of being cured and the expectation that they will be permanently relieved of haemophilia, they share the characteristics of “patient-in-waiting”.

Therefore, gene therapy might lead to a group of people who are not best described as living with haemophilia, nor as being free from haemophilia. Instead, a new group arises: people living both with and without haemophilia, who live with an uncertainty about their future well-being.

ETHICAL CONSEQUENCES

There are several ethical consequences regarding this uncertain state. To begin, people may need to cope with uncertainty and fear for their future health and wellbeing. Qualitative research indicates that, for some people who participated in a gene therapy trial, seeing their clotting factor levels go down created stress, as they started to worry about the moment the effects would disappear and they would need to return to prophylactic therapy.8,9

This state also raises questions about what medical care is suitable and appropriate. For some people living with haemophilia, being cured might entail being free from doctor’s appointments and medical checkups. However, regular check-ups may be necessary to monitor how the person is doing and if their clotting factor levels are still sufficiently high. Moreover, participation in follow-up research is highly desirable to obtain knowledge about the long-term effects of gene therapy, which is required to allow people living with haemophilia to make informed treatment choices in the future.

Additionally, awareness of this “in-between” state is essential for decision making regarding gene therapy. This outcome is different from the way gene therapy is often portrayed, i.e., as a definitive cure for haemophilia. This discrepancy may lead to unrealistic expectations of gene therapy, which could impact the informed decisionmaking process. The difference between expectations and reality of a ‘cure’ after gene therapy may occur for people living with various disorders and conditions. However, the issue is particularly salient for haemophilia. There are already several treatment options available for haemophilia; thus, opting for gene therapy (if available to the person in question) is a choice rather than a necessity, which contrasts disorders for which no or very few other treatment options are available. The choice of a certain treatment option may, therefore, depend on its effects on quality of life, as well as personal preference.

These ethical consequences require attention from the medical community. To begin, the psychological distress that may occur requires appropriate care and support. Other authors have already argued for the importance of offering psychosocial care to people undergoing gene therapy.8 In providing this care, there should be a focus on realistic expectations of what life will look like after gene therapy and the uncertainty surrounding the long-term effects of the therapy.

Furthermore, when discussing gene therapy with people living with haemophilia, healthcare providers might consider using a term other than ‘cure’ to describe the expected outcome of gene therapy. The notion of a cure is likely to elicit expectations of life-long effects, which may be unrealistic. Instead, choosing words that more concretely describe the effects of gene therapy may allow people to make a more well-informed treatment decision.

CLOSING REMARKS

To a certain extent, reaching this state in between health and disease is inherent to gene therapy; haemophilia will remain a congenital disorder, which can be passed on to future generations, and joint damage that has been incurred before will not disappear. Yet, a part of this uncertain state may be temporary. For instance, because of the improved standard of care for haemophilia, younger generations will incur less joint damage, and thus will have a smaller burden of being “in remission” than older generations, who have not always benefitted from this standard. Furthermore, as the amount of follow-up data from gene therapy increases, we may be able to better predict how long the effects will last. Moreover, in the developmental process of gene therapies, a product may be developed with a more stable and longer-lasting effect, thereby decreasing the uncertainty about the return of haemophilia (symptoms). Nevertheless, at this moment, the outcome of being ‘not entirely with haemophilia, nor entirely without’ after gene therapy is an important consideration for people living with haemophilia who are choosing between various treatment options.

References

1. Mannucci PM. Hemophilia treatment innovation: 50 years of progress and more to come. J Thromb Haemost. 2023;21(3):403-12.

2. Leebeek FWG, Miesbach W. Gene therapy for hemophilia: a review on clinical benefit, limitations, and remaining issues. Blood. 2021;138(11):923-31.

3. Baas L et al. Can hemophilia be cured? It depends on the definition. Res Pract Thromb Haemost. 2024;8(6):102559.

4. Frank AW. The Remission Society. In: Sociology of Health and Illness. 6th ed. 2001.

5. Timmermans S, Buchbinder M. Patients-in-waiting: living between sickness and health in the genomics era. J Health Soc Behav. 2010;51(4):408-23.

6. Krumb E, Hermans C. Living with a “hemophilia-free mind” – the new ambition of hemophilia care? Res Pract Thromb Haemost. 2021;5(5):e12567.

7. Kwon JM, Steiner RD. “I’m fine; I’m just waiting for my disease”: the new and growing class of presymptomatic patients. Neurology. 2011;77(6):522-3.

8. Fletcher S et al. The experiences of people with haemophilia and their families of gene therapy in a clinical trial setting: regaining control, the Exigency study. Orphanet J Rare Dis. 2022;17(1):155.

9. Baas L et al.; SYMPHONY consortium. Ethical aspects of hemophilia gene therapy: a qualitative interview study with stakeholders. Res Pract Thromb Haemost. 2023;7(7):102237.

Re-evaluating European Haemophilia Standards: Towards a More Inclusive Global Framework

Authors: *M. Joseph John,1 Cecil Ross2

1. Department of Clinical Haematology, Haemato-Oncology & Bone Marrow (Stem cell) Transplantations, Christian Medical College, Ludhiana, India

2. Department of Hematology and Bone Marrow Transplant, St. John's Medical College Hospital, Bengaluru, Karnataka, India *Correspondence to mjosephjohn@cmcludhiana.in

Disclosure: The authors have declared no conflicts of interest.

Received: 13.05.25

Accepted: 29.06.25

Keywords: European Haemophilia Comprehensive Care Centres (EHCCC), European Haemophilia Treatment Centres (EHTC), haemophilia treatment centres (HTC), healthcare disparities, India, stratification.

Citation: EMJ Hematol. 2025;13[1]:94-98. https://doi.org/10.33590/emjhematol/AYNE2390

INTRODUCTION

TEST In this feature, the authors critically analyse the European standards for Haemophilia Treatment Centres (HTC), examining their applicability across socioeconomic and geographical settings, particularly in regions such as India. The authors explore the disparities in healthcare delivery, and highlight how global variations in resources, infrastructure, and clinical expertise can limit the feasibility of adhering to uniform European benchmarks. To address these challenges, the authors propose an inclusive classification system (a universal stratification model) that accounts for these contextual differences. This model allows for progressive functionality in both clinical and laboratory services, enabling centres to optimise haemophilia care delivery based on available resources. The authors also emphasise the role of quality improvement processes and the establishment of key performance indicators (KPI), which together can pave the way for certification and accreditation pathways, ultimately strengthening patient outcomes and system accountability.

PHILOSOPHY OF HAEMOPHILIA CARE

‘Principle’ is a fundamental truth or proposition that serves as the foundation for a system of belief, behaviour, or reasoning.1 Principles of care are the core values that underpin care delivery, ensuring that individuals are treated with dignity, respect, and compassion while promoting their independence and choice. Standards of care are specific, measurable guidelines and expectations for healthcare providers that define the minimum level of care a patient should receive in particular situations or medical conditions.

In 2008, the European Association for Haemophilia and Allied Disorders (EAHAD) published 10 European principles of haemophilia care through the interdisciplinary working group. This gave the provision for elements of haemophilia care that should be available in each European country.2 In 2018, the Asia-Pacific Haemophilia Working Group (APHWG) prepared a document with 12 principles of care relevant to

Minimum caseload (severe PwH)

24-hour cover

Laboratory repertoire plus TAT

Inhibitor and immune-tolerance management

Multidisciplinary services

Education and outreach

Network role

≥10 patients with severe haemophilia

A/B or Type 3 VWD

Must guarantee emergency treatment (factor infusion and clinical staff) around the clock

PT, aPTT, thrombin time, mixing studies (TAT ≤3 hours)

FVIII/FIX assays, inhibitor screen (TAT ≤6–12 hours)

Other factor assays possible via referral

Treats/monitors inhibitors in collaboration with an EHCCC

Assured access (on-site or via EHCCC) to physiotherapy, orthopaedics, dentistry, hepatology, obstetricsgynaecology, paediatrics, genetics, psychology, and social work

Delivers genetic counselling; participates in patient/HCP training programmes

Provides routine local care and maintains a formal linkage with at least one EHCCC

≥40 patients with severe haemophilia

Must provide a 24-hour advisory hotline and 24-hour laboratory service for factor assays and inhibitor screens

Full diagnostic/reference lab able to perform all clotting-factor, vWF, and platelet tests with 24-hour availability

Provides specialist inhibitor care (including surgery) and runs immune-tolerance induction programmes

Same services plus on-site specialist orthopaedic surgery, rheumatology, hepatology-HIV care, and genetic diagnosis (carrier and prenatal)

Leads regional training; offers referral advice to affiliated EHTCs and other HCPs

Functions as tertiary referral hub: coordinates audit, research, and quality-improvement across its network

aPTT: activated partial thromboplastin time; EHCCC: European Haemophilia Comprehensive Care Centre; EHTC: European Haemophilia Treatment Centre; FIX: Factor IX; FVIII: Factor VIII; HCP: healthcare professional; PT: prothrombin time; PwH: persons with haemophilia; TAT: turn-around-time; vWF: von Willebrand factor.

its perspective on the context-specific development of haemophilia care.3 In 2020, the 3rd edition World Federation of Hemophilia (WFH) guidelines for the management of haemophilia enumerated 12 principles of care that had some overlap with the previous two principles of care publications.4 The purpose of these publications was for planning, and for them to serve as an advocacy tool to enhance care for people with haemophilia.

In 2014, the European standards for haemophilia centres5 were established through a consensus process by the European Haemophilia Network (EUHANET)

with the help of national health authorities, health professionals, patient organisations, and EUHANET Project Partnership.6 The guidelines defined the standards and criteria of two levels of care delivery: European Haemophilia Treatment Centres (EHTC), providing local routine care, and European Haemophilia Comprehensive Care Centres (EHCCC), providing specialised and multi-disciplinary care, and functioning as tertiary referral centres (Table 1).

The intention was to implement the certification of haemophilia centres, which would contribute to the reduction of health inequalities through the standardisation of

Table 1: European Haemophilia Treatment Centre and European Haemophilia Comprehensive Care Centre standards.5

the quality of care in EU member states. Today, there are 409 known haemophilia centres in Europe, with 5–350 persons with haemophilia being treated.7 Of those centres, 45 are EHTCs and 128 are EHCCCs among 34 countries, ranging from 1–23 centres per country.

While this is an excellent concept, centres in other parts of the world may find it challenging to meet the same standards due to socioeconomic or geopolitical challenges in many regions. This discrepancy creates a false dichotomy, as it overlooks the diverse range of care levels worldwide, and does not adequately account for the distinct realities that HTCs face in different contexts. A survey on adherence to this classification conducted in 21 centres across 14 European

countries revealed that 36% of patients received treatment outside of centres that met the definition of EHTCs or EHCCCs.8 The feasibility of implementing the proposed model is based on only a pilot study, and the authors acknowledge that further validation across other low- and middle-income countries will enhance its scalability.9

In 2017, a pilot study conducted in India assessed the care provided by various HTCs, with a focus on categorising laboratory and clinical services. Among the 52 centres surveyed (85% response rate) across 17 states, only 53% had functional laboratories, despite offering haemophilia care. Only four centres met the criteria for EHTCs, and only two qualified as EHCCCs.

Ability to manage acute bleeds. A doctor trained in basic haemophilia care.

Maintain an in-house database and make efforts to work towards sending data to the National Haemophilia Registry.

Level II

Level III

Level IV

In addition to Level I, ability to support patients with chronic synovitis/arthropathy.

In addition to Level II, ability to perform surgery for PwH, 24hour clinical facility, and facility to initiate continuous or intermittent prophylaxis. Ability to use bypassing agents. Submit data to the National Haemophilia Registry.

Ability to conduct ITI treatment. Work in close association with National Haemophilia registry.

Availability and expertise to use CFC; dedicated/part-time nurse who can administer CFC.

Level I plus physiotherapist with or without facility for radioisotope synovectomy.

Level II plus haematologist/MD physician or paediatrician who is trained in haemophilia surgical care. Back-up surgical team and 24-hour emergency services. Ability to manage other rare bleeding disorders. There is a dedicated nurse coordinator; PMR doctor and occupational therapist; social worker; dentist; and psychiatrist (multidisciplinary care). Provides advisory services, including genetic counselling, to patients and healthcare professionals.

Level III plus physician/haematologist trained in ITI.

CFC: factor concentrate; HTC: Haemophilia Treatment Centre; ITI: immune tolerance induction; MD: Doctor of Medicine; PMR: Physical Medicine and Rehabilitation: PwH: persons with haemophilia.

Table 2: The levels of clinical services in Haemophilia Treatment Centres.

Levels of facility Functionality

Level I

Level II

Level III

Level IV

PT, aPTT, TT, mixing studies/correction studies, daily use of quality controls (PNP or commercial plasma)*

Factor VIII and IX assay,† time dependent inhibitor screen‡

Inhibitor titre/Bethesda assay. Other rare factor assays. vWF assays (quantitative and functional), platelet function tests§

Facility for mutation studies and ability to perform antenatal testing through CVS (Chorionic villous sampling)

*TAT: within 3 hours.

Facility requirement

Manual/semi-automated/automated instruments

Trained manpower

Level I plus trained manpower to perform these tests

Level II plus platelet aggregometer

Level III plus molecular lab

†All routine assays should be performed at least once every 2 weeks.

‡The inhibitor screen is an aPTT-based test that evaluates the effect of mixing test plasma with control plasma after incubation for 1–2 hours. A positive inhibitor screen indicates the presence of an inhibitor and necessitates an inhibitor assay (Bethesda or Nijmegen modifications10).

§Should be able to perform in case of emergency whenever required.

aPTT: activated partial thromboplastin time; PNP: pooled normal plasma; PT: prothrombin time; TAT: turn-aroundtime; TT: thrombin time.

While all centres managed acute bleeds, only half addressed chronic joint disease (Level III), and 16% performed surgeries (Level II). Only one-third of the laboratories also adhered to quality control standards and conducted factor assays9 (Tables 2 and 3).

Due to the lack of availability of both clinical and laboratories services in most centres, it would be pragmatic to adopt a dichotomised approach, separating both the clinical and laboratory levels based on facility and functionality criteria. The Donabedian approach emphasises the importance of structure (facilities) and processes determining the outcomes of a service.11

The proposed stratified model addresses this by introducing a flexible, multi-tier system comprising four clinical and four laboratory levels, allowing for stepwise

development and decoupling of clinical services from laboratory services. This approach facilitates gradual capacitybuilding, context-specific scaling of multidisciplinary care, and alignment with national priorities through KPIs, rather than centralised certification. The model promotes inclusivity, accommodates variable caseloads, and supports phased upgrades, making it better suited to diverse healthcare ecosystems, particularly in LMICs.

Incorporating clear quality improvement processes and establishing KPIs specific to clinical and laboratory services is essential for advancing haemophilia care. An evaluation framework that includes these elements will not only help monitor and assess the effectiveness of treatment, but also provide a structured path for haemophilia centres to achieve certification and accreditation. These standards act

Table 3: The levels of diagnostic/laboratory services in Haemophilia Treatment Centres.

as benchmarks for care delivery, ensuring that centres meet minimum quality criteria while striving for continuous improvement. The establishment of such an evaluation framework is crucial, as it guides centres in identifying gaps in care, optimising resource use, and aligning services with international best practices. Furthermore, it empowers healthcare providers to track performance, set goals, and implement evidence-based practices, ultimately improving patient outcomes and fostering a culture of excellence in haemophilia care.

CONCLUSION

The European model of haemophilia care, structured around the EHTC and EHCCC designations, has significantly advanced comprehensive care in high-resource settings through standardised criteria such as caseload thresholds, 24-hour coverage, and full multidisciplinary teams.

References

1. Oxford English Dictionary. Principle, n. meanings, etymology and more. 2025. Available at: https://www.oed. com/dictionary principle_n?tab=factsheet&tl=true#28387145. Last accessed: 7 May 2025.

2. Colvin BT et al.; Inter Disciplinary Working Group. European principles of haemophilia care. Haemophilia. 2008;14(2):361-74.

3. Dunkley S et al.; Asia-Pacific Haemophilia Working Group (APHWG). Principles of haemophilia care: the Asia-Pacific perspective. Haemophilia. 2018;24(3):366-75.

4. Srivastava A et al.; WFH Guidelines for the Management of Hemophilia panelists and co-authors. WFH Guidelines for the management of

However, these rigid standards may be difficult to implement in low- and middleincome countries due to disparities in infrastructure, staffing, and laboratory capabilities. In response, the proposed stratified model introduces graded levels (I–IV) for both clinical and laboratory services, enabling centres to develop progressively based on their available resources and local realities.

Unlike the centralised and prescriptive European approach, the stratified model supports flexible growth by emphasising quality improvement, institutional selfassessment, and linkage to national registries. It can incorporate KPIs aligned with the Donabedian model, evaluating structure, process, and outcome, to drive service enhancement. This context-sensitive framework empowers haemophilia centres to evolve without being penalised for not meeting uniform benchmarks, offering a practical and scalable pathway towards certification and improved patient care in diverse global settings.

hemophilia, 3rd edition. Haemophilia. 2020;26(Suppl 6):1-158.

5. Giangrande P et al. The European standards of Haemophilia Centres. Blood Transfus. 2014;12(Suppl 3):s525-30.

6. Candura F et al. The methodology for defining the European standards for the certification of Haemophilia Centres in Europe. Blood Transfus. 2014;12(Suppl 3):s519-24.

7. EAHAD. European Haemophilia Centres Accreditation. 2022. Available at: https://www.eahad.org/eahadprojects/european-haemophiliacentres-accreditation/. Last accessed: 2 April 2025.

8. Fischer K et al.; European Haemophilia Therapy Standardisation Board. The

European Principles of Haemophilia Care: a pilot investigation of adherence to the principles in Europe. Haemophilia. 2013;19(1):35-43.

9. John MJ et al. Hemophilia treatment center: a stratification model for developing countries: a pilot study from India. CHRISMED Journal of Health and Research. 2017;4(4):253-8.

10. Verbruggen B et al. The Nijmegen modification of the Bethesda assay for factor VIII:C inhibitors: improved specificity and reliability. Thromb Haemost. 1995;73(2):247-51.

11. Tossaint-Schoenmakers R et al. The challenge of integrating eHealth into health care: systematic literature review of the Donabedian model of structure, process, and outcome. J Med Internet Res. 2021;23(5):e27180.

Low-dose Rituximab in Adults with Autoimmune Haematological Disorders: A Review

Key Points

1. Low-dose rituximab (LDR) has been shown to be an effective treatment for autoimmune haematological disorders such as immune thrombocytopenia, thrombotic thrombocytopenic purpura, and autoimmune haemolytic anaemia, with comparable efficacy to standard doses and fewer adverse effects.

2. LDR, when used in combination with other therapies, has demonstrated improved outcomes in both patients with relapsed disease and those who are newly diagnosed. LDR combined with eltrombopag or romiplostim has shown enhanced efficacy in immune thrombocytopenia, and its use in combination with dexamethasone in autoimmune haemolytic anaemia has led to high response rates.

3. Despite its promising results, more prospective studies are required to fully establish LDR’s role in the treatment of autoimmune haematological disorders.

INTRODUCTION

Rituximab, a monoclonal anti-CD20 antibody, has become the secondline treatment for autoimmune haematological disorders such as immune thrombocytopenia (ITP), thrombotic thrombocytopenic purpura (TTP), and autoimmune haemolytic anaemia (AIHA).1 Both peripheral and bone marrow B lymphocytes are depleted by rituximab, reducing the autoreactive B cell burden in autoimmune disease.2,3

According to the American Society of Hematology (ASH), the standard dose regimen (SDR) of rituximab is 375 mg/m2 weekly for 4 weeks, originally approved for the treatment of Non-Hodgkin’s lymphoma. This standard dosing approach has achieved a 69% overall response rate (ORR) and a 35% sustained response rate in relapsed or refractory (R/R) ITP. In acute TTP, standard of care (SOC) plus rituximab reduced inpatient stay and relapse.4,5 Relapse-free survival (RFS) was superior after a combined therapy including rituximab in the SDR, rather than monotherapy with steroids in AIHA.

Aiming to reduce rituximab-related adverse events, infusion time, and costs whilst maintaining efficacy, a reduced dosing schedule (100 mg weekly for 4 weeks) has been proposed for autoimmune haematological disorders.6 Therefore, this review explores the evidence supporting the efficacy and safety of low-dose rituximab (LDR) for the treatment of ITP, TTP, and AIHA.

IMMUNE THROMBOCYTOPENIA

ITP is characterised by isolated thrombocytopenia due to autoantibodymediated platelet destruction in the spleen and liver.7 Notably, children with ITP tend to experience spontaneous remission within months. On the contrary, up to 70% of adults diagnosed with ITP will continue to have a chronic condition with recurrence and will require further therapy lines.8 The goal of therapy is to prevent bleeding through immunomodulation of the pathological B cells. Although steroids in first-line treatment provide a high initial response, only 30–50% of patients achieve a sustained response (SR).8 LDR in combination with steroids has

demonstrated superior outcomes compared to the latter alone.9 Therefore, LDR is a potential therapy line for patients with relapsed disease.

A small, single-arm study reported an ORR and complete response (CR) rate of 75% and 43%, respectively, in 28 patients with R/R ITP who were treated with LDR. These are comparable rates to the SDR.10 Subsequently, LDR therapy was confirmed to be effective in an additional cohort of 48 patients with previously treated ITP. The ORR and CR were 60.5% and 39.5%, respectively, with an RFS at 24 months of 45%. Of note, relapse was more probable in patients with a higher weight and those who experienced a longer time interval from diagnosis to treatment.11 These Phase II studies demonstrated the utility of LDR as a salvage therapy for ITP, as well as its limitations, such as inefficacy related to body weight. Only one infectious complication was reported.11 Retrospective real-world studies further support the use of LDR in the salvage setting.6,12

In the front-line setting, a single-arm trial evaluated the efficacy and safety of LDR in combination with high-dose (HD) steroids (40 mg dexamethasone daily for 4 consecutive days) in 21 patients with newly diagnosed (ND) ITP. Remarkably, the ORR at Day 28 and the CR at 6 months were 90.5% and 76.2%, respectively. The median duration of CR was 17 months. Only 9.5% of patients presented adverse events, including Grade 1 chills (n=1) and Grade 1 flu-like symptoms (n=1). Notably, no infectious complications were reported either.13 In a recent retrospective study in the same centre, consistent ORR and CR at Day 28 (88.2% and 58.8%, respectively) were reported in an additional group of 17 patients with ND ITP.14 Both of these studies proved the superior efficacy of LDR in ND ITP compared to R/R ITP, which suggests that an ‘all in’ strategy should be used in the front-line setting.

In a 2021 meta-analysis, LDR for ITP was compared to standard dose through 12 studies, which included a total of 869 patients. When compared to the control groups, rituximab improved the ORR, CR,

and sustained response rate without a significant increase of infectious or other adverse events. No statistically significant differences were found between LDR and the SDR in relation to efficacy.15 These results consolidate LDR’s non-inferiority to the SDR. Consequently, an important reduction in costs while maintaining efficacy is attainable. However, the follow-up periods during the individual studies were short (1.0–19.5 months),15 and therefore long-term infectious complications could be underestimated. A long-term follow up of patients treated with the SDR determined the 2-year serious infectious event rate was 11.3 per 100 person-years, especially in older patients with additional comorbidities.16 A large retrospective study of patients diagnosed with rheumatoid arthritis determined that LDR had statistically lower infectious complications.17

Due to the limitations of LDR, a prospective multicentre, open-label, randomised controlled trial was conducted to compare a single administration of the SDR versus LDR in 94 patients with ITP who relapsed or were corticoid-refractory. The efficacy was not different between the regimens regarding ORR or CR. Nonetheless, singledose rituximab resulted in a better healthrelated quality of life and fewer physician visits.18 Trials in paediatric populations have also reported superior benefits from single dosing versus LDR.19 In the future, this regimen may be preferred in some patients for reducing hospital visits. Nonetheless, body weight-related inefficacy has not been described in the single-dose regimen. More research is needed to confirm if this strategy is able to bypass this limitation compared to LDR.

Finally, LDR has been studied in combination with other drug groups. A recent case series of 10 patients with R/R ITP reported the efficacy of eltrombopag in combination with LDR.20 In the front-line setting, 13 patients with ND ITP were included in a single arm, open-label study and received HD dexamethasone, eltrombopag, and LDR, archiving a 100% ORR. The duration of response was 11 months.21 Moreover, the safety and efficacy of romiplostim plus LDR plus HD dexamethasone has

been evaluated in a pilot study including 13 patients with ND ITP. The 1-month ORR and CR reported were 92.3% and 84.6%, respectively.22 These studies prove the improvement in efficacy of thrombopoietin receptor agonists in combination with LDR and HD steroids for both R/R ITP and ND ITP. Likewise, a two-arm randomised clinical trial compared LDR ± all-trans retinoic acid (ATRA) in 168 patients with R/R ITP. The addition of ATRA to LDR resulted in an improvement in ORR (80% versus 59%) and sustained response rates (61% versus 41%). However, the combination groups

demonstrated a higher incidence of adverse events (70.5% versus 53.6%).23 While LDRbased combination therapies are promising, more trials are needed to establish them as part of the SOC for ITP.

In summary, LDR is an efficacious option for patients with R/R ITP and those with ND ITP, with low rates of complications and lower direct costs (Table 1). Nonetheless, the ideal dosing of rituximab should be determined by further exploration in both sets of patients.

Table 1: Selected low-dose rituximab studies in immune thrombocytopenia.

Zaja et al.10

et al.11

El‐Saied et al.12

GómezAlmaguer et al.13

CoronadoAlejandro et al.14

Ni et al.18

Chu et al.20

GómezAlmaguer et al.21

ColungaPedraza et al.22

Wu et al.23

x4 plus

mg/day x 28 plus

mg weekly x6 versus RTX 100 mg weekly x6 plus ATRA 20 mg/m2 daily x12 weeks

Table 1: Selected low-dose rituximab studies in immune thrombocytopenia (Continued).

AE: adverse event; ATRA: all-trans retinoic acid; CR: complete response; ELT: eltrombopag; HD-Dex: high-dose dexamethasone; ND: newly diagnosed; NR: not reported; ORR: overall response rate; Pt: patient; R/R: relapsed or refractory; ROM: romiplostim; RTX: rituximab; vs: versus.

THROMBOTIC THROMBOCYTOPENIC PURPURA

TTP is a thrombotic microangiopathy characterised by the formation of microvascular platelet-rich thrombi, which results in microangiopathic haemolytic anaemia, thrombocytopenia, and endorgan ischaemia.24 Plasma exchange (PEx) is recognised as the first-line treatment in TTP, with rituximab being used preferably in R/R TTP.24 Some studies have assessed the potential of LDR in acute TTP or R/R TTP (Table 2).

In 2013, Pequeño-Luévano et al.27 successfully treated four patients with acute TTP using LDR, PEx, and a short course of steroids with an excellent outcome.27 In another case series, two patients with systemic lupus erythematosus who presented with TTP reported successful therapy with LDR in combination with PEx. Neither had TTP relapses or systemic lupus erythematosus flares within the 24-month follow-up.28 In a third case series of two patients with refractory TTP treated with LDR, the patients had a sustained long-term remission for 19 and 23 months, respectively.29

Table 2: Selected low-dose rituximab studies in thrombotic thrombocytopenic purpura.

Reddy et al.25

Zwicker et al.26

AE: adverse events; CR: complete response; NR: not reported; PR: partial response; Pt: patient; RTX: rituximab; TTP: thrombotic thrombocytopenic purpura.

Reddy et al.25 performed a retrospective analysis over 13 years of 39 patients with TTP who were treated with either 100 mg weekly (2–4 doses) or 375 mg/m2 weekly (2–4 doses). Time to remission from the first rituximab dose was 6 days in patients receiving the standard regime and 5 days in patients treated with LDR (p=0.09). Eleven PEx procedures were performed in the standard dose group versus eight in the low

dose group (p=0.206). Length of stay was shorter in the lower dose group (p=0.023).25

Due to the lack of prospective studies evaluating the efficacy and safety of LDR in the treatment of TTP, a clinical trial was performed by Zwicker et al.26 in 2019. The trial reported that, in patients with acute TTP and ADAMTS13 activity of <10%, LDR along with PEx and corticosteroids was

associated with a significant decrease in the incidence of exacerbation and refractory TTP.26 The results of this study establish that LDR can be used in the immediate treatment of TTP.26

Due to a lack of consistent evidence, more prospective studies evaluating LDR in the context of TTP are needed. With the current evidence, LDR cannot currently be securely integrated into the SOC. Other therapeutic alternatives have recently emerged, such as caplacizumab, a nanobody directed against the A1 domain of von Willebrand factor. This agent, in combination with therapeutic plasma exchange and corticosteroids, has shown to reduce mortality, relapse rates, and therapeutic plasma exchange in patients with TTP, although it may be associated with adverse effects such as mucosal bleeding.30-32 Both caplacizumab and rituximab are complementary agents with potential utility during acute episodes, achieving a more rapid clinical response

when used in combination (14 days) compared to treatment with rituximab alone (24 days).33

AUTOIMMUNE HAEMOLYTIC ANAEMIA

Rituximab has emerged as an alternative treatment in patients with R/R AIHA, milder disease, or a high risk of side effects due to standard dose. To date, steroids have been the first-line treatment option for patients with AIHA. Several studies have analysed other interventions such as rituximab, alemtuzumab, cyclophosphamide, and bortezomib along with steroids. Some studies have even tested LDR in ND warm AIHA (wAIHA)34-37 (Table 3). Standard and low doses of rituximab have shown to improve haemoglobin levels and reduce the need for blood transfusion in these patients.

Table 3: Selected low-dose rituximab studies in autoimmune haemolytic anaemia.

Jaime-Pérez et al.38

Barcellini et al.

Yao et al.37

Table 3: Selected low-dose rituximab studies in autoimmune haemolytic anaemia (Continued).

*No infusion-related adverse events with the rituximab.

†Grade 1 fever after alemtuzumab administration.

‡Subtype not specified.

AE: adverse event; AIHA: autoimmune haemolytic anaemia; ATB: alemtuzumab; BTZ: bortezomib; CP: cyclophosphamide; CR: complete response; Dex: dexamethasone; HD-Dex: high-dose dexamethasone; LowR-BD: low dose rituximab-bortezomib and dexamethasone; NR: not reported; ORR: overall response rate; PRED: prednisone; Pt: patient; RTX: rituximab; wAIHA: warm autoimmune haemolytic anaemia; wAIHA+C: warm autoimmune haemolytic anaemia IgG plus C3d.

A retrospective cohort containing 18 patients with newly diagnosed wAIHA treated with LDR and HD dexamethasone as a front-line therapy reported an RFS at 6, 36, and 72 months of 92.3%, 58.7%, and 44.1%, respectively. All patients achieved a response, and there was no statistical difference in RFS between patients treated with steroids and those treated with LDR plus steroids as a front-line treatment. Eight patients were treated with LDR and HD dexamethasone after the diagnosis of refractory wAIHA. All of the patients achieved a response (three complete responses and five partial responses).38

The GIMEMA study included 308 patients with AIHA, 19 of whom received LDR as a second or third-line therapy. The intervention induced a CR of 100% in patients with wAIHA IgG plus C3d (C3d complement), mixed and atypical. Patients with wAIHA achieved a CR of 80%, followed by a CR of 37.5% and a partial response (PR) of 37.5% in cold agglutinin disease. Predictors of response to LDR were wAIHA, younger age, and a shorter interval of time between the diagnosis and rituximab therapy.39

LDR in combination with alemtuzumab has proven to be safe and capable of inducing an important clinical response in patients with active symptomatic steroid-refractory AIHA. Gómez-Almaguer et al.34 evaluated the safety and efficacy of this combined regimen in refractory AIHA. ORR was 100% and CR was 75%. Patients in this regime had a median duration of response of 46 weeks.34

A monocentric retrospective study including 49 patients with refractory AIHA was performed in 2016, and it compared the

efficacy of intermittent cyclophosphamide IV plus steroids in one group, as well as LDR plus steroids in a second group. Patients receiving intermittent cyclophosphamide IV plus steroids achieved an ORR of 92.5% and a CR of 37%. Patients in the LDR plus steroids group achieved an ORR of 100% and a CR of 50%. LDR treatment seemed to have a quicker and greater effect on the patients than cyclophosphamide.36

In 2022, a retrospective study with seven patients evaluated the efficacy of LDR with dexamethasone and bortezomib to treat wAIHA. The ORR was 85.71%, with a PR of 57.41% and a CR of 28.75%. They demonstrated that LDR combined with bortezomib and dexamethasone is effective and relatively safe in patients with wAIHA.37

Given the lack of standardisation of the rituximab doses to be used in autoimmune diseases such as AIHA, Moser et al.40 performed a Phase II open-label trial in 2024 that investigated the effects and safety of “very” LDR, which range from 5 mg/m2 to 100 mg in patients with AIHA. Rituximab doses as low as 5 mg/ m2 transiently depleted CD20+ cells in almost all patients, but the tested low-dose regimens failed to permanently suppress CD20+ cells.40

In 2021, a Phase II single-arm trial including 23 patients evaluated oral prednisone plus LDR as a first-line therapy in ND wAIHA and CAD, and as a second-line therapy in wAIHA that had relapsed after standard oral prednisone. Patients with wAIHA accomplished an SR of 100%, a CR of 69.2%, and a PR of 20.8% at 12 months, as well as a relapse rate of 0%. In CAD, an SR

of 50%, a CR of 16.6%, and a PR of 33.3% were achieved, with a relapse rate of 33.3% at 12 months. This study concluded that LDR in addition to a short course of steroid therapy is a safe and effective treatment, particularly in wAIHA and in patients with newly diagnosed disease. Nonetheless, in CAD, the risk of relapse was higher.35 A 10 year follow-up update reaffirmed the efficacy and safety of LDR in primary AIHA as a short-term response and long-term outcome. It was demonstrated that LDR is more effective and leads to an SR in wAIHA compared to CAD.41

CONCLUSION

LDR is an effective treatment in both frontline and salvage settings in autoimmune haematological diseases. Few adverse events are related to LDR, with very low infectious complications.

References

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2. Vieira CA et al. Rituximab for reduction of anti-HLA antibodies in patients awaiting renal transplantation. Transplantation. 2004;77(4):542-8.

3. Leandro MJ et al. Bone marrow B-lineage cells in patients with rheumatoid arthritis following rituximab therapy. Rheumatology. 2007;46(1):29-36.

4. Medeot M et al. Rituximab therapy in adult patients with relapsed or refractory immune thrombocytopenic purpura: long-term follow-up results. Eur J Haematol. 2008;81(3):165-9.

5. Scully M et al. A phase 2 study of the safety and efficacy of rituximab with plasma exchange in acute acquired thrombotic thrombocytopenic purpura. Blood. 2011;118(7):1746-53.

6. Provan D et al. Activity and safety profile of low-dose rituximab for the treatment of autoimmune cytopenias in adults. Haematologica. 2007;92(12):1695-8.

7. Cooper N, Ghanima W. Immune Thrombocytopenia. N Engl J Med. 2019;381(10):945-55.

8. Mithoowani S et al. High-dose dexamethasone compared with prednisone for previously untreated

Furthermore, LDR has been safely added to combination regimens. In the future, LDR may be established as a relevant option for front-line treatment in both haematological42 and not-haematological immune-mediated pathologies.43 Nevertheless, as exemplified by TTP, more trials are needed before it can be safely integrated into clinical practice. Currently, studies with small samples predominate, and thus cannot powerfully determine how LDR could fit into the SOC. Clinically relevant questions, such as whether LDR reduces the incidence of late-onset neutropenia or decreases the need for intravenous or subcutaneous Ig, remain unanswered due to limited evidence, and warrant further investigation. Future research, with greater sample sizes and controlled designs, should focus on the specific patient subgroups that could benefit the most from LDR combinations.

primary immune thrombocytopenia: a systematic review and meta-analysis. Lancet Haematol. 2016;3(10):e489-96.

9. Li Z et al. Low-dose rituximab combined with short-term glucocorticoids up-regulates Treg cell levels in patients with immune thrombocytopenia. Int J Hematol. 2011;93(1):91-8.

10. Zaja F et al. Lower dose rituximab is active in adults patients with idiopathic thrombocytopenic purpura. Haematologica. 2008;93(6):930-3.

11. Zaja F et al. Low‐dose rituximab in adult patients with primary immune thrombocytopenia. Eur J Haematol. 2010;85(4):329-34.

12. El-Saied DG et al. Clinical efficacy of two different doses of rituximab as a treatment option in adult patients with chronic immune thrombocytopenia. Egypt J Intern Med. 2024;36(1):60.

13. Gómez‐Almaguer D et al. High response rate to low‐dose rituximab plus high‐dose dexamethasone as frontline therapy in adult patients with primary immune thrombocytopenia. Eur J Haematol. 2013;90(6):494-500.

14. Coronado‐Alejandro EU et al. Low‐dose rituximab plus high‐dose dexamethasone in newly diagnosed immune thrombocytopenia. Eur J Haematol. 2023;110(6):778-9.

15. Dong Y et al. The efficacy and safety of different dosages of rituximab for adults with immune thrombocytopenia: A systematic review and meta-analysis. BioMed Res Int. 2021;2021(1):9992086.

16. Stabler S et al. Serious infectious events and immunoglobulin replacement therapy in patients with autoimmune disease receiving rituximab: a retrospective cohort study. Clin Infect Dis. 2021;72(5):727-37.

17. Henry J et al. Doses of rituximab for retreatment in rheumatoid arthritis: influence on maintenance and risk of serious infection. Rheumatology. 2018;57(3):538-47.

18. Ni X et al. Single-dose versus low-dose rituximab in corticosteroid- resistant or relapsed ITP: A multicenter, randomized, controlled study. Am J Hematol. 2022;97(4):440-7.

19. Zhu XJ et al. [Comparison of the efficacy and safety of 2 lowdose rituximab regimens in the second-line treatment of primary immune thrombocytopenia in children]. Zhonghua Er Ke Za Zhi. 2022;60(11):1185-90. (In Chinese).

20. Chu TH et al. Refractory immune thrombocytopenia responding to combination therapy of eltrombopag and low-dose rituximab: a case series. Hematol Transfus Cell Ther. 2024;46(Suppl 5):S299-304.

21. Gómez‐Almaguer D et al. Eltrombopag, low‐dose rituximab, and dexamethasone combination as frontline treatment of newly diagnosed immune thrombocytopaenia. Br J Haematol. 2019;184(2):288-90.

22. Colunga‐Pedraza PR et al. Romiplostim, low‐dose rituximab and high‐dose dexamethasone for newly diagnosed immune thrombocytopenia: a pilot study. Br J Haematol. 2024;DOI: 10.1111/bjh.19923.

23. Wu YJ et al. All-trans retinoic acid plus low-dose rituximab vs low-dose rituximab in corticosteroid-resistant or relapsed ITP. Blood. 2022;139(3):333-42.

24. Sukumar S et al. Thrombotic thrombocytopenic purpura: Pathophysiology, diagnosis, and management. J Clin Med. 2021;10(3):536.

25. Reddy MS et al. Comparison of low fixed dose versus standarddose rituximab to treat thrombotic thrombocytopenic purpura in the acute phase and preemptively during remission. Transfus Apher Sci. 2020;59(6):102885.

26. Zwicker JI et al. Adjuvant lowdose rituximab and plasma exchange for acquired TTP. Blood. 2019;134(13):1106-9.

27. Pequeño-Luévano M et al. Low-dose rituximab for the treatment of acute thrombotic thrombocytopenic purpura: report of four cases. Hematology. 2013;18(4):233-6.

28. Ma W et al. Successful treatment of refractory thrombotic

thrombocytopenic purpura associated with systemic lupus erythematosus with combination of plasma exchange and low-dose rituximab. Lupus. 2020;29(14):1961-7.

29. Tong HY et al. Long-term remission induced by low-dose rituximab for relapsed and refractory thrombotic thrombocytopenic purpura: A report of two cases. Exp Ther Med. 2015;10(6):2295-8.

30. Scully M et al. Caplacizumab treatment for acquired thrombotic thrombocytopenic purpura. N Engl J Med. 2019;380(4):335-46.

31. Coppo P et al. Caplacizumab use in immune-mediated thrombotic thrombocytopenic purpura: an international multicentre retrospective Cohort study (The Capla 1000+ project). EClinicalMedicine. 2025;82:103168.

32. Gómez‐Seguí I et al. Caplacizumab treatment in elderly patients with iTTP: experience from the Spanish TTP Registry. HemaSphere. 2025;9(4):e70109.

33. Izquierdo CP et al. Real-world effectiveness of caplacizumab vs the standard of care in immune thrombotic thrombocytopenic purpura. Blood Adv. 2022;6(24):6219-27.

34. Gómez-Almaguer D et al. Low-dose rituximab and alemtuzumab combination therapy for patients with steroidrefractory autoimmune cytopenias. Blood. 2010;116(23):4783-5.

35. Barcellini W et al. Low-dose rituximab in adult patients with idiopathic autoimmune hemolytic anemia: clinical

efficacy and biologic studies. Blood. 2012;119(16):3691-7.

36. Fu R et al. A monocentric retrospective study comparing pulse cyclophosphamide therapy versus low dose rituximab in the treatment of refractory autoimmune hemolytic anemia in adults. Int J Hematol. 2016;104(4):462-7.

37. Yao M et al. Combination of lowdose rituximab, bortezomib and dexamethasone for the treatment of autoimmune hemolytic anemia. Medicine (Baltimore). 2022;101(4):e28679.

38. Jaime-Pérez JC et al. Treatment of autoimmune hemolytic anemia: real world data from a reference center in Mexico. Blood Res. 2019;54(2):131-6.

39. Barcellini W et al. Clinical heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients. Blood. 2014;124(19):2930-6.

40. Moser MM et al. Very low doses of rituximab in autoimmune hemolytic anemia—an open-label, phase II pilot trial. Front Med. 2024;11:1481333.

41. Fattizzo B et al. Low-dose rituximab in autoimmune hemolytic anemia: 10 years after. Blood. 2019;133(9):996-8.

42. Colunga-Pedraza PR et al. Low-dose rituximab in steroid-refractory chronic graft-versus-host disease. Transpl Immunol. 2023;81:101959.

43. Vannucchi G et al. Efficacy profile and safety of very low-dose rituximab in patients with graves’ orbitopathy. Thyroid. 2021;31(5):821-8.

100 Years of von Willebrand Disease

Authors: *Emmanuel Favaloro,1,2,3 Leonardo Pasalic,1,4 Jennifer Curnow4,5

1. Department of Haematology, Sydney Centres for Thrombosis and Haemostasis, Research and Education Network (REN) and Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Westmead, Australia

2. Faculty of Science and Health, Charles Sturt University, Wagga Wagga, Australia

3. School of Medical Sciences, The University of Sydney, Westmead Hospital, Westmead, Australia

4. Westmead Clinical School, Westmead Hospital, Westmead, Australia

5. Clinical Haematology, Sydney Centres for Thrombosis and Haemostasis, Westmead Hospital, Westmead, Australia

*Correspondence to Emmanuel.Favaloro@health.nsw.gov.au

Disclosure: The authors have declared no conflicts of interest.

Acknowledgements

Favaloro wrote the original draft of the manuscript, which was then revised according to input from all other contributors; all authors approved the manuscript for submission and publication.

Disclaimer The opinions expressed in this manuscript are those of the authors, and not necessarily those of our affiliated institutions. Data availability statement: no new data was generated in this review that is not already available in the scientific literature.

Received: 15.04.25

Accepted: 28.05.25

Keywords: Haemophilia, von Willebrand disease (VWD), von Willebrand factor (VWF).

Citation: EMJ Hematol. 2025;13[1]:109-120. https://doi.org/10.33590/emjhematol/LFUM3909.

Abstract

von Willebrand disease (VWD) is considered the most common inherited bleeding disorder, even surpassing haemophilia A. Nevertheless, VWD may be underdiagnosed, overdiagnosed, or misdiagnosed, depending on the expertise of the managing clinician and the testing laboratory. This is due to the heterogeneity of VWD and the complexities of laboratory assessment. For example, in haemophilia, there is a deficiency or defect in a single clotting factor, either factor VIII or factor IX, for haemophilia A and B, respectively. In contrast, at least six types can be identified in VWD, classified according to the defect and/or deficiency in the plasma protein von Willebrand factor. von Willebrand factor has numerous functions, most of which can be assessed by laboratory testing. However, unlike haemophilia, a battery of laboratory tests is required to enable a diagnosis or exclusion of VWD, as well as its type classification. This complexity is not well understood by many clinicians or scientists. VWD was first described by Erik von Willebrand in 1926, and so 2025 represents 100 years of VWD. The authors review some of the history of VWD, as well as outlining the current state of play for diagnosis and treatment.

Key Points

1. von Willebrand disease (VWD) is the most common inherited bleeding disorder, and is caused by a deficiency of, or defect in, the adhesive plasma protein von Willebrand factor.

2. The first case of VWD was published in 1926, making 2025 its 100-year anniversary.

3. This review briefly describes the history of and summarises current strategies for VWD diagnosis and management.

INTRODUCTION

von Willebrand disease (VWD) is considered to be the most common inherited bleeding disorder, even surpassing haemophilia A. The estimated prevalence of haemophilia A, a sex-linked condition, is around one in 5,000 males, or around one in 10,000 people.1 The estimated prevalence of VWD is less clear. Using epidemiological data, or estimates based on patients providing test results potentially consistent with VWD, the estimated prevalence of VWD would be around one in 100 people (or up to 1% of the population).2,3 However, based on data reported to the World Federation for Hemophilia (WFH), the prevalence of VWD would also be around one in 10,000 people.1 Nevertheless, VWD may be underdiagnosed, overdiagnosed, or misdiagnosed, depending on the expertise of the managing clinician and testing laboratory.4 This is due to the heterogeneity of VWD, and to the complexities of laboratory assessment.

In haemophilia, there is a deficiency or defect in a single clotting factor, either factor VIII (FVIII) or factor IX (FIX), for haemophilia A and B, respectively. Accordingly, laboratories are in general able to assess for these clotting factors, or their deficiency, using standard haemostasis assays (typically one-stage assays, and occasionally chromogenic assays) on automated haemostasis analysers.5 Therefore, at least in developed countries, the reported number of haemophilia cases is close to 100% of the expected prevalence (Figure 1A). Nevertheless, in less developed countries, the reported number of haemophilia cases may be well below the expected prevalence.

In contrast to haemophilia, the divide in reported prevalence of VWD according to geographic jurisdiction is even more disparate.6 In most developed countries, the number of reported cases of haemophilia and VWD is similar (Figure 1B), resulting in an expected ratio of haemophilia/VWD of close to one (Figure 1C). However, this ratio exceeds 100 in some developing countries (Figure 1C), meaning that VWD is predominantly undiagnosed or potentially misdiagnosed in those countries. On the other hand, in some countries, the reported prevalence of VWD is higher than expected (Figure 1C), raising the possibility of overdiagnosis. Alternatively, this may reflect more accurate data collection, thereby again raising the possibility of underdiagnosis in other countries.

At least six types of VWD can be identified, with these classified according to the defect and/or deficiency in the plasma protein von Willebrand factor (VWF).7 However, VWD is conventionally divided into three major types: 1, 2, and 3. Type 1 VWD represents a deficiency of VWF, and thus is a quantitative disorder. The VWF that is present in plasma, albeit in reduced quantity, has similar function to that in individuals without the disease (i.e., Type 1 VWD does not generally represent a qualitative defect; a potential exception is a subtype subject to higher plasma clearance). Type 2 VWD is represented by qualitative defects in VWF, and thus represents qualitative disorders. VWF has numerous functions, most of which can be assessed by laboratory testing. Type 2 VWD is subclassified into four (sub) types: loss of high molecular weight (HMW) VWF (Type 2A VWD); heightened VWF activity leading to the clearance of HMW VWF and platelets from circulation (Type

Figure 1: Geographical disparities in reporting cases of haemophilia and von Willebrand disease.

Data from WFH1 (Figures A, B, C) and Favaloro 20112 (Figure D)

(A) Geographical disparities in reporting cases of haemophilia. Close to 100% of estimated haemophilia cases are reported to the WFH from developed countries. Haemophilia cases seem to be underreported in some (e.g., developing) countries.

(B) Geographical disparities in reporting cases of haemophilia and VWD. Similar numbers of haemophilia and VWD are reported in most developed countries. Much fewer VWD cases than haemophilia cases appear to be reported in some (e.g., developing) countries.

(C) Data as per figure B, reported as cases per million population. Considering similar prevalence, the ratio of H/ VWD should be close to one, which is the case for most developed countries. However, in some (e.g., developing) countries, the ratio exceeds 100, indicating a considerable underdiagnosis of VWD.

(D) Geographical disparity in VWD type diagnosis. Type 1 VWD is the most prevalent or reported VWD type in developed countries, and Type 3 VWD the least. In many developing countries, the situation is reversed, with Type 3 VWD the most prevalent or reported VWD type, and Type 1 VWD the least.

H/VWD: haemophilia/von Willebrand disease; WFH: World Federation of Haemophilia; VWD: von Willebrand disease.

Türkiye

2B VWD); loss of VWF ability to bind to FVIII, leading to clearance of FVIII from circulation (Type 2N VWD); and finally reduced VWF activity not associated to any of the above (Type 2M VWD). Type 3 VWD is the most severe, but globally the rarest form of VWD. It is characterised by a total deficiency of VWF production. Not only is there a geographic disparity in VWD versus haemophilia diagnosis, but there is also a geographic disparity in VWD subtype diagnosis (Figure 1D), with Type 1 and Type 3 VWD representing more straightforward to identify compared to Type 2 VWD. Type 1 VWD is the most commonly identified type, especially in developed countries,2 although it is also subject to overdiagnosis. In developed countries, the reported prevalence of Type 3 VWD is around one in one million people. In contrast, Type 3 VWD is often the predominant VWD type diagnosed in developing countries.2 This disparity may be due to an increased prevalence of Type 3 VWD in these countries, perhaps resulting from more frequent consanguineous relationships. Furthermore, since this type is the most severe, patients with Type 3 VWD are most likely to seek medical attention. Type 2 VWD is variously reported, as these diagnoses require multiple laboratory investigations, which are not always available in some countries.6

In summary, unlike haemophilia, a battery of laboratory tests is required to enable a correct diagnosis or exclusion of VWD, as well as to enable effective type classification.8,9 This complexity is not well understood by many clinicians or scientists. VWD was first described by Erik von Willebrand in 1926,10 and so 2025 represents 100 years of VWD. The authors review some of the history of VWD, and outline the current state of play for diagnosis and treatment.

A SHORT HISTORY OF VON WILLEBRAND DISEASE DIAGNOSIS

As noted, VWD was first described by Erik von Willebrand in 1926,10 although he termed it ‘hereditary pseudo-haemophilia’. He described an index case of a 5-yearold female he first assessed in April 1924,

as well as an investigation of her extended family. The patient was admitted to hospital for investigation of severe bleeding from her nose and gums. Her parents were cousins, and there was a positive bleeding history within the family.11 Her siblings had a bleeding history, and three had died from gastrointestinal bleeds. In contrast to haemophilia, both sexes were affected, and mucosal bleeding represented the predominant symptom. A prolonged bleeding time with a normal platelet count was the most important laboratory abnormality identified, suggesting a functional disorder of the platelets associated with a systemic lesion of the vessel wall. Naturally, at that time, no tests for VWF or its many activities were available.

In the 1950s, after preliminary methods were established to measure FVIII (then called anti-haemophilic factor), several clinicians described patients of both sexes who had prolonged bleeding times associated with reduced FVIII.11 These investigators proposed that these patients were deficient in a factor other than that responsible for classic haemophilia A. It was not until 1971 that it was understood that the deficiency of a new factor, later recognised to be VWF, and different from FVIII, was actually responsible for the disease.11

An antiserum against a highly purified preparation of FVIII was developed by Zimmerman’s group in the early 1970s, and then used to identify this new plasma protein using an immunochemical technique.12 This protein, initially named FVIII-related antigen, and later understood to be VWF antigen (VWF:Ag), was present in individuals without the disease and in those with haemophilia A, but was lacking in patients with VWD. This immunologic technique became the cornerstone of laboratory testing that was able to distinguish patients and carriers of haemophilia from those with VWD.12 Around the same time, Howard and Firkin observed that an antibiotic called ‘ristocetin’ caused platelet agglutination in platelet-rich plasma from individuals without disease, but not in the platelet-rich plasma of patients with VWD.13 This ristocetin effect could be linked to the presence of the FVIII-related

antigen (i.e., VWF:Ag). This development led to the subsequent use of the ristocetininduced platelet agglutination/aggregation assay, as well as a quantitative assay for VWF activity called ristocetin cofactor (VWF:RCo).13,14 The dual application of these VWF:Ag and VWF:RCo assays using the plasma of patients with VWD permitted the identification of different VWD types during the late 1970s, in various countries, and by various workers in the emerging field of VWD diagnosis.11

In the early 1980s, Ruggeri and Zimmerman reported a pivotal observation of abnormal multimeric structure of VWF in different VWD variants.15 Many laboratories have since used this technique, as well as developing various improvements, to identify additional VWD variants characterised by the loss of HMW VWF multimers and abnormal VWF structure. The VWF gene was cloned in 1985, which led to increasing understanding of the molecular basis of VWD.11,16,17 In 1994, Sadler published the initial VWD classification, where Type 2 was divided into the four categories that are still used today: 2A, 2B, 2M, and 2N.18

Also in the 1980s came the development of additional VWF activity assays to supplement the original VWF:RCo assay. In 1986, Brown and Bosak first described the original VWF collagen binding assay (VWF:CB),19,20 and in 1989, an assay to identify Type 2N VWD was first described; this being the VWF FVIII binding (VWF:FVIIIB) assay.21

In the 1990s, the discovery of the VWF cleaving protease, ADAMTS13, was made.22,23 The authors can probably fasttrack here to the new millennium, the 2000’s, where further refinements were made to various VWF activity assays, as well as to the standard VWF:Ag and VWF:RCo assays.24 First, VWF:Ag assays moved from immunological gel based procedures (time-consuming, complex, and unsuited to high throughput) to ELISA, permitting large-scale testing or patient screening. They then advanced to latex immunoassays (LIA) on automated haemostasis analysers, which now represents the predominant VWF:Ag

methodology. Similarly, VWF:RCo moved from initial visual platelet agglutination to semi-automated methods using platelet aggregometers, and then to modern methods using automated haemostasis analysers. In addition, the standard VWF:RCo assay, using platelets, usually fixed or lyophilised, has morphed into more modern alternatives using inert particles (latex or magnetic beads) and recombinant glycoprotein Ib (GPIb), this being the platelet VWF receptor responsible for platelet agglutination/aggregation in the presence of ristocetin. These newer assays are called ‘VWF:GPIbR’ (R for recombinant), and can be run like LIA on automated haemostasis analysers, as well as by chemiluminescence immunoassay on an instrument called the AcuStar® (Werfen, Barcelona, Spain). Finally, a newer VWF activity assay uses gain-of-function GPIb mutations to enable agglutination of latex particles without the need for ristocetin. This assay, called ‘VWF:GPIbM’ (M for mutant recombinant), can also be run like LIA on automated haemostasis analysers.

The 2000s and 2010s also saw the development and refinement of standardised bleeding assessment tools to enable qualification and quantification of bleeding symptoms, which provide a clinical aid in assessing bleeding severity or risk.25-27

A SHORT HISTORY OF VON WILLEBRAND DISEASE MANAGEMENT

Needless to say, the management of VWD has similarly seen quite an evolution over the past 100 years. There was really no suitable treatment available for VWD until 1956, when a plasma fraction called ‘I-O’ was prepared by Blombäck and Blombäck.28 This fraction was able to correct both FVIII and bleeding time defects. A second advance was made when Pool and Robinson were able to demonstrate that a cold fraction of plasma cryoprecipitate contained anti-haemophilic factor, and could correct the bleeding defects in both haemophilia A and VWD.29 Cryoprecipitate was easily prepared by blood banks, and was thence extensively used for management of VWD, because it provided

large amounts of VWF without causing volume overload. Cryoprecipitate may still be used in some countries worldwide, where specific VWF concentrates are not yet available, and remains on the WHO listing of essential medicines.30 However, a major disadvantage of cryoprecipitate is that virucidal methods cannot be applied to it, so it carries a small but real risk of transmitting blood-borne infections.31,32

In 1977, Mannucci et al.33 pioneered the use of desmopressin (DDAVP) into clinical practice, following the earlier work of Cash et al.34 DDAVP was effective in achieving haemostasis in patients with mild haemophilia and VWD who were undergoing surgery, without major side effects. The use of DDAVP can, in some circumstances, avoid the use of VWF/FVIII concentrates, and probably prevented many cases of viral infection in the early 1980s.11

The development of clotting factor concentrates became increasingly successful, providing increasing purity and safety, with various virucidal methods applied. Therefore, virus-inactivated FVIII/ VWF concentrates, originally developed for the treatment of haemophilia A, played increasingly important roles in the management of patients with VWD who were unresponsive to DDAVP. The first pasteurised FVIII/VWF concentrate, Haemate-P/Humate-P, became available in Germany in 1981.11 Many additional FVIII/VWF concentrates have since been developed. Using various purification and viral inactivation processes, all current FVIII/VWF concentrates are effective for VWD management. However, individual concentrates may differ in terms of relative levels of FVIII and VWF, as well as in their retention of HMW VWF.35 Indeed, some VWF concentrates are virtually devoid of FVIII, whereas other concentrates have similar proportions of FVIII and VWF. In 2025, these can be variously applied to different types of VWD, or at different periods of their management, according to the concept of personalised management.35,36

Another major advance in VWD management was the development and availability of a recombinant VWF concentrate.37 This

concentrate does not contain FVIII, but expresses high levels of HMW VWF, since the material has never been exposed to ADAMTS13. Its use can be applied with or without additional (recombinant) FVIII, depending on VWD type and the clinical situation, again according to the concept of personalised management.35,36

There are additional (adjunct) therapies that may also be applied to individuals with VWD, as detailed in the section ‘MANAGEMENT OF VON WILLEBRAND DISEASE IN 2025’, as well as elsewhere.35

DIAGNOSIS OF VON WILLEBRAND DISEASE IN 2025

The diagnosis of VWD requires both clinical assessment and laboratory testing.8,9 For clinical evaluation, a physical evaluation is required, especially to assess for bruising, and a clinical history for the patient and extended family taken. The clinical history can be obtained using structured tools such as a bleeding assessment tool, or via standard consultation.

In 2025, well-equipped laboratories have an armamentarium of tools to assist the diagnosis or exclusion of VWD, as well as its correct classification.38,39 The main assays in use for this purpose are summarised in Table 1. Not all tests need to be performed on all patients under investigation for VWD. It is usual to start with a set of VWD ‘screening’ assays, namely FVIII:C, VWF:Ag, and one of the VWF GPIb binding (VWF:GPIbB) activity assays (i.e., VWF:RCo, VWF:GPIbR, or VWF:GPIbM).8,9 If all three tests are normal, and if the ratio of VWF:GPIbB/Ag is >0.7, then VWD can be excluded with a high degree of confidence. If all three tests are normal, but the ratio of VWF:GPIbB/Ag is <0.7, then Type 2 VWD cannot be excluded, and the patient should be further investigated.

If one or more of the three tests are abnormal, but the ratio of VWF:GPIbB/Ag is still >0.7, then Type 1 VWD is possible. If one or more of the three tests are abnormal, but the ratio of VWF:GPIbB/Ag is <0.7, then Type 2 VWD is possible. If one or more of the three tests are abnormal,

Table 1: Summary of the main tests used to diagnose/exclude von Willebrand disease.

Test

Factor VIII coagulant activity

VWF antigen

VWF glycoprotein Ib binding activity

VWF ristocetin cofactor

VWF GPIb binding using recombinant GPIb

VWF GPIb binding using recombinant mutated GPIb

VWF collagen binding activity

VWF factor VIII binding activity

Ristocetin induced platelet aggregation/ agglutination

VWF multimers

What the test measures

The level of functional FVIII. Usually by one stage clotting assay based on a modified APTT; sometimes by chromogenic assay (several manufacturers/suppliers).

The level of VWF (both functional and not). Historically by ELISA, now mostly by LIA (several manufacturers/suppliers); sometimes by CLIA (one manufacturer/supplier).

Various methods (see below).

A VWF:GPIbB performed using platelets and ristocetin to measure platelet agglutination (several manufacturers/suppliers). Historically, the original VWF activity assay.

A VWF:GPIbB performed using latex or magnetic particles, recombinant GPIb, plus ristocetin to respectively measure latex agglutination or chemiluminescence based events (one manufacturer/supplier). A modern alternative to VWF:RCo.

A VWF:GPIbB performed using latex (commercial method; one manufacturer/supplier) or ELISA (not yet commercialised), recombinant mutated gain of function GPIb (but no ristocetin) to respectively measure latex agglutination or ELISA colour generation. Another modern alternative to VWF:RCo.

Primarily performed by ELISA (a large number of manufacturers/suppliers), and increasingly by CLIA (one manufacturer/supplier).

Primarily performed by ELISA (one manufacturer/supplier; or using in house/laboratory developed methods).

Performed by platelet agglutination/aggregation (one manufacturer of ristocetin, but distributed by several suppliers).

Performed by agarose gel electrophoresis (one commercial semi-automated method; otherwise in house/laboratory developed methods).

APTT: activated partial thromboplastin time; CLIA: chemiluminescence immunoassay; FVIII:C: factor VIII coagulant activity; GPIb: glycoprotein Ib; LIA: latex immunoassay; RIPA: ristocetin induced platelet aggregation/agglutination; VWF: von Willebrand factor; VWF:Ag: von Willebrand factor antigen; VWF:CB: von Willebrand factor collagen binding activity; VWF:FVIIIB: von Willebrand factor VIII binding activity; VWF:GPIbB: von Willebrand factor glycoprotein Ib binding activity; VWF:GPIbM: von Willebrand factor glycoprotein Ib binding using recombinant mutated glycoprotein Ib; VWF:GPIbR: von Willebrand factor glycoprotein Ib binding using recombinant glycoprotein Ib; VWF:mult: von Willebrand factor multimers; VWF:RCo: von Willebrand factor ristocetin cofactor.

but the ratio of FVIII:C/VWF:Ag is <0.7, then Type 2N VWD is possible, although haemophilia A or a preanalytical issue is perhaps more likely. In any of these cases, additional investigation is required. In the case of possible Type 1 VWD, clinical history is key, since the new international guidelines suggest a diagnosis of Type 1 VWD in the case of VWF test results <30U/dL (or %), or where VWF test results are 30–50U/dL (or %) with a positive clinical history of bleeding. In these patients, it is

also usual to repeat the basic test panel for confirmation, as VWF levels may fluctuate for a variety of reasons, for example, increasing during times of stress or after exercise. In the case of possible Type 2N VWD, this can be confirmed using the VWF:FVIIIB assay or genetic analysis of the VWF gene.8,9 Alternatively, repeat testing can be performed to exclude a preanalytical issue, given that FVIII is a labile coagulation factor and degrades quickly in plasma post-collection, or after plasma freeze-

thaw events. Haemophilia A and Type 2N VWD should be distinguished, as different therapies are applied (FVIII concentrate for haemophilia A; VWF concentrate in Type 2N VWD). Clinical history, including family history and sex-linkage, will be useful to help distinguish them.

In cases where VWF:GPIB/Ag are <0.7, irrespective of whether the VWF tests themselves are normal or low, then Type 2A, 2B, or 2M is possible, as is the possibility of platelet type (PT) VWD, albeit rare.8,9 In these cases, clinical history is again important, as the presence of a family history suggests a congenital disorder, whereas a short personal history of bleeding/bruising, without a family history, may suggest an acquired condition. If VWF test results are normal, but VWF:GPIB/Ag is <0.7, then acquired VWD, Type 2B, or PT VWD are more likely than Type 2A or 2M VWD. If one or more VWF test results are abnormal, with VWF:GPIB/Ag <0.7, then Type 2A and 2M VWD are likely. In any of these situations, additional VWF tests are required for proper classification. In the case of possible Type 2B or PT VWD, the authors would reflex first to ristocetin-induced platelet aggregation (RIPA) assessment (with RIPA mixing if indicated), perform VWF:CB testing, and, only if required, conduct VWF multimer assessment.6,38,39 In the case of possible Type 2A or 2M VWD, the authors would still reflex first to RIPA assessment to exclude Type 2B or PT VWD, perform VWF:CB testing, and perform VWF multimer assessment to distinguish Type 2A from 2M VWD.

A flowchart of the authors’ diagnostic algorithm is provided in Figure 2. This algorithm differs from that recommended by the international guidelines,8,9 in that the authors employ the VWF:CB assay as a frontline assay, because they have previously identified several patients with VWD, especially those with Type 2M VWD,40 who would have been missed based on the standard three-test panel currently recommended by the international guidelines. This occurs due to assay variability and since VWF:GPIbB/Ag ratios are sometimes normal (i.e., >0.7) in Type 2M VWD.

MANAGEMENT OF VON WILLEBRAND DISEASE IN 2025

The authors have previously outlined their management approach for VWD.35,41 In brief, they would undertake a DDAVP trial for most patients with VWD to assess effectiveness, as this differs on a patient-by-patient basis. In the authors’ geographic locality, recombinant VWF is not available, and so they would apply their locally available VWF/FVIII concentrate, which is Biostate® (CSL Behring, Broadmeadows, Australia) as required based on the patient’s VWD type and situation. Additional therapies, including hormonal agents, and the anti-fibrinolytic agent tranexamic acid, may be used in select situations. The authors’ approach would be similar to that applied in other geographic locations, although Biostate will be substituted with recombinant VWF, or other locally available VWF/FVIII concentrates. In some locations, nasal DDAVP is available, and in others, aminocaproic acid may be used in place of tranexamic acid.

WHY DOES VON WILLEBRAND DISEASE REMAIN UNDERDIAGNOSED, OVERDIAGNOSED, AND MISDIAGNOSED IN 2025?

So, given the armamentarium of tests available to everyone in 2025, why is VWD still underdiagnosed, overdiagnosed, or misdiagnosed in 2025? Underdiagnosis is the most likely scenario.4 As indicated in the introduction, VWD is underdiagnosed in many countries (Figure 1), most likely because incomplete test panels are employed (e.g., only FVIII:C or VWF:Ag; or only FVIII:C and VWF:Ag). VWD, in particular Type 2 VWD or Type 2B or PT VWD, may be underdiagnosed because in many cases, VWF tests results are in the normal range. The clue for these may be the reduced VWF:GPIbB/Ag ratio, but its significance missed.

Misdiagnosis of VWD is the second most common scenario.4 Type 3 VWD is sometimes misdiagnosed as haemophilia A. This will occur when patients are only assessed for FVIII:C, and VWF testing is

Figure 2: Algorithmic approaches to von Willebrand disease diagnosis or exclusion.

Initial test panel

FVIII:C + VWF:Ag + VWF:CB + VWF:GPIbB*

Low VWF with VWF:CB/Ag and VWF:GPIbB*/Ag both ≥0.6

Type 1 VWD (VWF:Ag <30U/dL) or ‘low VWF’ (VWF:Ag 30–50U/dL)

VWF:CB/Ag and/or VWF:GPIbB* /Ag <0.6

Type 2A, 2B, 2M, or PT-VWD

All normal Not VWD

Undetectable VWF:Ag (very low VWF:CB, VWF:GPIbB*, FVIII:C)

Type 3 VWD

Normal or reduced response

RIPA Enhanced response

2A or 2M VWD

2B or PT-VWD

Disproportional low FVIII:C (FVIII:C/VWF:Ag <0.7)

Distinguish: haemophilia A versus 2N VWD

VWF:FVIIIB and/or genetic testing (VWF & F8)

VWF Multimers

RIPA mixing and/or genetic testing (VWF & GPIB)

Loss HMW VWF - 2A No ‘significant’ loss HMW VWF - 2M†

* VWF:GPIbB = GPIb binding = VWF:RCo or VWF:GPIbR or VWF:GPIbM

† usually VWF:GPIbB*/Ag <0.6 but VWF:CB/Ag ≥0.6 (2MGPIb)

Sometimes VWF:CB/Ag <0.6 and VWF:GPIbB*/Ag ≥0.6 (2MCB )

Sometimes VWF:CB/Ag and VWF:GPIbB*/Ag both <0.6 (2M)

Figure 2: Algorithmic approaches to von Willebrand disease diagnosis or exclusion. (Continued)

Initial test panel

FVIII:C + VWF:Ag + VWF:GPIbB‡

Low VWF:Ag and low VWF:GPIbB, with VWF:GPIbB*/Ag ≥0.6

All normal Not VWD**

VWF:Ag & VWF:GPIbB* <5U/dL, FVIII:C <10U/dL

Type 1 VWD (VWF:Ag <30U/dL)** or ‘low VWF’ (VWF:Ag 30–50U/dL)**

Low VWF:GPIbB* and/or low VWF:GPIbB/Ag ratio (<0.6)

Type 3 VWD

Disproportional low FVIII:C (FVIII:C/VWF:Ag <0.7)

Type 2A, 2B, 2M, or PT-VWD**

RIPA

Normal or reduced response

2A or 2M VWD

VWF:CB and/or VWF Multimers

Enhanced response

2B or PT-VWD

Distinguish: haemophilia A versus 2N VWD

VWF:FVIIIB and/or genetic testing (VWF & F8)

RIPA mixing and/or genetic testing (VWF & GPIB)

Loss HMW VWF - 2A; no ‘significant’ loss HMW VWF - 2M; assess VWF:CB/Ag§

‡ VWF:GPIbB (GPIb binding; VWF:RCo or VWF:GPIbR or VWF:GPIbM)

§ repeat using fresh sample for confirmation (if relevant, exclude artifactual increase in VWF due to inflammation, infection, anxiety, stress, pregnancy)

**for 2M: usually VWF:GPIbB*/Ag <0.6 but VWF:CB/Ag ≥0.6 (2MGPIb)

Sometimes VWF:CB/Ag <0.6 and VWF:GPIbB*/Ag ≥0.6 (2MCB )

Sometimes VWF:CB/Ag and VWF:GPIbB*/Ag both <0.6 (2M)

A) The approach taken in the authors’ laboratory using an initial 4-test panel. B) A potential alternative approach where laboratories are restricted to use of an initial 3-test panel.

*VWF:GPIbB = GPIb binding = VWF:RCo or VWF:GPIbR or VWF:GPIbM

†Usually VWF:GPIbB*/Ag <0.6 but VWF:CB/Ag ≥0.6 (2MGPIb); sometimes VWF:CB/Ag <0.6 and VWF:GPIbB*/Ag ≥0.6 (2MCB); sometimes VWF:CB/Ag and VWF:GPIbB*/Ag both <0.6 (2M)

‡VWF:GPIbB (GPIb binding; VWF:RCo or VWF:GPIbR or VWF:GPIbM)

§Repeat using fresh sample for confirmation (if relevant, exclude artifactual increase in VWF due to inflammation, infection, anxiety, stress, pregnancy)

**For 2M: usually VWF:GPIbB*/Ag <0.6 but VWF:CB/Ag ≥0.6 (2MGPIb); sometimes VWF:CB/Ag <0.6 and VWF:GPIbB*/ Ag ≥0.6 (2MCB); sometimes VWF:CB/Ag and VWF:GPIbB*/Ag both <0.6 (2M)

FVIII:C: factor VIII coagulant activity; GPIb: glycoprotein Ib; HMW VWF: high molecular weight von Willebrand factor; PT-VWD: platelet type von Willebrand disease; RIPA: ristocetin induced platelet aggregation/agglutination; VWF: von Willebrand factor; VWF:Ag: von Willebrand factor antigen; VWF:CB: von Willebrand factor collagen binding activity; VWF:FVIIIB: von Willebrand factor VIII binding activity; VWF:GPIbB: von Willebrand factor glycoprotein Ib binding activity; VWF:GPIbM: von Willebrand factor glycoprotein Ib binding using recombinant mutated glycoprotein Ib; VWF:GPIbR: von Willebrand factor glycoprotein Ib binding using recombinant glycoprotein Ib; VWF:mult: von Willebrand factor multimers; VWF:RCo: von Willebrand factor ristocetin cofactor; VWD: von Willebrand disease.

Adapted from Favaloro and Pasalic6

not performed. Type 2N VWD is also often misdiagnosed as haemophilia A. This is because haemophilia A is more common than Type 2N VWD, and the possibility of 2N VWD is not considered, especially in male patients. In particular, access to genetic testing for the VWF gene or to the VWF:FVIIIB assay is not readily available, especially in developing countries.6

Overdiagnosis of VWD is also possible, especially for Type 1 VWD. A reduced level of VWF does not, on its own, confirm a diagnosis of VWD; there also needs to be a positive clinical history.8 Incorrect diagnosis of VWD can also occur due to preanalytical issues, which may yield false low levels of VWF.42 Here, repeat testing for confirmation is critical. Individuals with blood group O have lower levels of VWF than those non-blood group O, and are therefore at greater risk of overdiagnosis.4

CONCLUSION

The authors provide an updated and concise review of the diagnosis and management of VWD, with reference also to its preceding history in this, the 100th anniversary of VWD. VWD remains underdiagnosed, overdiagnosed, or misdiagnosed in 2025, due to a variety of factors, including limitations in the test panels used, lack of recognition regarding test patterns, and the limitations of various VWF tests. VWD diagnosis can be improved by education and by increasing the number of tests used for any given patient, including the inclusion of a VWF:CB assay. VWF assays have increasingly improved over the years, including the development of more modern alternatives to VWF:RCo. These refinements will continue to develop over the next 100 years of VWD history. The management of VWD will also improve, as recombinant VWF becomes increasingly deployed worldwide and is used to tailor individual therapy according to the VWD type and clinical situation, under the concept of personalised therapy.

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Synchronous Twin Malignancies in a 32-Year-Old Female: A Rare and Complex Case Report

Authors: *Aniket Mohite,1,2 Sulaxmi Kurade,1 Mahendra Kawedia,1 Satyajit Pawar1

1. Jehangir Hospital, Pune, India

2. Novo Solitaire Care, Pune, India

*Correspondence to lifelineaniket@gmail.com

Disclosure: The authors have declared no conflicts of interest. Written informed consent was taken from the patient prior to the publication of this article.

Received: 01.05.25

Accepted: 30.06.25

Keywords: Breast cancer, synchronous malignancies, thyroid cancer, twin malignancies.

Citation: EMJ Hematol. 2025;13[1]:121-127. https://doi.org/10.33590/emjhematol/MRII7792

Abstract

Synchronous twin malignancies, defined as the simultaneous occurrence of two distinct primary cancers in the same patient, represent a rare and challenging clinical scenario. Synchronous diagnosis of haematological and solid malignancy poses a challenge in treatment planning. This case study details the presentation, diagnosis, treatment, and eventual outcome of a 32-year-old female with acute promyelocytic leukaemia and metastatic non-small cell lung carcinoma. The patient's complex clinical course, including the development of pancytopenia with bleeding manifestations, therapy-related issues, and progressive disease, underscores the need for a high index of suspicion in managing such rare oncological presentations.

Key Points

1. Dual presentations of haematologic and solid tumours remain extremely uncommon. The literature notes dismal outcomes for synchronous acute myeloid leukaemia-solid tumour cases, with a median overall survival of just 3.6–20.0 months.

2. Synchronous acute promyelocytic leukaemia and non-small cell lung carcinoma is extremely rare (≈0.2–1.5%) and is consistently associated with poor prognosis.

3. New or persistent symptoms in a patient with cancer who was treated warrant thorough imaging and molecular testing to detect possible second primaries.

INTRODUCTION

Multiple primary cancers are not an unusual phenomenon in current oncology practice. These are commonly metachronous (more than 6 months between the diagnoses of two malignancies) or less commonly synchronous (within 6 months of the first primary diagnosis).1-3 There are many cancer predisposition syndromes in which the sequential occurrence of different types of primary malignancies has been reported.1-5

There are limited data on synchronous twin malignancies. The simultaneous occurrence of haematologic and solid tumours presents unique diagnostic and therapeutic challenges, often requiring an integrated approach for management.5-12 This case report discusses a rare presentation of synchronous acute promyelocytic leukaemia (APML) and non-small cell lung carcinoma (NSCLC) in a young female, focusing on the clinical complexities and treatment strategies employed.

CASE PRESENTATION

A 32-year-old female, with a medical history notable only for treated tuberculosis with pleural effusion 3 years prior, presented with breathlessness, ecchymotic patches on her skin, and increased per vaginum bleeding lasting 3–4 days. On examination, there was no organomegaly or lymphadenopathy. A complete blood count revealed pancytopenia (complete blood count: 4.8/4,890/8,000, P35L30M35), prompting her admission to the ICU due to signs of heart failure.

Peripheral smear analysis showed the presence of Faggot cells and abnormal promyelocytes, comprising 30–32% of the cell population (Figure 1). The smear tested positive for myeloperoxidase (MPO). While liver and kidney function tests remained normal, her coagulation profile was abnormal, with an activated partial thromboplastin time of 46 seconds (control 33 seconds) and low fibrinogen levels (152 mg/dL).

Figure 1: Bone marrow biopsy showing hypercellular marrow with 80–90% abnormal promyelocytes, with large nuclei, Auer rods, and Faggot cells.

Her BMA/Bx was performed immediately, which revealed hypercellular marrow with 80–90% abnormal promyelocytes, large nuclei, open chromatin, markedly coarse granular cytoplasm (hypergranular) with prominent to inconspicuous nucleoli, a few Auer rods, and a few lobulated nuclei.

Flow: positive for CD38, CD33, CD117, HLA-DR, CD64, and MPO.

BMA: bone marrow aspiration; Bx: biopsy; CD33: cluster of differentiation 33; CD38: cluster of differentiaton 38; CD64: cluster of differentiation 64; CD117: cluster of differentiation 117; HLA-DR: human leucocyte antigen DR; MPO: myeloperoxidase.

Bone marrow aspiration and biopsy indicated hypercellular marrow with 80–90% abnormal promyelocytes characterised by large nuclei, open chromatin, markedly coarse granular cytoplasm (hyper granular) with prominent to inconspicuous nucleoli, and a few Auer rods (Figure 1).

Fluorescence in situ hybridisation confirmed the presence of 98% of cells positive for the

t(15,17) PML-RARA fusion gene, leading to a diagnosis of APML. Initial high-resolution CT and PET-CT scans revealed multiple mildly fluorodeoxyglucose (FDG)-avid patchy areas of ground-glass opacities in both lungs, an FDG-avid nodular lesion in the left upper lobe (2.2 cm), and an FDG-avid mass in the left pre-vascular area (3.2 cm; Figure 2).

Multiple mildly FDG-avid patchy areas of GGOs in both lungs.

FDG-avid nodular enhancing lesion in left upper lobe; 1.2 cm; SUV: 11.

FDG-avid enhancing nodal mass in left prevascular area: 2.2 cm; SUV max: 9 No skeletal lesions.

FDG: fluorodeoxyglucose; GGO: ground-glass opacity; SUV: standardised uptake value.

TREATMENT OF ACUTE PROMYELOCYTIC LEUKAEMIA

She was started on arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) therapy, accompanied by supportive care. She received Lo-coco protocol induction ATO (0.15 mg/kg dose) and ATRA (45 mg/m2) for 45 days, along with posaconazole and valacyclovir prophylaxis for fungal and herpes infection, respectively, from Day 1 of therapy.

The patient tolerated that well, with differentiation syndrome managed with hydroxyurea and dexamethasone. Her bone marrow aspiration and biopsy after morphologically normal complete blood count reports were done after 45 days of ATO + ATRA, and she was in complete remission. She did not have any pseudotumor cerebri with ATRA during the therapy, and her real-time quantitative polymerase chain reaction (RQPCR) for PML RARA was 0.024% at the end of induction.

Figure 2: PET-CT and CT chest at baseline.

DIAGNOSIS OF SYNCHRONOUS MALIGNANCIES

She was started on the Lo-coco consolidation protocol with ATO and ATRA for 28 weeks. While the patient was undergoing consolidation therapy, she developed persistent headaches. Both an MRI of the brain and her cerebrospinal fluid analysis for malignant cells and cytology were normal. ATRA was stopped from Week 8 of consolidation therapy for ATRA-induced pseudotumor, and she was started on acetazolamide tablets. She continued to have a gradually worsening headache despite anti-cerebral oedema measures. Her repeat RQPCR for PML RARA was 0.0%, confirming the disease was in remission.

Given the persistent headaches, MRI of the brain and spine revealed multiple lytic lesions in the cervical spine, suggestive of metastatic disease. A repeat PET-CT scan identified new FDG-avid lesions in the liver and bones, raising suspicion for a second primary malignancy (Figure 3).

CT-guided biopsy of the liver lesion revealed carcinosarcoma with adeno-carcinomatous and sarcomatoid components (Figure 4). Immunohistochemistry confirmed the presence of adenocarcinoma cells positive for CK7, CK19, TTF1, and napsin, with sarcomatous cells positive for vimentin and P53. Genetic profiling by next-generation sequencing detected an EML4-ALK mutation, consistent with NSCLC.

Figure 3: Multiple lytic lesions in the cervical spine with no nerve root or cord compression.

FDG-avid left supra-clavicular node: 2.5 cm; Well-defined FDG-avid left upper lobe lung mass: 2.6 cm; Few small

FDG-avid nodules in both lobes of lung; largest: 1.2 cm; FDG-avid prevascular LN mass: 4.2 cm; FDG-avid lesion in right lobe of liver: 3.2 cm.

Lytic lesions involving skull vault, base of skull, multiple cervical vertebrae, bilateral humerus, left clavicle. Multiple dorsolumbar vertebrae, sacrum, acetabulum suggestive of metastases from possible lung cancer.

FDG: fluorodeoxyglucose; LN: lymph node.

TREATMENT AND DISEASE PROGRESSION

The patient underwent a complex treatment regimen tailored to both malignancies. For APML, she received ATO and ATRA-based induction and consolidation therapies. Due to the development of ATRAinduced pseudotumour cerebri, ATRA was discontinued after 8 weeks of consolidation. Her APML therapy was stopped after diagnosis of NSCLC, as APML was in remission (RQPCR for PML RARA was 0.0%) while she had metastatic NSCLC.

For NSCLC, she received chemotherapy with paclitaxel and carboplatin while the

immunohistochemistry report was awaited for debulking therapy, followed by targeted therapy with alectinib for the ALK-positive mutation. She underwent radiofrequency ablation for the D1 lesion followed by vertebroplasty, and subsequently received external beam radiation therapy to the clivus metastasis (20 Gy/5#), which achieved pain relief.

Repeat PET-CT was suggestive of oligoprogressive disease with reduction of nodal and lung lesion, and a few new bone lesions. She then experienced worsening of back pain, and a repeat MRI was suggestive of multiple metastatic lesions with surrounding marrow oedema involving

Figure 4: PET-CT showing extensive disease metastases.

the vertebrae, with associated extraosseous soft tissue and pathological compression fractures in D1 and D10 vertebrae. She then received radiotherapy to D1 and D10, followed by four cycles of gemcitabine + docetaxel. Repeat PET-CT was suggestive of progressive disease with new sites of nodal disease and an increase in hepatic lesion in segment V of the right lobe of the liver to 16 x 15.7 cm.

She was then started on pazopanib 400 mg tablets once daily and palliative radiotherapy 20 Gy/5# to the liver lesions. She had partial response of the liver lesions but increase in paratracheal and paraesophageal nodes, with new bone lesions and peritoneal metastases. She eventually was kept only on pain management and died due to the metastases.

OUTCOME

Despite aggressive treatment, the patient’s condition deteriorated. Her final PET-CT scan showed progression of the liver and bone metastases, with new peritoneal metastases. She was transitioned to palliative care and eventually died from the disease.

DISCUSSION

Simultaneous occurrence of two primary malignancies in a single patient is a rare occurrence. It is usually associated with addictions like smoking, alcohol, or tobacco, and/or in patients with genetic risk of cancer or family history of cancers (germline mutation in the colon or BRCA in breast and ovarian cancers).

In 1879, Billroth first described multiple primary malignancies. The neoplasm may be limited to one organ or multiple different organs, and they are classified into two categories: synchronous, in which the cancers occur at the same time or within 2 months; and metachronous, in which the cancers follow in sequence, that is, more than 6 months apart.10

Metachronous primary malignancies are becoming increasingly common because the population is living longer than in the

past decades, there is a high number of cancer survivors, and there is greater awareness and improved diagnostic modalities. Following chemotherapy and/ or radiotherapy for solid organ cancers, occurrence of secondary malignancies after 2–10 years, such as myelodysplastic syndrome, acute myeloid leukaemia (AML) or acute/chronic lymphocytic leukaemia, is common and has been reported in literature (i.e., metachronous presentation). However, synchronous presentation of AML and solid tumours is rare.

Risk factors for AML are exposure to chemicals like benzene or radiation, and exposure to chemotherapy agents like anthracyclines or topoisomerase inhibitors.13-14 Topoisomerase II inhibitors or alkylating agents, and abnormalities of chromosomes such as 11q23, are known to cause myelodysplastic syndrome/AML in 1–10 years post-chemotherapy depending on the type of chemotherapy that is used.

Risk factors for lung cancer include smoking or tobacco, and exposure to industrial chemical fumes or asbestosis.13-14

In the literature review, the authors found that only a handful of articles have been published so far of synchronous AML with solid tumours. The outcome of all has been dismal when AML is associated with solid cancers synchronously, and none have survived so far.10-12 Vararajan11 published 12 cases of dual malignancies, of which seven patients presented with metachronous AML and lung cancer, and five patients had synchronous AML and lung cancer.11 Sheridan et al.12 published a case report of synchronous presentation of AML and breast cancer.

In a meta-analysis of 32 patients with synchronous haematological malignancies and solid tumours, there were only four cases of AML, out of which one case was of APML. Their overall survival varied between 3.6–20.0 months, with the eventual outcome being mortality. AML with synchronous solid tumours had poor outcomes, despite whatever strategies of treatment were employed.15

Treatment strategies in case of synchronous double malignancy depend on whether you are treating the malignancy that is more advanced first, or both are treated simultaneously. In the authors’ case, the NSCLC was metastatic, so the patient was treated for NSCLC rather than APML.15-18

Synchronous twin malignancies, particularly when a haematologic cancer like APML coexists with a solid tumour such as NSCLC, are exceedingly rare. This simultaneous presence of malignancies complicates both diagnosis and treatment strategies. The case underscores the necessity for comprehensive diagnostic evaluations, including advanced imaging techniques and molecular profiling, to inform treatment decisions.

Managing synchronous malignancies demands a multidisciplinary approach that balances the aggressive treatment of each cancer while addressing overlapping toxicities and complications.

Additionally, this case highlights the challenges associated with treatment-induced side effects, such as ATRA-induced

References

1. Lee TK et al. Multiple primary malignant tumors (MPMT): study of 68 autopsy cases (1963–1980). J Am Geriatric Soc. 1982;30(12):744-53.

2. Sandler DP et al. Cigarette smoking and risk of acute leukemia: associations with morphology and cytogenetic abnormalities in bone marrow. J Natl Cancer Inst. 1993;85(24):1994-2003.

3. Snyder R. Benzene and Leukemia. Crit Rev Toxicol. 2002;32(3):155-210.

4. Jayasudha AV et al. Synchronous occurance of acute myeloid leukemia and rhabdomyosarcoma. Indian J Hematol Blood Transfus. 2015;31(3):387-90.

5. Wang XM et al. An unexpected spectrum of p53 mutations from squamous cell carcinomas in psoriasis patients treated with PUVA. Photochem Photobiol. 1997;66(2):294-9.

6. Brownson RC et al. Cigarette smoking and adult leukemia: a meta-analysis. Arch Intern Med. 1993;153(4):469-75.

pseudotumor cerebri, emphasising the importance of vigilant monitoring and timely intervention.

CONCLUSION

Synchronous twin malignancies with AML and solid cancers have a dismal outcome, due to underlying disease and delays in the diagnosis of the second cancer, which eventually metastasises. Furthermore, it is challenging to treat both malignancies at the same time. Adverse events of one therapy also complicate the other therapy options and overall outcomes.

This case underscores the rarity and complexity of synchronous twin malignancies in oncology. The management of such cases necessitates a personalised approach, integrating multimodal therapies and vigilant monitoring to optimise patient outcomes. Further research is needed to understand the underlying mechanisms driving synchronous malignancies and to develop tailored treatment strategies.

8. Beyan C et al. Synchronous double malignancies of renal cell carcinoma and acute myeloid leukemia: an unreported coexistence. Am J Hematol. 2005;80(2):164.

9. Curtis RE et al. New malignancies among cancer survivors: SEER Cancer Registries, 1973-2000. 2006. Available at: https://seer.cancer.gov/archive/ publications/mpmono/MPMonograph_ complete.pdf. Last accessed: 25 February 2025.

10. Howe HL et al. Multiple Primary Cancers of the Ovary in the United States, 1992–1997. 2003. Available at: https:// acsjournals.onlinelibrary.wiley.com/doi/ pdf/10.1002/cncr.11348. Last accessed: 25 February 2025.

11. Varadarajan R et al. Metachronous and synchronous presentation of acute myeloid leukemia and lung cancer. Leuk Res. 2009;33(9):1208-11.

7. Gao NA et al. Synchronous occurrence of gastrointestinal stromal tumor and acute myeloid leukemia: a case report and review of the literature. Oncol Lett. 2016;11(5):2977-80.

12. Sheridan WP et al. Simultaneous occurrence of acute myeloid leukemia and carcinomatosis. Br J Haematol. 1984;58(1):199-200.

13. Hecht S.S et al. A study of tobacco carcinogenesis. XLII. Bioassay in A/J mice of some structural analogues of tobacco-specific nitrosamines. Cancer Lett. 1988;42(1-2):141-5.

14. Crane MM et al. Correlation between selected environmental exposures and karyotype in acute myelocytic leukemia. Cancer Epidemiol Biomarkers Prev. 1996;5(8):639-44.

15. Liu S et al. Thirty-two case reports of synchronous hematological malignancy and solid tumor. Turk J Hematol. 2019;36:282-302.

16. Sampath KJ et al. A rare case of synchronous presentation of acute myeloid leukemia and lung cancer. J Cancer Ther. 2019;10(6):471-5.

17. Agarwal R. Synchronous dual malignancy; successfully treated cases. J Cancer Res Ther. 2007;3(3):153-6.

18. Di Martino E et al. Survival in second primary malignancies of patients with head and neck cancer. J Laryngol Otol. 2002;116(10):831-8.

Bleeding Due to Vitamin K-Dependent Factor Deficiency in a Patient Taking Topiramate: A Case Report

Authors: *Sugam Gouli,1 Marcy Canary1

1. Bassett Medical Center, Cooperstown, New York, USA *Correspondence to sugam.gouli@rochesterregional.org

Disclosure: The authors declare no conflicts of interest. The patient provided informed consent for details of this case to be published.

Received: 15.03.25

Accepted: 30.06.25

Keywords: Bleeding, case report, topiramate, vitamin K factor deficiency.

Citation: EMJ Hematol. 2025;13[1]:128-132. https://doi.org/10.3390/emjhematol/ZYOF6655

Abstract

Topiramate is a well-known medication used for migraine and epilepsy. Bleeding is a rare and less documented side-effect of this treatment. The authors present a rare case of bleeding in a patient who was started on topiramate, which was likely due to a vitamin K-dependent factor deficiency. Clinicians should take caution if any bleeding event is noted in patients on topiramate, and stop administering this drug.

Key Points

1. Coagulopathy is a rare side effect in topiramate.

2. Though the mechanism is unclear, vitamin K dependant factor deficiency is seen in coagulation workup.

3. Treatment involves discontinuation of topiramate and fresh frozen plasma.

INTRODUCTION

Bleeding disorder is a rare and serious side effect of anticonvulsant drugs (ACD). Topiramate is a common ACD which has demonstrated good efficacy and safety in several randomised clinical trials and can be associated with coagulopathy. There are multiple mechanisms of action through which topiramate works. It can act through sodium and calcium channels, affect GABA-A receptor activity, and cause CYP3A4 enzyme induction. It is effectively

used in epilepsy and migraine prophylaxis. The mechanism of coagulopathy, however, is unclear.

Vitamin K is a fat-soluble vitamin that acts as a cofactor for γ-glutamyl carboxylase, which is essential for formation of several clotting factors and anticoagulant proteins. Vitamin K deficiency can affect the synthesis of these clotting factors and can cause bleeding diathesis in patients. Very few reported cases of topiramate-associated coagulopathy

have been reported in literature review. The authors present a case of vitamin K-dependent factor deficiency as a likely cause of bleeding in a patient treated with topiramate, and subsequent resolution of vitamin K deficiency after stopping topiramate and receiving fresh frozen plasma. This case identifies the importance of considering ACD-induced vitamin K-dependent factor deficiency in patients with bleeding.

PATIENT INFORMATION

The patient is a 68-year-old female with past medical history of diabetes, transient ischaemic attack, and coronary artery disease, who presented to the haematology clinic for evaluation of recently diagnosed coagulopathy. A few months ago, she was found to have thickening of the uterus and uterine polyps, for which she underwent hysteroscopy with dilatation and curettage of uterus. On the 6th post-operative day, she developed significant vaginal bleeding, and 1 week later, she had large ecchymotic areas and blood-filled blisters in her mouth. She also had a few episodes of epistaxis that were self-limited, and had to come to the emergency for further evaluation. Six years prior, she had an episode of deep vein thrombosis and underwent thrombectomy. She had one episode of bleeding after thrombectomy. After the procedure, she was treated with warfarin for 4 months and had international normalised ratios (INR) of 8–9s while being on warfarin therapy. An inferior vena cava filter was placed and warfarin was discontinued.

The patient had started topiramate for migraine a few weeks before surgery. Although topiramate was stopped a week prior to surgery, it was resumed postoperatively, and the patient was on topiramate at the time of bleeding. Other medications she was taking during the hospital visit were cholecalciferol, colesevelam, eszopiclone, febuxostat, furosemide, lansoprazole, magnesium, metoprolol succinate, multivitamin, omega-3 acid, potassium chloride, riboflavin, and venlafaxine, which were her chronic medications.

CLINICAL FINDINGS AND DIAGNOSTIC ASSESSMENT

Her labs (Table 1) showed severely elevated prothrombin time (PT)/INR and partial thromboplastin time (pTT; PT >124, INR >9.9, pTT >350) while her d-dimer (320), fibrinogen (351), and platelet counts (212,000) were all normal. Labs showed that factor VIII (162) level was normal, but factors II (58),VII (18), and X(41) were low. Warfarin level and von Willebrand factor multimers (146) were normal. Antiphospholipid, cardiolipin, and β2 glycoprotein antibodies were also negative. She was given four units of fresh frozen plasma at the time of the emergency, with improvement of her PT (16.2), INR (1.6), and pTT (75.9). Mixing studies showed normalisation of PT and pTT, consistent with coagulation factor deficiency, and ruled out the presence of any inhibitor.

THERAPEUTIC INTERVENTION

Topiramate was discontinued during the hospitalisation for concerns of coagulopathy. The patient received fresh frozen plasma, causing reversal of her coagulopathy.

FOLLOW-UP AND OUTCOMES

After stopping topiramate, she did have some minor vaginal bleeding, which stopped at follow-up visits. She also denied any new ecchymosis or epistaxis. After a few weeks, she was restarted on topiramate and she again had abnormal blood parameters. Her PT was 30.8, INR was 3.1, and activated pTT (apTT) was 34.7. The levels normalised when the topiramate was stopped permanently. Topiramate was replaced with valproic acid for her migraine. Her PT/INR and pTT levels were monitored regularly and have remained normal since stopping topiramate.

DISCUSSION

Vitamin K is an essential vitamin for the function of coagulation factors II, VII, IX, X, and the anticoagulants protein C and S.1

Publication

PT 124 (11s–13.5s)

INR 9.9 (<1.1)

pTT 350 (25–35)

d-dimer 320 (<500)

Fibrinogen 351 (200–400)

Platelet count 212,000 (150,000–450,000)

Factor II 58 (>100 mg/dL)

Factor VII 18 (60–140)

Factor VIII 162 (64–232)

Factor X 41 (70–200)

vWF 146 (50 IU/dL–200 IU/dL)

Antiphospholipid antibodies

Cardiolipin antibodies

β2 glycoprotein antibodies

Warfarin level

Mixing studies

Negative

Normal

The causes of vitamin K-dependent factor deficiency are malabsorption, dietary deficiency, liver disease, and drug interactions.2 The symptoms related to deficiency include bleeding, epistaxis, ecchymosis, vaginal bleeding, and rectal bleeding. The laboratory abnormalities that can be seen due to vitamin K-related factor deficiency are prolonged PT and aPTT, owing to deficiency of factors II, VII, IX, and X. Coagulopathy with the increase in PT and aPTT can also be caused by liver diseases, anti-coagulant use/toxins (inhibitors), disseminated intravascular coagulation, antiphospholipid antibodies, and a variety of inherited coagulation deficiencies. The changes in PT and aPTT due to factor deficiency versus inhibitors can be seen in Table 2

Topiramate is an ACD that is used for prophylaxis of migraine attacks and is approved for partial and generalised tonicclonic seizures.3,4 Common side-effects of topiramate include fatigue, dizziness, cognitive dysfunction, metabolic acidosis, etc. Anticonvulsants have been shown to cause bleeding disorders and inhibit vitamin K activity. It has been suggested that ACD consumption in pregnancy can cause bleeding disorders in the mother and newborn.5 Some case reports, case series, and small cohorts from birth registries have raised concerns of an elevated risk of obstetric bleeding complications in females on ACD, but the results are inconsistent.6-9 The possible cause mentioned is that ACDs easily cross the placenta and induce microsomal enzymes in the fetal liver, which will lead to deficiency of

Table 1: Patient’s lab results before fresh frozen plasma was given.

INR: international normalised ratio; PT: prothrombin time; pTT: partial thromboplastin time; vWF: von Willebrand factor.

Table 2: Changes in prothrombin time and partial thromboplastin time due to factor deficiency versus inhibitors.

↑ APTT Only

↑ PT/INR Only

Corrects Factor deficiency

Factors VIII, IX, XI, XII

HMWK, PK

Fibrinogen deficiency

Factors II, V, VII, X

Fibrinogen deficiency

Vitamin K deficiency

Warfarin

↑ APTT & PT/INR Warfarin ++

DIC

Chronic liver disease

Factors II, V, X

Fibrinogen deficiency

Vitamin K deficiency

Does not correct Inhibitors

Heparin

Factor IIa inhibitors

Lupus anticoagulant

Specific inhibitors

Excess heparin

Factor IIa inhibitors

Excess heparin

Factor IIa inhibitors

APTT: activated partial thromboplastin time; DIC: disseminated intravascular coagulation; HMWK: high molecular weight kininogen; INR: international normalised ratio; PK: prekallikrein; PT: prothrombin time.

vitamin K and reduced concentration of vitamin K-dependent factors.10 It should be noted that topiramate is a weak inducer of CYP3A4 microsomal enzyme, which is a key player in the body’s metabolism of drugs.11 It can decrease the effects of non-vitamin K antagonist oral anticoagulants (NOAC) by inducing CYP3A4 activity. Topiramate can also cause hepatotoxicity, which may contribute to decreased synthesis of clotting factors.12

Two case reports with epistaxis in a patient on topiramate were found during the literature search. Polimeni et al.13 reported a case of epistaxis in a 36-year-old female taking topiramate for migraine. The patient was advised to stop taking topiramate and the bleeding stopped 12 hours later.13 Another article by Page et al.14 mentioned epistaxis in a 61-year-old female patient who was prescribed topiramate 25 mg daily, and who developed epistaxis 7 days after treatment, which improved after stopping the topiramate.14 Both the articles suggested anti-platelet effects as a possible mechanism of topiramate, particularly in combination with antiplatelet medication. Wang et al.15 showed that when topiramate was combined with a NOAC, it was not associated with higher risks of major

bleeding (crude major bleeding incidence rate of 55.16% per 1,000 person years; risk ratio of 1.09 compared to a NOAC).15 Perrone et al.16 presented two cases of vitamin K–dependent clotting factor deficiency with pathogenic variants in the GGCX gene, where one patient exhibited severe earlyonset bleeding manifestations, including intracranial haemorrhage, necessitating frequent plasma infusions and high-dose vitamin K, while the other displayed a milder phenotype characterised by mucocutaneous bleeding, and responded favourably to intermittent vitamin K therapy.16

In the authors’ case, the patient was on topiramate and had bleeding abnormality consistent with vitamin K-dependent factor deficiency evident by low factor II, VII, and X levels, which was corrected by giving fresh frozen plasma and stopping topiramate.

DIFFERENTIAL DIAGNOSIS

Her coagulopathy could have been from vitamin K-dependent factor deficiency due to warfarin; however, she denied any recent warfarin use. Warfarin poisoning was also considered as her husband had been on warfarin, but her warfarin level was normal.

She also denied any accidental rat poison intake. She mentioned taking a standard diet with lots of salad, which made a nutritional cause highly unlikely.

STRENGTHS AND LIMITATIONS

Topiramate induced bleeding is a rare complication and only a few reports have been found in the literature, as mentioned previously. The authors’ case report can alert clinicians on this rare adverse event of topiramate, and help understand the timeline, laboratory findings, and management strategies. There were no possible confounders that

References

1. Mladěnka P et al. Vitamin K – sources, physiological role, kinetics, deficiency, detection, therapeutic use, and toxicity. Nutr Rev. 2022;80(4):677-98.

2. Shearer MJ et al. Vitamin K nutrition, metabolism, and requirements: current concepts and future research. Adv Nutr. 2012;3(2):182-95.

3. Brandes JL al. Topiramate for migraine prevention: a randomized controlled trial. JAMA. 2004;291(8):965-73.

4. Silberstein SD. Topiramate in migraine prevention: a 2016 perspective. Headache. 2017;57(1):165-78.

5. Panchaud Alice et al. Anticonvulsants and the risk of perinatal bleeding complications: a pregnancy cohort study. Neurology. 2018;91(6):e533-42.

6. Sveberg L et al. Women with epilepsy and post partum bleeding: is there a role for vitamin K supplementation? Seizure. 2015;28:85-7.

7. Borthen I et al. Delivery outcome of women with epilepsy: a populationbased cohort study. BJOG. 2010;117(12):1537-43.

would have caused the bleeding; however, the mechanism of the bleeding is not completely clear. Further studies to assess the bleeding risk are needed.

CONCLUSION

In conclusion, bleeding due to vitamin K-dependent factor deficiency is a rare side effect of topiramate. The possible mechanism is unclear. Careful use of topiramate by clinicians is recommended in patients with bleeding disorders, and prompt recognition and discontinuation of the drug can lead to resolution of symptoms and normalisation of coagulation parameters.

8. Borthen I et al. Obstetric outcome in women with epilepsy: a hospitalbased, retrospective study. BJOG. 2011;118(8):956-65.

9. Pilo C et al. Pregnancy, delivery, and neonatal complications after treatment with antiepileptic drugs. Acta Obstet Gynecol Scand. 2006;85(6):643-6.

10. Kaaja E et al. Enzyme-inducing antiepileptic drugs in pregnancy and the risk of bleeding in the neonate. Neurology. 2002;58(4):549-53.

11. Nallani SC et al. Dose-dependent induction of cytochrome P450 (CYP) 3A4 and activation of pregnane X receptor by topiramate. Epilepsia. 2003;44(12):1521-8.

12. Tsien MZ et al. Topiramate-induced acute liver failure in a pediatric patient: a case report and review of literature. J Pediatr Gastroenterol Nutr. 2016;63(3):e37-8.

13. Polimeni G et al. A case of topiramateinduced epistaxis. Current Drug Safety. 2009;4(3):207-8.

14. Page RL 2nd, Bainbridge JL. Intractable epistaxis associated with topiramate administration. Ann Pharmacother. 2006;40(7-8):1462-5.

15. Wang CL et al. Assessing major bleeding risk in atrial fibrillation patients concurrently taking non-vitamin K antagonist oral anticoagulants and antiepileptic drugs. Eur Heart J Cardiovasc Pharmacother. 2020;6(3):147-54.

16. Perrone S et al. Clinical, laboratory, and molecular characteristics of inherited vitamin k-dependent coagulation factors deficiency. Semin Thromb Hemost. 2025;51(2):170-9.

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