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Fifty shades of PTEN Genomics in AML: information on clinical relevance remains no longer ‘classified’ Checkpoint inhibition: waking sleeping giants in Hodgkin lymphoma Scouring the genome for desirable traits Bulgarian Medical Society of Hematology An update on Haematologica

This edition contains Report of the highlights of the 21st Congress of EHA

The official newsletter for members of EHA

SUMMER 2016

SUMMER 2016 | hematopics | EHA

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Cover Digital illustration of blood cells

Fifty shades of PTEN Genomics in AML: information on clinical relevance remains no longer ‘classified’ Checkpoint inhibition: Waking sleeping giants in Hodgkin lymphoma Scouring the genome for desirable traits Bulgarian Medical Society of Hematology An update on Haematologica

THIS EDITION CONTAINS REPORT OF THE HIGHLIGHTS OF THE 21ST CONGRESS OF EHA

The official newsletter for members of EHA

SUMMER 2016

SUMMER 2016 | HEMATOPICS | EHA

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Hematopics is published three times per year by the European Hematology Association. Membership of the European Hematology Association includes subscription to Hematopics. Co-Editors-in-Chief Elizabeth Macintyre, Stefan Fröhling Editors Lars Bullinger, Simon Hallam, Michael Milsom, Melania Tesio, guest editor Florian Heidel, Astrid Danen (Uitgeverij Jaap) Text editor Cait Kennedy Editorial coordination Ineke van der Beek, Jon Tarifa, Chared Verschuur-Ballo Photography, illustrations Shutterstock, Stefan Zeitz, Professor Margarita Guenova Graphic design Niels Eijsbroek, Biltvorming Copyright Copyright © 2016 European Hematology Association. All rights reserved. A note to the readers The views expressed in articles are the author’s and not necessarily those of EHA. Contact editors For remarks, questions and sugges­tions, e-mail: communication@ehaweb.org

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EHA | hematopics | SUMMER 2016

22 Report of the highlights of the 21st Congress of EHA


Contents

6

14

Fifty shades of PTEN

Scouring the genome for desirable traits

16 Bulgarian Medical Society of Hematology

8 Genomics in AML: information on clinical relevance remains no longer ‘classified’

18 An update on Haematologica

11 Checkpoint inhibition: waking sleeping giants in Hodgkin lymphoma

51 Save the date SUMMER 2016 | hematopics | EHA

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President’s Message

Dear reader, This volume of Hematopics contains a report of the 21st Congress

clinical trials research in Europe, albeit in a global context. For the

of EHA. The Bella Center in Copenhagen was EHA’s ‘home’ during

first round, 17 trainees will benefit from this course and the first

the second week of June. More than 10,000 individuals with an

workshop will start this November in Italy.

interest in developments within hematology attended this annual event and abstract submission was a record high. The Scientific

The HARMONY project is a European Network of Excellence that

Program Committee under the guidance of Andreas Engert, did an

will capture, integrate, analyze and harmonize big data from high-

exceptional job in compiling an exciting program covering so

quality multidisciplinary sources and unlock valuable knowledge

many topics. The highlights of this event are covered in the

on various hematologic malignancies. Recently, the proposal for

congress report. Sessions were recorded for congress delegates

HARMONY was approved by the Innovative Medicine Initiative (IMI);

to watch on the EHA Learning Center and interviews with experts

a public-private partnership between the European Union and the

on various topics covered in the congress program were also

pharmaceutical industry association EFPIA. The project is led by two

conducted.

EHA members; Professor Jesús María Hernández Rivas (Salamanca, Spain) and Professor Guillermo F. Sanz (Valencia, Spain). EHA is

During the congress, the new composition of the EHA Board was

involved in several work packages (WP) and we look forward to,

approved at the annual business meeting. Gert Ossenkoppele

together with the many partners, work on this ambitious initiative.

stepped down after serving his term as Board Member and I would like to thank him for his many important contributions. I am

Lastly I would like to bring to your attention the EHA Friends’ Fund

delighted that he will stay on in various committees and particularly

which has been established to help EHA in its mission to support

as the next chair of the Education Committee. Helen Papadaki from

research, education and clinical care in the field of hematology.

Greece was elected by EHA members to join the Board and it is with

Donations to the EHA Friends’ Fund will help us support a wide

great pleasure that we welcome her.

range of hematological initiatives across Europe and beyond. I encourage you to become an EHA Friend and help us improve the

Perhaps I could also highlight 3 new developments: the Clinical

outlook for patients with hematological disorders.

Research in Hematology Training (CRTH) program, the HARMONY initiative and the EHA Friends’ Fund.

With best wishes

With the CRTH, EHA provides junior researchers with a 9-month

Tony Green

long unique training and mentoring experience focused on

EHA President

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EHA | hematopics | SUMMER 2016


Message from the Editors-in-Chief Dear reader, Welcome to this special, post-Congress issue of Hematopics!

a multicenter clinical trial of the immune checkpoint inhibitor

In this issue, you will find familiar features such as our popular

nivolumab in patients with advanced-stage classical Hodgkin

“hot topics” in basic, translational and clinical hematology.

lymphoma, which were also presented at the 21st Congress of EHA in Copenhagen.

In his contribution “Scouring the genome for desirable traits”, Michael Milsom comments on an article in Cell that described the

This issue’s “National Society in Focus” is the Bulgarian Medical

use of a large-scale parallel reporter assay to screen for function-

Society of Hematology. In her contribution, President Margarita

ally relevant allelic variants originally identified by genome-wide

Guenova provides insight into the association’s history, current

association studies focused on red blood cell traits.

status and future vision.

In “Fifty shades of PTEN”, Melania Tesio reports on a recent article

Haematologica, the official journal of EHA, has climbed the lad-

in Nature Medicine about an unexpected pro-oncogenic role of

der and is now the number 4 hematology journal with an impact

the PTEN tumor suppressor in pre-B-cell acute lymphoblastic

factor of 6.671. Editor-in-Chief Jan Cools writes about the current

leukemia.

status and future development of the journal in “An update on Haematologica”.

In “Genomics in information on clinical relevance remains no longer classified”, Guest Editor Florian Heidel describes the results

This special issue also brings to you the report of the 21st Congress

of a study published in the New England Journal of Medicine

of EHA, held in June in Copenhagen. Relive the Congress in 30

that applied next-generation sequencing technology to refine

extra pages through highlights captured in a summary of various

the classification of acute myeloid leukemia and improve risk

sessions, breakthrough findings, latest research, statistics and

stratification for individual patients with this disease.

figures.

Simon Hallam’s contribution “Checkpoint inhibition: waking

Sit back, relax and enjoy reading this special issue of Hematopics!

sleeping giants in Hodgkin lymphoma” is a commentary on a recent article in Lancet Oncology that described the findings from

Elizabeth & Stefan

From left to right: Simon Hallam, Melania Tesio, Lars Bullinger, Elizabeth Macintyre, Stefan Fröhling and Michael Milsom.


Focus on basic malignant hematology

Fifty shades of PTEN In a recent Nature Medicine issue,

The PTEN (Phosphatase and tensin homolog deleted on chromo­

Seyedmehdi Shojaee and colleagues

solid and hematological cancers, such as acute myeloid leukemia,

some ten) gene is frequently deleted or mutated in many forms of

demonstrated that PTEN has an unexpected

mature B-cell lymphoma and T-cell acute lymphoblastic leukemia.

pro-oncogenic function.

codes for a protein phosphatase originally shown to antagonize

PTEN is therefore considered as a major tumor suppressor gene. It activation of PI3K/AKT signalling. In the past years, however, extensive investigations revealed novel additional functions, such as phosphatase independent activities, as well as longer isoforms

6

In autoreactive B cells, a strong BCR signal triggers

(left). In a similar manner, in pre-B ALL cells, PTEN

blasts (right). In this cellular context, PTEN deletion

hyperactivation of the PI3K/AKT pathway, which

deletion triggers hyperactivation of the PI3K/AKT

mimics the activation of an autoreactive BCR

in turn induces apoptosis of self-reacting B-cells

pathway, thereby inducing death of the leukemic

signal which occurrs during negative selection.

EHA | hematopics | SUMMER 2016


Focus on basic malignant hematology endowed with nuclear and mitochondrial functions1. Hence, since

AKT pathway is triggered by autoreactive BCR signalling and is

its identification in the late ‘90s, PTEN has continued to reveal novel

instrumental eliciting the death of self-reactive B-cells4. Based

unexpected facets.

on their results, Shojacee et al. hypothesized that the toxic effects exerted on pre-B ALL cells by Pten deletion could mimic

A new piece in this puzzle now comes from an elegant study by

the hyperactivation of the PI3K/AKT pathway occurring during

Seyedmehdi Shojaee and colleagues, who challenge the role of

negative selection (Figure). To demonstrate this point, the authors

PTEN as a tumor suppressor gene, revealing a pivotal pro-oncogenic

next reconstituted BCR-ABL1 expressing cells with an autoreactive

function in pre-B-cell acute lymphoblastic leukemia (ALL)2. This

pre-BCR and showed that its signalling was able to trigger cell

hematological malignancy is characterized by hyper proliferation

death. Notably, PI3K/AKT inhibitors blocked this phenomenon,

of immature B-cells, arrested at the pre-B stage of development.

further validating the hypothesis.

Two major abnormalities drive oncogenic transformation in this disease: the t(9;22) translocation generating the BCR-ABL1 fusion

Taken together, these data suggest that PTEN exerts a peculiar pro-

protein and mutational activation of the RAS pathway . In order

oncogenic function, which is strictly related to the B-cell lineage

to mimic these lesions, Shojaee et al. overexpressed the BCR-ABL1

and the pre-B stage of developmental arrest. Indeed, it is at this

fusion protein or a mutant active form of NRAS (NRAS

3

) in normal

stage that immature B cells start expressing a functional pre-BCR

murine pre B-cells, thereby generating two models of pre-B ALL

complex that leads them through the first checkpoints controlling

development. As expected, the two oncogenic drivers transformed

B-cell development. As such, further experimental evidence

pre-B-cells, leading to a fatal leukemia. Surprisingly, however,

demonstrated that PTEN exerts a pro-survival role exclusively

when the authors deleted Pten, they observed a rapid death of

in the B-cell lineage. In vitro, moreover, the pharmacological

the leukemic blasts in both disease models. Further analysis of a

inhibition of PTEN led to massive cell death of human pre-B-ALL

large cohort of pre-B ALL patient samples extended these findings

cells but did not induce apoptosis of BCR-ABL expressing myeloid

to the human setting: none of the patients screened harboured

blasts. These data are exciting as they suggest PTEN may be a

PTEN deletions/mutations or activating mutations of the PI3K/AKT

unique therapeutic target in pre-B-ALL. Although the in vitro

pathway, common in other hematological malignancies.

results need to be corroborated by extensive pre-clinical studies

G12D

using patients-derived xenografts, the study by Shojaee et al. is In order to explain their unexpected results, Shojacee et al. blocked

provocative and it imposes reappraisal of the classical role of PTEN

the activation of PI3K/AKT signalling, which is upregulated upon

as tumor suppressor. Twenty one years after its discovery, PTEN

PTEN loss. Selective pharmacological inhibitors of the PI3K and

keeps on revealing novel exciting aspects.

the AKT kinases significantly reduced death of the leukemic blasts, thus demonstrating that the toxic effects of Pten deletion rely on the activation of the PI3K/AKT pathway. These findings are

Author: Melania Tesio

intriguing since fine-tuned PI3K signalling regulates B-cell survival

Institut Necker-Enfants Malades (INEM),

and apoptosis throughout physiological B-cell development,

Institut national de recherche médicale (INSERM)

notably during negative selection, a process whereby autoreactive

U1151, Paris, France

B-cells are eliminated. In these cells, hyperactivation of the PI3K/

References 1.

2.

Song MS, Salmena L, Pandolfi PP. The functions and regulation

3.

Zhang J, Mullighan CG, Harvey RC, Wu G, Chen X, Edmonson M,

of the PTEN tumour suppressor. Nat Rev Mol Cell Biol. 2012 Apr

Buetow KH, Carroll WL, Chen IM, Devidas M, Gerhard DS, Loh

4;13(5):283-96.

ML, Reaman GH, Relling MV, Camitta BM, Bowman WP, Smith

Shojaee S, Chan LN, Buchner M, Cazzaniga V, Cosgun KN,

MA, Willman CL, Downing JR, Hunger SP.Key pathways are

Geng H, Qiu YH, von Minden MD, Ernst T, Hochhaus A,

frequently mutated in high-risk childhood acute lymphoblastic

Cazzaniga G, Melnick A, Kornblau SM, Graeber TG, Wu H,

leukemia: a report from the Children’s Oncology Group. Blood.

Jumaa H, Müschen M. PTEN opposes negative selection and enables oncogenic transformation of pre-B cells. Nat Med. 2016 Apr;22(4):379-87.

2011 Sep 15;118(11):3080-7. 4.

Cancro MP Signalling crosstalk in B cells: managing worth and need. Nat Rev Immunol. 2009 Sep;9(9):657-61.

SUMMER 2016 | hematopics | EHA

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Focus on translational malignant hematology

Genomics in AML: information on clinical relevance remains no longer ‘classified’

ual risk, as the prognostic impact of individual mutations (such

Reference

as NPM1) may be outweighed or altered by the co-occurrence of additional ‘drivers’.

Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic

In this seminal piece of work, the groups of Peter Campbell and

classification and prognosis in acute myeloid leukemia. New

Hartmut Döhner now dissect the driver landscape of AML, define

England Journal of Medicine 2016;374:2209-21.

its impact on prognosis and describe its molecular subgroups. This mutational landscape may – to some extent – also reflect clonal evolution of AML. By performing integrative genomic and clinical

During aging of the hematopoietic system, genetic alterations

analysis of 1540 patients enrolled in three prospective clinical trials

arise in hematopoietic stem cells of otherwise healthy individu-

and treated with myelosuppressive chemotherapy, the authors

als. Accumulation of genetic changes leads to development of

define novel genetic subgroups and define their relevance for

clonal hematopoiesis

and these aberrations can also be found

clinical outcome and survival. Driver mutations were identified

in pre-leukemic conditions and pre-leukemic stem cells 3. Somati-

by classical cytogenetic analysis and sequencing of 111 cancer

cally acquired mutations contribute to leukemic transformation

relevant genes. In total, the authors identified a set of 5234 driver

as so called ‘drivers’ of leukemia development. Novel approaches

mutations and the vast majority of patients (86%) revealed more

such as whole genome sequencing have provided insight into the

than one driver mutation. Using allele fractions of point mutations

mutational landscape of acute myeloid leukemia (AML) 4. Leuke-

to elucidate on clonal relationship, the authors provided evidence,

mic cells may reveal combinations of several ‘driver mutations’ in

that mutational events in epigenetic modifiers are often acquired

1,2

various leukemia genes and the presence of several competing subclones in a given patient adds another layer of complexity. Implementation of this knowledge in clinical practice, however, has

Author: florian heidel

been difficult in the past. To date, analysis of cytogenetic changes

Innere Medizin II, Hämatologie und Onkologie

and gene mutations has largely replaced morphology in risk-

Universitätsklinikum Jena, Germany

and treatment-stratification of AML patients

. Testing for single

5-7

mutations, however, may not inform us correctly on the individ-

8

EHA | hematopics | SUMMER 2016


early. Of note, these mutations can be already detected during

their former categorization as ‘intermediate-risk’ AML. The third

development of clonal hematopoiesis of the aging population

group of IDH2(R172) mutated cases showed similar outcome to

and confer an increased risk of developing blood cancer. Mutations

the NPM1 risk category.

of NPM1 appear to be secondary events and those of kinase Furthermore, co-occurring mutations influenced outcome and

pathway genes rather late events.

survival, over and above the previously described categories. The Describing that 48% of patients investigated in their cohort could

total number of driver mutations correlated with survival, inde-

not be classified according to the WHO 2008 classification , the

pendent of age and white blood count. In multivariate models, in-

authors re-evaluated genomic classification of AML using their

dependent deleterious effects were identified for TP53 mutations,

extended mutational data set. By developing a Bayesian statistical

chromatin-spliceosome genes and BRAF. Even with co-occurrence

model they were able to allocate AML into mutually exclusive

of specific mutations (e.g. ASXL1 and SRSF2), the negative impact

subgroups on the basis of their mutational (and co-mutational)

of each remained unchanged, independent of the other muta-

profile. Classical WHO-defined subgroups

could be confirmed

tions. In contrast, other cases revealed gene-gene interaction, by

and three novel subgroups could be defined: cases with mutations

which the prognostic impact was changed by co-mutation of an-

in regulators of splicing and chromatin (“chromatin-spliceosome

other gene. One prominent example for this was the interaction

group”; 18%), TP53 mutations and copy number alterations (TP53-

of DNMT3A, NPM1 and FLT3-ITD mutations (present in 6% of

aneuploidy group; 13%) and IDH2(R172) mutated AML (1%).

patients investigated). While FLT3-ITD influenced survival in a

8

8

negative manner in cases with concomitant DNMT3A and NPM1 Of note, the proposed genomic classification had implication on

mutations, this effect was not detectable in cases with either one

clinical parameters and patient survival. Patients allocated to the

or neither co-mutation. Likewise, the previously proposed positive

‘NPM1 mutated’ and ‘TP53-aneuploidy’ groups confirmed previ-

impact of NRASG12/13-mutations in NPM1-mutated AML was

ously described clinical characteristics and survival. In contrast,

exclusively detectable in DNMT3A/NPM1 co-mutated patients

patients in the chromatin-spliceosome group appeared more het-

but not in single or un-mutated cohorts. Thus, survival of NPM1-

erogeneous: low response rates, dysplastic features and dismal

mutated AML was strongly influenced by gene-interactions and

survival may help to distinguish 84% of patients in this group from

co-occurring mutations.

SUMMER 2016 | hematopics | EHA

9


Focus on translational malignant hematology Currently, diagnostic testing for cytogenetic lesions, and frequent mutational events (FLT3-ITD, NPM1 and CEBPA) is widely performed.

References

This inspiring new data set suggests that mutational events in TP53, SRSF2, ASXL1, DNMT3A and IDH2 should be included for prog-

1. Genovese G, Kahler AK, Handsaker RE, et al. Clonal

nostic stratification, as they are frequent and significantly influence

hematopoiesis and blood-cancer risk inferred from blood DNA

clinical outcome. With regard to AML classification, investigation

sequence. N Engl J Med. 2014;371(26):2477-2487.

of spliceosome genes (such as RUNX1, ASXL1 and MLL-PTD) could

2.

help allocate patients to the chromatin-spliceosome category.

hematopoiesis associated with adverse outcomes. N Engl J

The emergence of NPM1 as a separate entity remains a point of discussion, as it occurs a relatively late stage of leukemic develop-

Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal Med. 2014;371(26):2488-2498.

3. Shlush LI, Zandi S, Mitchell A, et al. Identification of pre-

ment and may be influenced by co-occurring genetic events. The

leukaemic haematopoietic stem cells in acute leukaemia.

fact that it may require an altered epigenetic landscape to exert its

Nature. 2014;506(7488):328-333.

transformative capacity – while still exerting its distinctive biologic

4.

impact - is one possible explanation.

Cancer Genome Atlas Research N. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368(22):2059-2074.

The authors present a novel genetic approach that has the poten-

5.

Dohner H, Estey EH, Amadori S, et al. Diagnosis and

tial to improve classification of the genetically heterogeneous AML

management of acute myeloid leukemia in adults:

and may support prognostic stratification of individual patients.

recommendations from an international expert panel, on

As these predictions allow more precise stratification of patients

behalf of the European LeukemiaNet. Blood. 2010;115(3):453-

undergoing treatment for AML, it will be very interesting to follow

474.

their prospective validation in future clinical trials.

6.

Grimwade D, Hills RK, Moorman AV, et al. Refinement of cytogenetic classification in acute myeloid leukemia: determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials. Blood. 2010;116(3):354-365.

7. Patel JP, Gonen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079-1089. 8.

Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114(5):937-951.

10

EHA | hematopics | SUMMER 2016


Commentary

Checkpoint inhibition: waking sleeping giants in Hodgkin lymphoma

Nivolumab for classical Hodgkin’s lymphoma after failure of both

mandate an ongoing search for more effective and less-toxic

autologous stem-cell transplantation and brentuximab vedotin:

routes to cure. Established therapies carry a significant burden of

a multicentre, multicohort, single-arm phase 2 trial.

late-effects, including second malignancies and cardiac disease.

Younes A, Santoro A, Shipp M, et al.

Patients unfit to receive, or relapsing after, established therapies

Lancet Oncol 2016; published online July 20.

usually have short survival.

http://dx.doi.org/10.1016/S1470-2045(16)30167-X. HL, in which tumour cells are massively outnumbered by and Risk and response-adapted use of combination chemotherapy,

engulfed in a mixed immune-cell population, is intuitively an

radiation therapy, and stem cell transplantation offer rates of cure in Hodgkin lymphoma (HL) that remain at the pinnacle of

Author: Simon Hallam

achievements in oncology care.

Department of Haematology-Oncology St. Bartholomew’s Hospital

There remain, however, very significant areas of unmet need that

Barts Health NHS Trust, London, UK

SUMMER 2016 | hematopics | EHA

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Commentary either received or were ineligible for ASCT received Nivolumab, of whom 20 responded, 4 with a CR. The Lancet Oncology article that forms the focus of this commentary adds significant momentum to this strategy in HL and has prompted accelerated approval of Nivolumab by the Food and Drug Administration for the treatment of HL, relapsed following ASCT and brentuximab vedotin. Professor Younes and colleagues report positive results from an ongoing single-arm phase 2 study of Nivolumab in 80 patients with HL (median age 37 years) relapsed following a median of 4 prior therapies including ASCT and brentuximab vedotin. Nivolumab was administered intravenously at 3 mg/kg every 2 weeks until progression, death, unacceptable toxicity, or withdrawal from study. attractive disease in which to attempt therapeutic manipulation of what appears to be an otherwise tumour-permissive, or even

The primary outcome measure of PET-CT objective response

supportive, immune microenvironment.

assessed by an independent radiological review committee at a minimum of 6 months follow-up was noted in 53 patients (66.3%,

Checkpoint inhibition, using monoclonal antibodies to release

95% CI 54.8–76.4), with a median time to first response of 2.1

potentially tumouricidal immune cells from tumour-induced

months and median duration of response of 7.8 months (95%

quiescence, offers an opportunity to wake a sleeping giant in

CI 6.6–not reached). 7 patients achieved a CR and 46 a partial

this disease.

remission (PR).

The physiologic and pathologic action of immune checkpoints,

The most common drug-related adverse events included fatigue

their pharmacological inhibition, and early therapeutic

(20 patients) infusion-related reactions (16 patients), and rash (13

experience in HL has been eloquently described in a recent

patients). 2 patients experienced pneumonitis which responded

comprehensive review (1).

to corticosteroids. The 3 patient deaths were not attributed to treatment; one being of unknown cause, one from disease

In brief, immune checkpoint proteins (including PD-1, CTLA-4 and

progression, and one from multi-organ failure attributed to EBV

LAG-3) are negative regulators of cellular immune responses that

positive peripheral T-cell lymphoma diagnosed at autopsy.

act to limit host tissue damage during inflammatory responses. Tumour cells, and cells of the tumour microenvironment that

Immunohistochemical analysis of tissue blocks obtained from

express checkpoint receptor ligands (such as PDL-1 and PDL-2)

biopsy during screening revealed that the PD-L1 H score (a

have the potential to suppress anti-tumour immune responses.

function of the frequency and intensity of PD-L1 staining of malignant cells) was positively correlated with the magnitude

Hodgkin Reed-Sternberg cells are characterized by almost

of 9p24.1 gain by FISH, and depth of best overall response.

universal alterations in 9p24.1 resulting in overexpression of PDL-

Nonetheless, the majority of patients in the lower quartile for

1/2, augmented further by EBV infection and JAK2 activation (2).

PD-L1 H score still achieved a PR. The PD-L1 H score of infiltrating non-malignant cells was not correlated with response.

Two Phase 1 studies with different anti-PD-1 monoclonal antibodies have demonstrated that the majority of heavily

29 patients have so far discontinued Nivolumab on this study,

pre-treated patients with HL exhibit a response to immune

13 for disease progression, 6 to proceed to allogeneic stem cell

checkpoint inhibition (3,4,5). 31 patients with relapsed or

transplantation, and 4 attributed to drug toxicity, 3 of which

refractory HL following chemotherapy and the antibody-drug

were of deranged liver biochemistry including 1 case of

conjugate brentuximab vedotin, who had either received or were

autoimmune hepatitis.

not fit for autologous stem cell transplantation (ASCT), were treated with Pembrolizumab. 20 responded, 5 with a complete

The 66% overall response rate in such heavily pre-treated patients,

response (CR). 23 patients with relapsed or refractory HL who had

allied with an apparently acceptable short-term toxicity profile

12

EHA | hematopics | SUMMER 2016


Commentary (supported by consistent improvements in measured quality of

Refining the use of checkpoint inhibition in HL will require

life while on treatment) , is striking and clearly justifies further

integrating the findings of very many ongoing complex and

interrogation of this strategy. There remain many unanswered

sometimes innovative clinical studies, incorporating a variety

questions and challenges for future studies to address.

of different checkpoint inhibitors, immunomodulatory drugs, conventional cytotoxics, and novel small molecules such as HDAC

The dynamic of responses to Nivolumab appears to be different

inhibitors. Establishing the most appropriate place for checkpoint

from that observed with established therapies. The majority of

inhibitors in clinical practice, and ensuring access to drug, will also

patients demonstrate a PR. At the time of analysis, 33 of the 53

necessitate dynamic and imaginative engagement by clinicians,

responses were ongoing, 31 censored before the median duration

scientists, patient groups and pharmaceutical companies with

of response, suggesting that the durability of PR is likely to

regulatory and funding bodies. This exciting but complex and

increase with prolonged follow-up. We need to better understand

challenging situation was recently described by Professor Philippe

the biological processes underlying these PRs as assessed by

Armand as a ‘frantic middle ground’ from which clarity will

PET-CT, whereby ongoing detected metabolic activity in the

emerge over the coming years.

tumour may reflect not only persistent malignant cells, but also, or perhaps exclusively, a vigorous and effective host-immune

This paper lends strong support to the strategy of harnessing the

response. Prolonged follow-up and allied laboratory studies will

otherwise dormant therapeutic potential of the florid immune-

reveal whether and how some of these PRs might translate in

infiltrate in HL, and with cautious optimism we look forward to

to long term remissions or late CRs. It is interesting to note that

the waking of this sleeping giant.

following a protocol amendment, 9 patients were treated beyond progression, of which 5 demonstrated subsequent tumour regression. These non-conventional patterns of response should take us back from the bedside to the laboratory bench, to further elucidate

References

the mechanism of action of checkpoint inhibitors in HL. The conventional wisdom is that checkpoint inhibition releases CD8+

1.

Vardhana S, Younes A

cytotoxic T-cells to respond to tumour antigens presented by

The immune microenvironment in Hodgkin lymphoma: T cells, B

MHC class I molecules. In HL, however, MHC class I expression is

cells, and immune checkpoints

not seen on the malignant cell owing to loss of B2-microglobulin.

Haematologica Jul 2016, 101 (7) 794-802; Doi: 10.3324/

Elucidating the roles in disease and responses to checkpoint

haematol.2015.132761

inhibition of CD4+ T-cells, macrophages, NK cells and T-regulatory

2.

Roemer MGM, Advani RH, Ligon AH, et al. PD-L1 and PD-L2

cells in HL might inform rationale optimization of this strategy,

genetic alterations define classical Hodgkin lymphoma and

as would an understanding of how checkpoint inhibition might

predict outcome.

directly alter tumour cell biology.

J Clin Oncol 2016; published online April 11. DOI:10.1200/ JCO.2016.66.4482 3.

Ansell, S., Armand, P., Timmerman, J. M., Shipp, M. A., Bradley Garelik, M. B., Zhu, L., & Lesokhin, A. M. (2015). Nivolumab in Patients (Pts) with Relapsed or Refractory Classical Hodgkin Lymphoma (R/R cHL): Clinical Outcomes from Extended Followup of a Phase 1 Study (CA209-039). Blood, 126(23), 583.

4.

Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin’s Lymphoma. The New England journal of medicine. 2015;372(4):311-319. doi:10.1056/NEJMoa1411087.

5.

Armand P, Shipp MA, Ribrag V, et al. PD-1 Blockade with Pembrolizumab in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Safety, Efficacy, and Biomarker Assessment. Blood. 2015;126(23):

SUMMER 2016 | hematopics | EHA

13


Focus on basic non-malignant hematology

Scouring the genome for desirable traits Genome wide association studies (GWAS) performed across

(SNP) extremely difficult. In a recent Resource article in the

large experimental cohorts represent a powerful methodol-

journal Cell, the group of Vijay Sankaran describes the use

ogy to link common variations within the human genome to

of a large scale parallel reporter assay in order to screen for

important physiologic characteristics that may be linked to

functionally relevant allelic variants, originally identified by

disease pathology. One of the major limitations of this ap-

GWAS focused on red blood cell (RBC) traits1.

proach is that each locus that is identified as correlating with a particular biological feature, tends to correspond to large

The vast majority of genetic variants identified by GWAS map

regions of the genome, containing hundreds of variant alleles

to non-coding genomic loci, suggesting that these SNPs occur

and multiple protein coding genes. In addition, the majority

in regulatory regions, such as enhancers, which are likely to be

of variant alleles identified using GWAS represent non-coding

highly cell-type specific in their activity. The process of attributing

regions of the genome, making the a priori prediction of func-

a causal relationship between a putative regulatory variant allele

tional relevance of a given single nucleotide polymorphism

and a biological effect is extremely laborious, requiring extensive

Synthetic constructs, consisting of approxi-

minimal promoter and inert ORF. Following

mRNA transcript for the same test sequence, in

mately 145 bp sequences flanking SNPs within

transfection into a target cell line, the ratio of

order to determine whether the variant allele

regions identified by GWAS, were cloned into

barcoded plasmid DNA for each specific test

has any putative regulatory impact on the

barcoded reporter constructs upstream of a

sequence was calculated versus the amount of

minimal promoter.

14

EHA | hematopics | SUMMER 2016


Focus on basic non-malignant hematology experimental validation in the tissue or specific target cell of inter-

Author: Michael Milsom

est. Therefore, a high-throughput screening platform is required

HI-STEMa Heidelberg Institute for Stem Cell

to highlight individual SNPs for further study. In an effort to gen-

Technology and Experimental Medicine,

erate a resource of SNPs with a functional role in the process of

Heidelberg, Germany

erythropoiesis, Ulirsch et al. devised a massively parallel reporter assay (MRPA) to screen 2,756 allelic variants contained within 75 regions identified in prior GWAS on RBC traits2. For each SNP inter-

the MFVs identified using the screening approach were causative

rogated in the MRPA, three synthetic constructs for each variant

for the biological variability assessed in the original GWAS. Taken

were synthesized. These corresponded to approximately 145bp

together, these multiple lines of evidence suggested that a novel

of the endogenous genomic locus, with the SNP located at the 5’,

resource of functionally relevant polymorphisms that impact on

center or 3’ end of the locus, in order to maximize the chances of

erythropoiesis had been generated (http://www.bloodgenes.org/

capturing any functionally relevant components within the im-

RBC_MPRA/).

mediate genomic context of the SNP. These putative regulatory elements were then cloned upstream of a minimal promoter,

As a proof of concept, three of these MFVs were targeted using a

followed by an inert open reading frame (ORF) and a series of

CRISPR/Cas9 genome editing approach to generate isogenic cell

14 barcodes that were unique for each construct. The pooled

lines harboring deletions at the site of the variant alleles. These

library of barcoded reporter constructs was then transfected into

deletions resulted in substantial alterations in gene expression

the human K562 erytholeukemic cell line, and the aggregate

for one or more genes within a 1 Mb window surrounding the

mRNA:DNA ratio for each barcode was determined by sequencing

MFVs. ChIP-seq data in heterozygous donor-derived erythroblasts

both DNA obtained from the original plasmid library and reverse

demonstrated differential occupancy of TAL1, LDB1 and/or GATA1

transcribed mRNA isolated from the transfected K562 cells. This

across the allelic variants of these MFVs. Interestingly, two of the

mRNA:DNA ratio could then be used to calculate the relative ac-

MFVs are not predicted to directly alter any TF binding site, sug-

tivity of a given construct within erythroid cells, when compared

gesting that MFVs can either directly alter TF binding sites or can

to either the whole library or, perhaps of more relevance, rela-

instead impact on TF activity by altering the DNA topology sur-

tive to other allelic variants. This comparison yielded 32 variants

rounding TF binding sites. Finally, the authors focused on one of

with a differential allelic activity at the level of gene expression,

the putative target genes whose expression was altered across

that were subsequently termed MPRA functional variants (MFVs).

allelic MFVs, the RNA-binding protein RBM38. The shRNA-medi-

Importantly, these MFVs were found to be enriched for open

ated down-regulation of RBM38 in primary erythroid cell culture

chromatin structure as determined by DNAse I hypersensitivity

resulted in delayed erythroid differentiation, likely due to alterna-

in primary human erythroid progenitor cells and K562 cell lines,

tive splicing, and correlated with the altered mean cell volume

and were also found to correlate with regions that were enriched

and hematocrit parameters associated with this variant allele in

for occupancy by important erythroid transcription factors (TFs)

the original GWAS data.

such as GATA1 and TAL1. In silico analysis using several computational algorithms was performed to verify the likelihood that

This study highlights the development of a potentially important high throughput methodology to assess the functional relevance

References

of SNVs in non-coding regions of the genome, to important biological or disease specific traits. Although this screening methodology is unlikely to be comprehensive and will undoubtedly

1.

2.

3.

Ulirsch JC, Nandakumar SK, Wang L, Giani FC, Zhang X,

result in the generation of false negative results, for example due

Rogov P, et al. Systematic Functional Dissection of Common

to the inability to assess broader endogenous chromatin contexts

Genetic Variation Affecting Red Blood Cell Traits. Cell. 2016 Jun

or to determine the combinatorial contribution of several loci to

2;165(6):1530-45.

regulation of a single promoter, the authors do provide a convinc-

Van der Harst P, Zhang W, Mateo Leach I, Rendon A, Verweij N,

ing proof of concept that this approach is a large step towards

Sehmi J, et al. Seventy-five genetic loci influencing the human

advancing our ability to dissect the relevance of GWAS targets. It

red blood cell. Nature. 2012 Dec 20;492(7429):369-75.

is conceivable that, with further technological optimization3, such

Tewhey R, Kotliar D, Park DS, Liu B, Winnicki S, Reilly SK, et al.

an approach could also be extended in the future to interrogate

Direct Identification of Hundreds of Expression-Modulating

disease-relevant somatic mutations in non-coding regions of the

Variants using a Multiplexed Reporter Assay. Cell. 2016 Jun

genome, such as those identified by sequencing of tumor entities.

2;165(6):1519-29.

SUMMER 2016 | hematopics | EHA

15


National Society in Focus

Bulgarian Medical Society of Hematology The statistics

projects. A one-day “controversies-in-hematology” session was

The Bulgarian Medical Society of Hematology (Българското

held during the 10th Balkan Day of Hematology, which was

медицинско сдружение по хематология) currently has 175

organized during the 10th National Hematology Congress in 2015

members in total, including medical doctors, nurses and

and raised significant discussions and interest.

biomedical specialists working in the field of hematology.

To date, 7 Working groups have been established (Chronic

The society is led by 11 board members: Margarita Guenova,

lymphocytic leukemia and lymphoma, Plasma cell disorders,

President ; Julian Raynov, Past President; Georgi Mihaylov; Stefan

Myeloproliferative neoplasms and myelodysplastic syndromes,

Goranov; Gueorgui Balatzenko; Evgenii Hadjiev; Janet Grudeva-

Anemia and hemorrhagic disorders, Hematopoietic stem cell

Popova; Valeria Kaleva; Lilia Sivcheva; Angelina Vasileva.

transplantation, Gaucher’s disease and Laboratory diagnosis). The WGs have developed guidelines and conducted nation-wide

Foundation and aim

studies on the epidemiologic and major clinical and laboratory

The Bulgarian Medical Society of Hematology (BMSH) was

features of hematological entities. Workshops have been

founded in 1964. The aim of the society is to support the

organized and useful interdisciplinary collaborations initiated.

development of hematology in Bulgaria and to contribute to the medicine, to mediate the dialogue and relationships with local

Young Hematologists in the Focus of the Bulgarian Medical Society of Hematology

and central health authorities in order to achieve a high level of

The young generation has been the focus of the society in

medical care for patients with blood diseases. A major objective

recent years. A survey among 42 young hematologists was

of the society is to unite and assist its members working in the

conducted, investigating their attitudes towards development

field of hematology and to favor their professional development,

of hematology in Bulgaria. Clearly, hematology is evaluated

in particular of young residents and specialists, by providing

as a modern discipline, enabling research, which is the main

training and continuous education.

reason for the choice of the specialty for most of the responders.

enhancement of the role and the importance of the discipline in

Major achievements The key strategic domains of the BMSH include the settlement of a national policy in hematology. The society developed the Medical Standards in Hematology, which was approved by the Ministry of Health, as well as the National guidelines for diagnosis, prevention and treatment of haematological diseases. Implementation of high standards and quality assurance are central issues also in providing training and continuous medical education aiming at harmonization with European practice. The BMSH organizes a congress every four years in October and national thematic conferences every two years, which are mainly aimed at education and updates of concepts and practice on particular topics. The society has active relationships with the hematological societies from the Balkan countries, originating from the EHA meetings of the National Societies Presidents. This instigated regular expert exchange meetings with scientific and educational sessions, triggering new collaborations and common

16

EHA | hematopics | SUMMER 2016


National Society in Focus Within the factors supporting the highest satisfaction, the most

and then translated and distributed to the members as well as

significant are the opportunities “to work with patients with

uploaded on the society web site. The on-line version of the CV

complex diseases” referred to by the majority of respondents

Passport is available in Bulgarian language allowing for using this

(93%), “to attend educational and scientific events abroad”

invaluable tool by Bulgarian trainees.

(55%), “to participate in research projects and publish scientific

EHA has traditionally been presented at national meetings

articles” (41%) and “to collaborate with colleagues” (38%). The

for many years. For the first time a session was devoted to

major problems indicated in the survey were associated

the “Hematology European Dimension” during the National

with poor access to medicines (66%) and highly

Congress of the Society in 2007 with the participation of Robin

specialized studies (41%). Only half of the

Foà and Alvaro Urbano-Ispizua, presenting EHA

responders have undergone training abroad,

perspectives. EHA projects and programs

including individual training and educational

for career development, including the

postgraduate courses. The results of the survey

Curriculum project and the Hematology

were carefully analyzed and various activities

Master Class, were presented by Gareth

were initiated aimed at the development of a

Evans-Jones (EHA Office), Szabolcs

new European generation of professionals able to meet the requirements of time with confidence and

Modok and Margarita Guenova (EHA Curriculum Committee) during a session

knowledge. A dedicated symposium is organized annually for

entitled “Young Hematologists in the Focus of the European

young hematologists and the society gives out yearly awards for

Hematology Association” at the young hematologists’ symposium

the best presentations.

in 2012. In 2014 young hematologists could experience the progress test developed by the Swedish Society of Hematology

Collaboration between BMSH and EHA

in an interactive session during their annual meeting presented

The BMSH belongs to the European family of hematological

by Gunnar Birgegård (EHA Linkers Group). The BMSH awarded

associations. There has been a longstanding collaboration with

all young participants who took the test with an annual EHA

the European Hematology Association particularly in the field

membership fee. These activities raised the awareness on EHA

of education. The Bulgarian society has implemented the EHA

activities resulting in a high interest to programs and tools such

guidelines and standards for CME since 2006 and has been given

as the Hematology Master Class, where eight Bulgarian mentees

the status of a contracted EHA CME provider thereafter. Since

have already graduated, as well as the Learning Center attracting

2015 the name of the accreditation body has changed its name

a good number of Bulgarian users. Along with the ability to

to the European Board of Accreditation in Hematology (EBAH).

participate in the Annual Congress of EHA and SWG meetings,

BMSC has also been involved in the CV passport project and the

this has resulted in growing EHA membership.

H-Net project from the beginning. All versions of the European Hematology Curriculum have been endorsed by the BMSH

Prof Dr Margarita Guenova, President

Workshop of the representatives of the hematology societies of the Balkan countries and board members of the Bulgarian Medical Society of Hematology during the 10th National Hematology Congress - October 2015. Prof Hehlmann as a special guest.”

SUMMER 2016 | hematopics | EHA

17


Best of Haematologica

An update on Haematologica At the beginning of 2016, we made - as one does - our resolutions

therapy” by Fabio Da Roit that colleagues already cited more

for the New Year. Two main points of attention were put forward

than 20 times (Web of Science: 22; Scopus: 31).1 In this study,

for the journal: (1) to make an effort to become a stronger journal

the researchers investigated the effects of the novel kinase

with more impact in the field of hematology, and (2) to further

inhibitors ibrutinib and idelalisib, on all known mechanisms of

improve our educational role by publishing strong review articles.

action of both type I and type II anti-CD20 antibodies. Ibrutinib

Now, six months later, it is rewarding to see that our pursuit of

and idelalisib are promising drugs for the treatment of chronic

excellence has been recognized by an increase in the impact

lymphocytic leukemia and B-cell non-Hodgkin lymphoma, either

factor to 6.671, making Haematologica the number 4 hematology

alone or in combination with anti-CD20 antibodies. The study

journal (table 1). Despite the well-known shortcomings of

by Da Roit and colleagues indicates that the design of combined

impact factors, they remains an important guide for authors

treatment schedules of anti-CD20 antibodies with these kinase

and institutions to assess the impact that a journal makes in a

inhibitors should consider the multiple negative interactions

particular field. With an increasing impact factor, Haematologica

between these classes of drugs.

clearly shows its determination to publish high quality research that makes an important contribution to the broad

In line with the important educational role of EHA, we aim

field of hematology.

to publish strong review articles. In the first 7 issues of 2016 we published 13 review articles, including 5 in our ‘Leaders in

In 2016, we also started to have article metrics available on all

Hematology’ review series.2-6 Some of the future review articles

manuscripts published in Haematologica. The ‘Info & Metrics’ tab

will address the management of hematological disorders, while

now provides detailed information on citations, downloads and social media sharing for each paper. These data indicate high

Author: Jan Cools

interest on several studies published last year with the article

Editor-in-Chief Haematologica

“Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination

18

EHA | hematopics | SUMMER 2016


Best of Haematologica

Table 1. Top 10 journals in the field of hematology (of a total of 70 journals in this field) based on the most recent impact factors (information

References

from ‘Journal Citation Reports’, Thomson Reuters, published in June 2016).

1.

Rank

Journal

1. Da Roit F, Engelberts PJ, Taylor RP, Breij EC, Gritti G, Rambaldi A, Introna M, Parren PW, Beurskens FJ, Golay J. Ibrutinib

2015 Impact Factor

interferes with the cell-mediated anti-tumor activities of

1

Leukemia

12.104

therapeutic CD20 antibodies: implications for combination

2

Blood

11.841

therapy. Haematologica. 2015;100(1):77-86.

3

Circulation Research

11.551

4

Haematologica

6.671

5

Blood Reviews

6.627

6

Journal of Hematology & Oncology

6.263

7

Arteriosclerosis Thrombosis and Vascular Biology

5.969

Stem Cells

5.902

8 9 10

2.

Theocharides AP, Rongvaux A, Fritsch K, Flavell RA, Manz MG. Humanized hemato-lymphoid system mice. Haematologica. 2016;101(1):5-19.

3.

Dreyling M, Ferrero S; European Mantle Cell Lymphoma Network. The role of targeted treatment in mantle cell lymphoma: is transplant dead or alive? Haematologica.

Journal of Thrombosis and Haemostasis

5.565

British Journal of Haematology

5.401

2016;101(2):104-14. 4.

Sonneveld P, Broijl A. Treatment of relapsed and refractory multiple myeloma. Haematologica. 2016;101(4):396-406.

5.

Storb R, Sandmaier BM. Nonmyeloablative allogeneic hematopoietic cell transplantation. Haematologica.

others will cover research methods or will provide insight in specific pathways or mechanisms of disease. In addition to review

2016;101(5):521-30. 6.

articles, we are also highly interested in publishing guideline

Hodgkin lymphoma: T cells, B cells, and immune checkpoints.

articles prepared by international groups, and we welcome new proposals. One of the highlights of 2016 was the publication of

Vardhana S, Younes A. The immune microenvironment in Haematologica. 2016;101(7):794-802.

7.

Engert A, Balduini C, Brand A, Coiffier B, Cordonnier C, Döhner

the ‘Roadmap for European Hematology Research’ published

H, de Wit TD, Eichinger S, Fibbe W, Green T, de Haas F, Iolascon

in the February issue and authored by almost 300 European

A, Jaffredo T, Rodeghiero F, Salles G, Schuringa JJ, EHA

hematology researchers. This document describes the major

Roadmap for European Hematology Research. The European

achievements in diagnosis and treatment of blood disorders

Hematology Association Roadmap for European Hematology

and also summarizes the greatest unmet clinical and scientific

Research: a consensus document. Haematologica.

needs in hematology. Use this document wherever you can

2016;101(2):115-208.

7

to underscore the importance of hematology research and to advocate for more funding.

SUMMER 2016 | hematopics | EHA

19


20

EHA | hematopics | SUMMER 2016


Report of the st highlights of the 21 Congress of EHA Copenhagen, Denmark June 9-12, 2016

SUMMER 2016 | hematopics | EHA

21


Report of the highlights of the 21st Congress of EHA

After eight years, the EHA Annual Congress returned to beautiful Copenhagen, a truly green city surrounded by clean waters and green spaces, combining architecture and design with a multitude of organic restaurants. The modern, glass-roofed Bella Center, one of the largest congress venues in Scandinavia with a keen eye for sustainability, suited the 21st Congress message perfectly: keep innovating the field of hematology.

Education and research In his opening speech, EHA President Professor Tony Green

Committee was the opportunity for young researchers to present

welcomed the well over 10,000 participants to the 21 Congress.

one-minute poster pitches during the oral sessions at the

He thanked the Scientific Program Committee, chaired by

annual congress. Another initiative that was launched at the

st

Professor Andreas Engert, for an excellent job in selecting

congress was the training and mentoring program Clinical

approximately 2,500 abstracts and composing a program of 240

Research Training in Hematology (CRTH), aiming to provide a way

sessions that had something to offer for everyone, spanning

to young hematologists to become specialists in the area of

all areas of basic, translational and clinical research. Professor

clinical trials.

Green: “EHA’s mission is clearly based on two pillars: education and research.” He specifically mentioned the online EHA Learning

Awards

Center as a good example of EHA’s attention to education.

EHA’s Career Development Program granted twelve young

“Without reducing our commitment to education, we would

researchers with a fellowship, offering funding and training

now like to tweak that spotlight and focus it onto the second

opportunities. The Jean Bernard Lifetime Achievement Award –

pillar: research”, announced Professor Green. This is reflected in

honoring outstanding physicians and scientists for their lifetime

the new theme of the year for 2016-2017: ‘Research at the heart

contribution to the advancement of hematology – was presented

of hematology’. “Research into basic mechanisms, more disease-

to Professor Clara Camaschella (San Raffaele Hospital, Milan, Italy)

focused translational research and clinical trials are all absolutely

for her contribution to the understanding of the pathophysiology

vital for us to ensure that hematology continues to provide

of inherited disorders of iron metabolism. Professor Camaschella

paradigms of very broad biological and clinical relevance.”

thanked the EHA for the award. “It is a great honor for me. It

One of the new initiatives of the newly established Research

is really a privilege, and I accept this honor on behalf of my

22

EHA | hematopics | WINTER 2016


EHA Fellowship Award Winners 2015-2016, from left to right: Hendrik Poeck,

st Report of the highlights ofAntonella the 21 Congress of EHA Gerard Jansen, Nai, Diana Passaro, Mihaela Crisan,

Marie Robin, Ida Hude, Amina Kozaric, Lucille Couronné, Laura Escribà Garcia, Yoshitaki Sunami, Maria Sabater Lleal.

collaborators, because the dedication and passion of our

poor prognosis. “I think anemia is and will be the main problem

collaborators make the difference in research.”

for the majority of patients with MDS”, said Professor Hellström.

For the first time the award was followed by an honorary lecture,

Her group focused on treating and deciphering the reasons for

in which Professor Camaschella recapitulated the story of her

anemia in MDS. They found that ineffective erythropoiesis is

research on hereditary hemochromatosis, genetic iron deficiency

mediated by mutations in SF3B1 resulting in aberrant splicing

and iron-loading anemias. She has made major contributions to

of ABCB7 and other genes. Targeting this pathway may provide

the demonstration of hepcidin and ferroportin as regulators of

opportunities for precision medicine in MDS. In addition, the

iron homeostasis. In addition she summarized the latest results of

investigators found that patients with lower-risk del(5q) MDS

her group on the role of iron in erythropoiesis.

display clonal instability, with TP53 mutations conferring a poor

Professor Eva Hellström Lindberg (Karolinska Institute, Stockholm,

prognosis. Professor Hellström expects that in the future next

Sweden) received this year’s José Carreras Award, an award for

generation sequencing will have an important role in both clinical

leading and active investigators who have made a substantial

decision making and therapeutic follow-up in MDS.

contribution to the field of hematology. In the honorary lecture Professor Hellström presented an intriguing overview of her

With events like the poster cocktails, the Early Career Reception

research, of which the focus has been to unravel the pathogenesis

and EHA Grooves, the congress offered excellent opportunities

of myelodysplastic syndrome (MDS) and discover novel

to meet with fellow hematologists from all over the world. The

therapeutic targets. “I am happy that for the first time patients

21st Congress of EHA; a great place for learning and sharing

with MDS are recognized by this award”, she said.

knowledge, as well as for networking, making it a hotspot for

They often experience erythroid failure and in general have a

innovation in the field of hematology.

SUMMER 2016 | hematopics | EHA

23


Report of the highlights of the 21st Congress of EHA

Red and white cell disorders

difference”, he said in a podcast interview for the EHA. In the absence of systematic registries, it is difficult to estimate the

At the EHA Annual Congress in Copenhagen, attention was

exact numbers of cases, but in Kulozik’s experience in Germany,

given to hematological challenges arising from increased

both sickle cell disease and thalassemia occur at approximately

migration in Europe of refugees from countries where

the same rate, and are a problem quantitatively. He does not

inherited hemoglobinopathies are more common. Two

expect that many patients will turn up at emergency rooms with a

presentations discussed the biology of iron overload in

complication of hemoglobinopathies without a known diagnosis.

hemochromatosis, and its risk for cardiovascular disease.

“Surprisingly, that is not the case in my experience. Most of the patients that we have seen in our department had a known

Hemoglobinopathies in refugees

diagnosis, and most were treated adequately, especially those

The refugee migration crisis in Europe poses new hematological

coming from Syria.”

challenges. Hemoglobinopathies are relatively common in

Especially in adult hematology, the practical exposure to patients

southern Europe, UK and France, but are now becoming

with hemoglobinopathies has been limited, and Kulozik expects it

more common in European countries where they were

will take some time for physicians to become experienced.

previously rare. These diseases are now a problem throughout Europe, confirmed Prof Andreas Kulozik,

Novel drug as a potential therapy for sickle cell disease

head of the department of Pediatric Oncology at the

Polymerization of a mutant form of hemoglobin (HbS) plays a key

University of Heidelberg in Germany. “In Germany, we always

role in the pathophysiology of sickle cell disease (SCD). A novel

had some patients with hemoglobinopathies, because we

small molecule, GBT440, increases the affinity of hemoglobin

had some migrants coming from the Mediterranean area,

for oxygen, thereby preventing polymerization of HbS and cell

but the numbers we are experiencing now are quite a

sickling. At the EHA Congress, Dr Paul Telfer (The Royal London

24

EHA | hematopics | SUMMER 2016


Hospital, UK) reported the first results of a phase 1/2 study with

Biology of iron overload in hemochromatosis

GBT440 in healthy volunteers and SCD patients.1 The study was

Iron bound to transferrin plays a central role in iron homeostasis.

conducted by investigators from Global Blood Therapeutics

Most of the iron in the body is recycled from senescent red blood

(South San Francisco, USA) and eight hospitals in the UK.

cells that are taken up by reticuloendothelial macrophages. Each

Thirty SCD patients randomly received 500 or 700 mg GBT440

day only about 5% is lost, which is complemented by dietary

or placebo for a period of 28 days. In general, the drug was well

intake in the duodenum. Hereditary hemochromatosis type IV is

tolerated, with headache and pain being the most common

characterized by a mutation in ferroportin, which is expressed in

adverse events. The oxygen affinity of hemoglobin increased in

macrophages and duodenal enterocytes, resulting

patients treated with GBT440 as compared to the placebo group.

in uncontrolled iron export into the blood stream and systemic

Unconjugated bilirubin, a marker of hemolysis,

iron overload.

markedly decreased during the treatment period, returning

Dr Sandro Altamura (University of Heidelberg, Germany) and

to baseline levels within two weeks after stopping treatment.

colleagues generated a mouse model with mutated ferroportin

In addition, the investigators observed increases in hemoglobin,

that recapitulates hemochromatosis.3 The investigators observed

and decreases in erythropoietin, sickle cell counts and the

iron depletion in cell types that export iron in the spleen and the

inflammatory marker P-Selectin. These results support the

duodenum. The mice had severely elevated plasma iron levels,

hypothesis that preventing HbS polymerization by treatment

and excess iron was deposited in the liver. In addition, they had

with GBT440 can lead to less damage and improved lifespan

more and larger red blood cells.

of red blood cells, improved tissue oxygen delivery, and less

Next, they generated tissue-specific knock in mice expressing

inflammation. The investigators concluded that GBT440 has

mutated ferroportin in either macrophages or in the duodenum.

potential as a new therapy for sickle cell disease, and should be

Only the duodenal-specific knock in mice had increased

studied further.

plasma iron levels and hepatic iron overload, recapitulating hemochromatosis. “Macrophage iron recycling from

Treatment with pyruvate kinase activator increases Hb

erythrocytes does not account for iron overload in hereditary

Pyruvate kinase deficiency, a severe congenital anemia, is caused

hemochromatosis”, concluded Altamura. “Dysregulated iron

by mutations in erythrocyte pyruvate kinase (PK-R), an enzyme

export from duodenal enterocytes is self-sufficient to generate

required for maintenance of ATP in red blood cells. The orally-

a hemochromatosis-like phenotype. These results are quite

available small molecule AG-348 binds to both wild-type and

important, because these models will allow us to develop

mutated PK-R, increasing its catalytic activity and restoring ATP

specific strategies aimed at limiting the iron export in

levels. Dr Rachael Grace (Dana-Farber Boston Children’s Cancer

hereditary hemochromatosis.”

and Blood Disorder Center, USA) presented early clinical trial results with AG-348.2

High iron levels promote atherosclerosis in mice

The ongoing DRIVE PK study aims to enroll 50 transfusion-

High systemic iron levels have been suggested to promote

independent PK deficient adults. After randomization, the

atherosclerosis and cardiovascular disease. Iron can be found to

patients received either 50 or 300 mg orally twice daily for a

accumulate in atherosclerotic lesions, however, studies testing

period of six months. At the data cut-off of 27 March 2016,

the ‘iron overload’ hypothesis have provided conflicting evidence.

eighteen patients have been treated. Three of these patients

At the EHA Annual Congress, Dr Francesca Vinchi (University of

completed the six-month period. Two patients remain on

Heidelberg & EMBL, Germany) presented results suggesting that

treatment in the extension arm.

iron overload is a risk factor for atherosclerosis.4

In general, AG-348 was well tolerated. Patients experienced only mild to moderate adverse events, with nausea and headache

The investigators crossed a mouse model of type IV hereditary

being the most common.

hemochromatosis, that has a defect in the iron exporter

Treatment with either 50 or 300 mg AG-348 resulted in rapid

ferroportin (FPNWT/C326S), with a mouse model that has increased

and sustained hemoglobin (Hb) increases. Half of the patients

susceptibility to atherosclerosis (ApoE-/-). At 6 and 12 months of

demonstrated an increase in Hb >1.0g/dL in a median time of

age, the ApoE-/-FPNWT/C326S mice showed more and larger aortic

1.9 weeks. The marked increase in Hb appeared to be related

lesions than ApoE-/- mice. High circulating iron levels resulted

to the genotype, all of these patients had at least one missense

in increased oxidation of low-density lipoprotein. The mice

mutation. The investigators did not observe any discernible effect

demonstrated enhanced endothelial activation and increased

on ATP levels. In most patients with an Hb increase>1.0 g/dL the

vascular permeability.

pharmacodynamic marker 2,3-DPG decreased, however, more

Iron accumulated in the vascular smooth muscle cells of the

data are required to confirm a correlation.

arterial media, and correlated with vascular oxidative stress

SUMMER 2016 | hematopics | EHA

25


Report of the highlights of the 21st Congress of EHA and calcifications. The investigators also observed increased

Myeloid malignancies

macrophage recruitment to plaques, which together with decreased collagen and increased lipids may contribute to the

As more details are revealed on the biology of myeloid

higher vulnerability of the plaques. Echocardiography revealed

malignancies, it becomes clear that many subtypes exist,

left ventricle hypertrophy, which may be a compensation for the

which may require different treatments. Patients with chronic

increased arterial stiffness.

myeloid leukemia (CML) who have achieved deep molecular

An iron-deficient diet rescued the severe atherosclerotic

response for at least a year can safely stop TKI treatment, as

phenotype in the interbred mice. The investigators conclude that

was shown by the EURO-SKI trial. Immunological factors may

high systemic iron level is a risk factor for cardiovascular disease.

be able to predict which patients can successfully discontinue TKI treatment, as was summarized in the Education Session -

References

Chronic myeloid leukemia.

1. Lehrer-Graiwer J, et al. EHA 2016: abstract P371.

A combination of a novel antibody-drug conjugate with

2. Grace RF, et al. EHA 2016: abstract S466.

hypomethylating agents shows encouraging responses in

3. Altamura S, et al. EHA 2016: abstract S147.

elderly patients with poor risk acute myeloid leukemia (AML).

4. Vinchi F, et al. EHA 2016: abstract S134.

Next generation sequencing demonstrated that elderly patients with AML more often have persisting mutations at remission, indicating the persistence of a pre-leukemic clone. Two presentations discussed specific genetic alterations that are common in subtypes of AML, and may contribute to leukemogenesis. A phase 3b study demonstrated that polycythemia vera patients who are resistant or intolerant to hydroxyurea benefit from the kinase inhibitor ruxolitinib. And finally, a presentation in Plenary Session 2 discussed the concept of clonal hematopoiesis and its role in myelodysplastic syndrome. Stopping tyrosine kinase inhibitors The introduction of tyrosine kinase inhibitors (TKI) has greatly improved outcome for patients with CML. Many patients can now achieve deep molecular responses. Several studies have shown that a substantial proportion of these patients remain in durable remission after TKI withdrawal, a prerequisite for potentially being cured.1,2 Aim of the EURO-SKI study was to define prognostic factors for successfully stopping TKI treatment.3 The investigators included 868 patients with CML in chronic phase from 61 centers across Europe. Most patients had been treated with imatinib. TKI treatment lasted for at least three years, with a median of 7.7 years. Deep molecular responses (MR4) had lasted on average 4.7 years. After stopping TKI treatment, patients were regularly screened by standardized PCR-monitoring. Out of 750 evaluable patients 62% demonstrated molecular relapse-free survival (RFS) at 6 months, 56% at 12 months, 52% at 24 months and 49% at 36 months. Duration of imatinib treatment and MR4 were the only factors significantly correlated with molecular RFS at six months. The optimal treatment duration for imatinib was at least 5.8 years. “Further analysis will be pursued in order to suggest an optimal cut-off for MR4 duration and to overcome the correlation between the two variables. Additionally, more data on IFN-pretreatment will be collected�,

26

EHA | hematopics | SUMMER 2016


said lead study author Dr Johan Richter (Skåne University

to a DNA-crosslinking agent. Upon incorporation, the drug is

Hospital, Lund, Sweden).

released by proteolytic cleavage, killing the cell. In preclinical

Approximately one third of the patients experienced mostly mild

studies, a combination of SGN-CD33A with hypomethylating

musculoskeletal symptoms due to TKI withdrawal. None of the

agents enhanced their cell-killing activities.

patients who relapsed progressed to accelerated phase or blast

In the ongoing phase I study to date, 53 patients with CD33+

crisis. “The study is still ongoing, but more than 80% of patients

AML received a combination of SGN-CD33A with azacitidine or

who restarted TKI therapy have reachieved MR so far”, told

decitabine.5 The median age was 75 years, and all patients had

Richter. “With inclusion and relapse criteria less strict than in many

declined intensive chemotherapy. After the initial four cycles,

previous trials, stopping of TKI therapy in a very large cohort of

patients demonstrating a response remained on treatment.

CML-patients appears feasible and safe.”

“The combination was well tolerated”, said Dr Amir Fahti

Immunological predictors of stopping treatment

most common adverse events were related to on-target effects,

4

(Massachusetts General Hospital Cancer Center, Boston, USA). The “There are many different mechanisms by which cancer is able

including neutropenia, thrombocytopenia and anemia. The early

to modulate the immune system”, said Prof Dr Satu Mustjoki

mortality rate was low. “Quite intriguing was the high response

(University of Helsinki, Finland) at the start of her presentation.

rate seen with the combination”, according to Fahti. Treatment

The result is a dysfunctional immune system, found in many

with the combination led to a composite remission rate of 71%,

types of cancer. Mechanisms found in CML include exhaustion

with 41% of patients achieving complete remission (CR). The

of leukemia-specific T cells, high expression of PD1 on CD8 cells

median time to remission was two treatment cycles.

putting a brake on the immune system, and qualitative and

“Response rates were higher, and achieved more quickly,

quantitative defects in NK cells.

than would be expected from historical data associated with

CML patients who discontinue TKI treatment still have some

hypomethylating agents alone”, concluded Fahti. “Overall survival

residual leukemic cells left, which in approximately half of those

is promising and continues to evolve.” A randomized controlled

patients does not result in relapse. Immune surveillance may be

phase III study with this combination in elderly AML patients is

able to keep those residual cells in check.

currently enrolling.

In several TKI discontinuation trials, patients who did not relapse had higher levels of NK cells. “In the EURO-SKI study as well, a

Persisting mutations in older AML patients

higher amount of NK cells seemed to be associated with a better

In some AML patients, the disease originates from a clone of

molecular relapse-free survival”, said Mustjoki.4 Patient-specific

pre-leukemic hematopoietic stem cells. These cells carry a

factors such as expression of NK cell receptors or HLA type, or

somatic mutation, for example in DNMT3A or TET2, but still can

disease-specific factors such as the underlying biology of the

differentiate normally. Only after acquiring additional mutations

disease or immunosuppression induced by the tumor cells may

do the cells transform and a leukemic clone will grow out. After

both contribute to the observed differences in NK cell activation.

treatment with induction chemotherapy, most patients achieve

An interesting possibility would be to activate the immune

morphological complete remission, however, pre-leukemic clones

system in those patients who are unable to stop TKI treatment,

may persist.

for example by treatment with interferon-alpha or immune

In order to determine the clinical significance of such persisting

checkpoint inhibitors. “The role of the immune system needs to

clones, a group of German investigators performed targeted

be analyzed in larger patient cohorts, with multivariate analyses

sequencing of 68 known leukemia-associated genes in matched

combined with clinical parameters, in order to find biomarkers for

samples taken at diagnosis and remission from 107 AML patients.6

successful TKI discontinuation”, concluded Mustjoki.

Most patients had intermediate risk cytogenetics, and 60% received an allogeneic stem cell transplantation.

High remission rates with SGN-CD33A in AML

“At diagnosis, we identified a total of 424 mutations in 104

Elderly patients with AML are particularly difficult to treat due to

patients”, told Dr Maja Rothenberg-Thurley (Ludwig-Maximilians-

poor tolerance to conventional intensive chemotherapy. These

Universität, Munich, Germany). “In the remission samples, 60

patients often receive hypomethylating agents (azacitidine,

mutations persisted in 38 patients.” The most common persisting

decitabine) as more gentle forms of treatments, but with lower

mutations were in DNMT3A, TET2, ASXL1 and SRSF2. Mutations in

response rates and limited benefits. In order to improve response

NPM1, NRAS, WT1 and FLT3-ITD were mainly cleared in remission.

rates in older AML patients, a phase I study combined a novel

“Importantly, almost all patients with persisting mutations had at

antibody-drug conjugate with standard hypomethylating agents.

least one additional mutation that was cleared in remission.” The

Almost all leukemic cells express CD33. SGN-CD33A

detection of persisting mutations at first remission likely indicates

(vadastuximab talirine) is a CD33-targeted antibody conjugated

the persistence of a pre-leukemic clone.

SUMMER 2016 | hematopics | EHA

27


Report of the highlights of the 21st Congress of EHA Age was the only clinical characteristic that correlated with the

both developed myeloid malignancies, which suggest that it can

presence of persisting mutations at remission. The median age

act as either a tumor suppressor or an oncogene, depending on

was 60 years for patients with a persisting mutation in DNMT3A

the expression levels.

and 66.5 years for other persisting mutations, compared to 48

The molecule hnRNP K (heterogeneous nuclear ribonucleoprotein

years for patients without persisting mutations. Patients with

K) is involved in pre-mRNA processing and influences several

persisting mutations had a significantly shorter RFS (median, 14.3

proteins, including p53, c-Myc and C/EBP, important regulators

vs. 58.0 months; P=0.009) and OS (median, 39.6 vs. >72 months;

of cell proliferation, differentiation and self-renewal. HNRNPK has

P=0.005). The type of mutation or the size of the clone did not

been found to be mutated in some cases of AML. Patients with

significantly impact RFS. “The persistence of leukemia-associated

deletion of the 9q21.32 locus demonstrate reduced expression

mutations might contribute to the higher relapse rate in elderly

of HNRNPK. “We hypothesized that HNRNPK may act as a tumor

patients”, Rothenberg-Thurley concluded.

suppressor by deregulating proliferation and differentiation programs”, said lead study author Dr Miguel Gallardo (MD

ZBTB7A mutation common in t(8;21) AML

Anderson Cancer Center, Houston, USA).

Approximately 5-10% of AML patients carry the translocation

He and his colleagues genetically engineered mice to be

t(8;21), which is associated with a favorable outcome. The

haploinsufficient for Hnrnpk.8,9 These mice exhibited reduced

resulting fusion protein disrupts the transcriptional activity of

levels of Hnrnpk and developed myeloproliferative neoplasms

the core binding factor complex. However, t(8;21) alone is not

and lymphomas, resulting in decreased survival. Expression of

sufficient to induce leukemia in mouse models, indicating that

the cell cycle and differentiation genes p21, C/EBPa and C/EBPb

additional lesions are required. Exome sequencing identified

was significantly reduced as well. “Looking at these results, we

ZBTB7A as a frequently mutated gene in t(8;21) positive AML.7

can say that HNRNPK is a tumor suppressor”, Gallardo concluded.

The investigators first sequenced matched diagnostic and

“However, the story is not so simple.”

remission samples from two AML patients carrying t(8;21). Both

When the investigators determined the expression of HNRNPK

patients had a mutation in ZBTB7A at diagnosis that was no longer

in AML patients without deletion of the 9q21.32 locus,

present at remission, indicating a somatic mutation. Targeted

they observed HNRNPK gene amplifications and increased

sequencing of 56 AML patients with t(8;21) identified ZBTB7A

expression, indicative of oncogenic activity. To their surprise,

mutations in 23% of the cohort. “Together with ASXL2, this was

a transgenic mouse model that overexpressed Hnrnpk in the

the most frequently mutated gene”, said Luise Hartmann (German

hematologic compartment had a highly similar phenotype as the

Cancer Research Center (DKFZ), Heidelberg, Germany), who

haploinsufficient mice. The transgenic mice also overexpressed

presented the results. Mutations in ZBTB7A occurred mutually

the pro-growth gene c-Myc.

exclusive of other gene mutations known to be involved in

Gallardo concluded that hnRNP K acts as a tumor suppressor

t(8;21) AML, such as in NRAS, KIT and FLT3. Mutations in ZBTB7A

when its expression is reduced, or as an oncogene when

were seldom found in other types of AML, suggesting a specific

overexpressed, influencing distinct cellular pathways.

association with t(8;21) AML. ZBTB7A – also known as LRF, FBI-1 or pokemon – is a

PV patients without splenomegaly profit from ruxolitinib

transcriptional repressor that plays an important role in lineage

High-risk polycythemia vera (PV) patients currently receive

fate decisions during hematopoiesis. The mutations found in

hydroxyurea (HU) in order to control hematocrit levels.

ZBTB7A interfered with DNA binding and repressor activity, and

Approximately 15% of patients become resistant to or intolerant

disrupted the anti-proliferative potential of wildtype ZBTB7A. In a

of HU. Ruxolitinib normalized blood cell counts, reduced spleen

cohort of cytogenetically normal AML patients, high expression of

volume, and improved symptoms in HU resistant or intolerant

ZBTB7A was associated with favorable outcome.

PV patients with splenomegaly. The RESPONSE-2 study now

“ZBTB7A is one of the most frequently mutated genes in AML with

demonstrates that patients without palpable splenomegaly

t(8;21). This was recently also confirmed in a smaller, independent

similarly benefit from ruxolitinib treatment, as was presented by

cohort. The fact that expression is prognostic in cytogenetically

Prof Francesco Passamonti (University of Insubria, Varese, Italy).10

normal AML suggests a general mechanism that goes beyond the

The phase 3b RESPONSE-2 study randomized 149 PV patients

group of t(8;21) AML”, concluded Hartmann.

between treatment with the JAK1/2 inhibitor ruxolitinib and best available therapy (BAT). All patients were resistant to or intolerant

Imbalance in HNRNPK expression contributes to AML

of HU, and had nonpalpable spleens. Most patients received only

HNRNPK is one of the genes residing in the 9q21.32 locus which

one prior line of therapy.

is deleted in a subset of AML patients. Mice with either reduced

At 28 weeks, 62% of patients treated with ruxolitinib achieved

or increased HNRNPK expression had a highly similar phenotype;

hematocrit control, compared to 19% of patients receiving BAT.

28

EHA | hematopics | WINTER 2016


The presence of clonal hematopoiesis was associated with reduced overall survival. Unexpectedly, this was not related to the increased risk of getting a hematologic malignancy, but to the higher risk of cardiovascular disease. Ebert and colleagues propose to refer to this provisional entity as Clonal Hematopoiesis of Indeterminate Potential (CHIP). Clonal progression in myelodysplastic syndrome (MDS) can occur in many ways, one of which is deletion of the long arm of chromosome 5. Multiple genes reside within this region, but the gene RPS14, encoding a ribosomal protein, is critical for macrocytic anemia, a defining feature of this deletion. In a mouse model knockout of the Rps14 gene resulted in impaired erythropoiesis.12 This effect involved upregulation of S100A8 and S100A9, both involved in the innate immune response. Del(5q) MDS is sensitive to treatment with lenalidomide. This drug was found to modulate the activity of a ubiquitin ligase, resulting in ubiquitination and degradation of the kinase CK1a. The gene encoding CK1a is located in the 5q region, and is already expressed at haploinsufficient levels, providing a therapeutic window for lenalidomide action. The majority of patients (81%) treated with ruxolitinib did not require any phlebotomies. Significantly more patients receiving

References

ruxolitinib achieved complete hematologic remission, and more

1. Mahon FX, et al. Lancet Oncol 2010;11(11):1029-35.

patients experienced a substantial reduction in symptoms,

2. Ross DM, et al. Blood 2013;122(4):515-22.

including pruritus.

3. Richter J, et al. EHA 2016: abstract S145.

Grade 3-4 adverse events occurred in 22% of patients receiving

4. Ilander MM, et al. Blood 2013;122(21):379.

ruxolitinib, compared to 27% with BAT. There were three

5. Fahti A, et al. EHA 2016: abstract S503.

thromboembolic events in the BAT arm, compared to one in the

6. Rothenberg M, et al. EHA 2016: abstract S146.

ruxolitinib arm.

7. Hartmann L, et al. EHA 2016: abstract S119.

The results are consistent with the RESPONSE study in patients

8. Gallardo M, et al. Cancer Cell 201528(4):486-99.

with splenomegaly, and the investigators suggest that ruxolitinib

9. Gallardo M, et al. EHA 2016: abstract S120.

could be considered as a standard treatment for HU resistant or

10. Passamonti F, et al. EHA 2016: abstract S112.

intolerant PV patients.

11. Jaiswal S, et al. N Engl J Med 2014;371(26):2488-98. 12. Schneider RK, et al. Nat Med 2016;22(3):288-97.

Clonal hematopoiesis and MDS Occasionally, cells with the capacity for self renewal, such as hematopoietic stem cells, acquire a mutation in a gene that leads to clonal expansion. In some cases, that clone will gain additional mutations leading to overt malignancy. Dr Benjamin Ebert (Brigham and Women’s Hospital, Boston, USA) and colleagues analyzed exome sequencing data from a cohort of 17,000 individuals without a hematologic malignancy, for which DNA was isolated from peripheral blood.11 They found that it was extremely rare for young individuals to have somatic mutations in genes that are known to be recurrently mutated in hematologic malignancies. However, by the age of 70, approximately 10% of all individuals carried a mutation in one of these genes. The epigenetic regulators DNMT3A, TET2 and ASXL1 were most frequently mutated. Almost all of the subjects had only a single mutation, which was present in a large, expanded clone.

SUMMER 2016 | hematopics | EHA

29


Congress Attendees

infographic

10676 attendees from 6 continents

Europe (47 countries)

Outside Europe (62 countries)

Europe

South America

Africa 76

448

7234

North America

Middle East 1451

304

Oceania

Asia

197

966

nurse 0.9%

thrombosis & hemostasis 3.7%

other 14.8%

trainee 3.4% oncologist 3.2%

pediatric hematology 3.8%

Profession

non-medical scientist 11.3%

hematologist 50.4%

other 13.0% transfusion 1.0%

red and white cell disorders 3.8% transplantation 4.5%

pharmaceutical representative 16.1%

myeloid malignancies 32.0% other 3%

other 17.7%

research and clinical practice 25.6%

Field of Interest

lymphoid malignancies 38.2%

Main Activity

clinical practice 31.1%

biology basic research 21.6%

Type of Research research (incl. clinical trials) 25.7%

translational research 27.5%

clinical trials 47.8%


Report of the highlights of the 21st Congress of EHA

Lymphoid malignancies

Kapodistrian University of Athens, Greece), who presented the results. “More importantly, 43% of patients achieved a complete

Several clinical studies presented at the EHA Annual Congress

response.” Median duration of response was not reached

show that for many lymphoid malignancies, progress can be

with daratumumab, compared to 17.4 months without. The

made with new agents or an intensified treatment regimen.

combination treatment had a manageable safety profile

The first randomized controlled studies with daratumumab

and was well tolerated. “Thus, the combination of daratumumab

in combination with standard of care agents demonstrate

with lenalidomide and dexamethasone potentially represents

impressive results in multiple myeloma (MM). In preclinical

a new standard of care for relapsed or refractory multiple

studies, inhibition of the potential therapeutic target

myeloma patients with one or more prior treatments”,

TAK-1 decreased MM tumor growth, while preventing

concluded Dimopoulos.

bone destruction.

The CASTOR study evaluated the combination of daratumumab

In adults with relapsed or refractory acute lymphoid leukemia

with bortezomib and dexamethasone (DVd), compared to

(ALL), blinatumomab treatment demonstrated almost

bortezomib and dexamethasone (Vd). The study randomized

doubled overall survival in a phase 3 study. A retrospective

498 patients with RRMM. “This patient population was already

study showed that the survival of young adults with ALL

exposed to available agents, with about 30% of them being

markedly improves when they are treated with intensive

refractory”, said Prof Antonio Palumbo (University of Torino, Italy)

chemotherapy according to pediatric protocols.

during his presentation.

Treatment with ibrutinib improved survival for a high-risk

In this study as well, the combination with daratumumab

group of chronic lymphocytic leukemia (CLL) patients with a

dramatically improved PFS. At a median follow-up of 7.4 months

deletion of chromosome 17p, as appeared from a combined

the risk of progression or death diminished significantly by 61%

analysis of three clinical studies.

(HR 0.39; P<0.0001). The PFS benefit was consistent across all

Patients with classical Hodgkin Lymphoma (HL) who progress

subgroups. Patients who received one prior line of treatment

after autologous stem cell transplantation (ASCT) and

appeared to profit most. “Early intervention is certainly relevant to

brentuximab vedotin may benefit from treatment with the

maximize the efficacy of this combination”, Palumbo remarked.

checkpoint inhibitor nivolumab, as was demonstrated by the

The ORR increased significantly to 83% compared to 63% with

first results from a phase 2 study.

Vd, and the rates of very good partial response (VGPR) and CR

Current studies and issues with checkpoint inhibitors in

approximately doubled. Most patients demonstrated a partial

lymphomas were put into perspective during the Plenary

response after one to two months of treatment. “On the other

Session 1.

hand, the achievement of a complete response requires a longer treatment duration of at least one year”, told Palumbo.

Phase 3 results with daratumumab in MM

Addition of daratumumab to Vd did not result in cumulative

The anti-CD38 antibody daratumumab targets myeloma cells

toxicities. “This might be potentially considered a new standard

both directly through on-tumor activity and indirectly via

of care for a large group of refractory patients currently receiving

immunomodulatory actions. In early phase trials, treatment with

bortezomib and dexamethasone alone.”

daratumumab combined with lenalidomide and dexamethasone resulted in unprecedented responses in patients with relapsed

TAK-1 as a novel therapeutic target in MM

or refractory multiple myeloma (RRMM). In Copenhagen, two

MM is often accompanied by progressive bone destruction. The

late-breaking abstracts presented results of the first randomized

TGF-b -activated kinase-1 (TAK-1) was identified as an upstream

controlled studies with daratumumab combined with standard of

regulator of Pim-2, may provide a novel therapeutic target for

care agents.1,2

improving survival and restoring bone, as was presented by Prof

The POLLUX study randomized 569 patients with previously

Masahiro Abe (Tokushima University, Japan).3

treated RRMM to receive lenalidomide and dexamethasone with (DRd) or without daratumumab (Rd). A pre-planned interim

The kinase Pim-2 is highly expressed in both MM cells and

analysis demonstrated a significant improvement of progression-

surrounding cells, including bone marrow stromal cells and

free survival (PFS), with a remarkable 63% reduction of the risk

osteoclasts. It plays a key role in the proliferation and survival

of progression or death (HR 0.37; P<0.0001). Daratumumab

of MM cells, and inhibits the formation of osteoblasts while

induced deep and durable responses. The overall response rate

stimulating the formation of osteoclasts, resulting in bone

(ORR) was 93% vs. 76% for DRd vs. Rd, respectively. “This was

resorption. In animal models treatment with Pim, inhibitors

the highest response rate ever seen in patients with relapsed or

markedly reduced MM tumor growth and prevented

refractory myeloma”, said Prof Meletios Dimopoulos (National and

bone destruction.

SUMMER 2016 | hematopics | EHA

31


Report of the highlights of the 21st Congress of EHA “In an intent-to-treat analysis, blinatumomab was able to double overall survival of this dismal patient population from 4.0 to 7.7 months”, said lead study author Dr Max Topp (Universitätsklinikum Würzburg, Germany). The overall response rate was significantly higher with blinatumomab, and more patients achieved complete remission. The improvement of survival was consistent across subgroups, regardless of age, prior salvage therapy or patients relapsing after stem cell transplantation. Adverse events were consistent with previous studies with blinatumomab. Patients treated with blinatumomab less often experienced grade 3 or higher neutropenia and infection compared to patients receiving SOC. “Of note, neurologic events appeared at a similar rate”, said Topp. These results led to early stopping of the trial. Topp: “Blinatumomab is the first immunotherapeutic agent demonstrating overall survival benefit when compared to chemotherapy in adult patients with relapsed or refractory ALL.” Abe and colleagues recently identified TAK-1 as an upstream regulator of Pim-2. The kinase TAK-1 acts directly downstream

Pediatric protocol improves survival of young adults with ALL

of TNF-family and IL6 receptors, activating the NF-kB and

Children with ALL are treated with more intensive chemotherapy

STAT3 pathways which results in increased expression of Pim-2.

regimens than adults, and have better survival rates of

The investigators found that TAK-1 is both overexpressed and

approximately 85% compared to 40% in adults. In order to

phosphorylated in MM cells. Treatment of MM cell lines with the

improve survival, young adults (aged 18-45 years) were offered

TAK-1 inhibitor LLZ-1640-2 suppressed proliferation and induced

treatment according to the pediatric NOPHO ALL2008 protocol in

apoptosis. In addition, TAK-1 inhibition abrogated IL-6 and TNF-

seven Nordic and Baltic countries.

a-induced signaling, resulting in suppression of Pim-2. The TAK-

A retrospective study collected data from 1,509 patients with Ph-

1 inhibitor also decreased MM cell adhesion to bone marrow

negative ALL aged 1-45 years, of which 221 patients were adults.6

stromal cells, impairing support of MM cell growth.

Diagnostics, risk stratification and treatment were identical for

TAK-1 inhibition restored osteoblastogenesis, whereas it

all patients. The median follow-up was four years. Patients were

suppressed osteoclastogenesis via RANKL. In murine MM models,

divided into four risk groups according to immunophenotype,

treatment with LLZ-1640-2 inhibited tumor growth and prevented

cytogenetics, white blood cell count at diagnosis, and response to

bone destruction. Abe concluded that TAK-1 is a key regulator in

induction therapy. The higher risk patients were eligible for a stem

MM, and may form an efficacious therapeutic target for improved

cell transplant. Adult patients more often had higher risk ALL.

survival while restoring bone.

At five years, event-free survival (EFS) was 88% for young children (1-9 years), 79% for teenagers (10-17 years), and 73% for adults

Blinatumomab improves overall survival in ALL

(18-45 years). This is a marked improvement compared to the

Adult ALL patients who are refractory or relapse after intense

historical 5-year EFS of 42% for Danish patients aged 18-45 years.

chemotherapy have a poor prognosis. In a phase II study,

“We are pleased with the results, and expect to continue this

treatment with the immunotherapeutic agent blinatumomab

treatment”, said Dr Nina Toft (Herlev University Hospital,

resulted in high response rates.4 In a phase 3 study,

Denmark) in her presentation. “We have improved the survival

blinatumomab almost doubled overall survival of relapsed or

for ALL patients aged 18-45 years with the NOPHO ALL2008

refractory (r/r) ALL patients.5

treatment. The cure rates are close to that of children when

Blinatumomab is a bispecific antibody construct that binds

stratified by risk group.” The difference in outcome between adults

specifically to CD19 on B cells as well as CD3 on T cells. It engages

and children was only significant for patients with intermediate

the patient’s own T cells to kill B-precursor ALL cells. The goal

risk ALL.

of the international phase 3 TOWER study was to determine

The intensive chemotherapy did not induce significantly more

whether blinatumomab can improve overall survival compared

severe toxicities in adults than in children, and intervals between

to standard of care (SOC) chemotherapy. A total number of

treatment phases were almost identical. Still, new drugs are

405 adults with Philadelphia-negative r/r B-precursor ALL were

needed, according to Toft. “With this treatment, we have reached

randomized 2:1 to receive blinatumomab or SOC.

the limit of toxicity that we found reasonable.”

32

EHA | hematopics | SUMMER 2016


infographic SUMMER 2016 | hematopics | EHA

33


Report of the highlights of the 21st Congress of EHA Integrated analysis of ibrutinib studies in CLL

pneumonia and hypertension. “Severe adverse events declined

with deletion 17p

over time, and only 15% of patients discontinued therapy because

CLL patients with a deletion of chromosome 17p (del17p) have

of an adverse event”, said Dr Jeffrey Jones (Ohio State University

a particularly dismal prognosis, and historically survive only two

Comprehensive Cancer Center, Columbus, USA), who presented

to three years post initial treatment. Ibrutinib, an oral inhibitor

the results in Copenhagen. At the time of analysis, 45% of patients

of Bruton’s tyrosine kinase, has marked activity in del17p CLL

still remained on treatment with ibrutinib.

allowing treatment of the disease without chemotherapy. It

“In this group of 243 patients with high-risk CLL, all of them with

has been approved for the treatment of patients with CLL or

del17p, the estimated 30-month progression-free and overall

small lymphocytic leukemia (SLL), including those with del17p.

survival surpass those reported for all other existing therapies for

An integrated analysis of three clinical studies with ibrutinib

del17p CLL”, Jones concluded.

evaluated the efficacy and safety outcomes of 243 CLL patients with del17p.7

Nivolumab new option for relapsed HL patients

The patients remained on study for a median time of 28 months.

Patients with HL who progress after second line chemotherapy

In the combined studies, 84% of the patients responded to

and stem cell transplantation, have a particularly poor prognosis.

treatment with ibrutinib, with 9% of the patients achieving CR or

The phase 2 study Checkmate 205 reports encouraging results

CRi, and 67% achieving PR. The ORR was consistently high across

with nivolumab in patients with classical HL after failure of both

all studies analyzed. Median PFS was not reached at 30 months.

ASCT and subsequent brentuximab vedotin treatment.8

At that time, the estimated PFS was 55%, and the estimated

The PD-1 checkpoint inhibitor nivolumab is only the second new

OS was 67%.

agent to be approved by the FDA for the treatment of relapsed

Grade 3 or higher adverse events included neutropenia,

HL patients in more than three decades. Reed-Sternberg cells –

34

EHA | hematopics | SUMMER 2016


accelerated approval in HL. Amplification of the chromosomal region 9p24.1 is highly common in HL, resulting in increased expression of PD-L1 and PD-L2 on the cell surface. In phase 1 studies, heavily pretreated patients with HL demonstrated high objective response rates of 87% and 65% when treated with nivolumab or pembrolizumab, respectively.9 Preliminary results from two registration phase 2 studies – Checkmate 205 and KEYNOTE-087, both presented at the EHA annual congress8,10 – demonstrated similar ORR with these checkpoint inhibitors. Most of the examined tumors were positive for PD-L1 and PD-L2 expression. Several types of non-Hodgkin Lymphoma (NHL) express PDL1 or PD-L2, and clinical trials are ongoing. In diffuse large B cell lymphoma (DLBCL), nivolumab appeared to have limited whose presence is characteristic for classical HL – express high

activity, but subsets of DLBCL may be more sensitive, based on

levels of the PD-1 ligands, PD-L1 and PD-L2, making HL a good

their expression of PD-L1. However, not all malignancies that

candidate for checkpoint inhibition.

express PD-L1 respond to PD-1 blockade, among which MM and

The ongoing, multicohort Checkmate 205 study evaluated

CLL. Conversely, PD-1 inhibitors can be active in PD-L1 negative

nivolumab in classical HL. At the EHA Congress Prof Anas Younes

malignancies, for example in follicular lymphoma. “Perhaps what

(Memorial Sloan Kettering Cancer Center, New York, USA)

this reflects is our incomplete understanding of the biology

reported the results from one cohort which enrolled 80 patients

underlying these responses”, said Armand.

who received nivolumab every two weeks after progression

Some studies are looking into the possibility of combining stem

following ASCT and brentuximab vedotin.

cell transplants with checkpoint blockade. The conditioning

After a median follow-up of 8.9 months, the ORR as assessed

regimen for an autologous transplant is more and more

by an independent radiologic review committee (IRCC) was

recognized to have an immunogenic effect, which may be

66%. Seven patients (9%) achieved CR, 58% had PR, and 23%

exploited for treatment with checkpoint inhibitors. Clinical data

demonstrated stabled disease (SD). “The waterfall plot was

to support these ideas are limited, various studies are ongoing.

impressive. Almost everyone had some reduction of tumor

For allogeneic transplants, data from AML suggest that the tumor

burden between measurements”, said Younes. Responses were

may use upregulation of checkpoint as an escape mechanism

quick and durable. The median time to response was 2.1 months.

against the donor immune system.

The median duration of response was 7.8 months, with most

Armand stressed the importance of a better understanding of

patients continuing to respond at the time of analysis. Younes:

the biology of PD-1 blockade, in order to identify predictors of

“The study is still ongoing, so it is too early to call the exact

response and toxicity, and to be able to pick the right partners for

progression-free survival.”

clinical studies. “We have so many pathways that we can target.

The safety profile of nivolumab was similar to what has been seen

The number of trials that we can do and combinations that we

in other tumors. “It was reasonably well tolerated”, said Younes.

can make is astronomical. We have to think strategically about

“Nivolumab is an important new treatment to address the unmet

how we can leverage all this knowledge to conduct the right trial

need in patients with classical HL with progressive disease and

as early as possible”, Armand concluded.

limited treatment options, especially after autologous transplant.” References Checkpoint inhibitors in lymphoma

1. Dimopoulos M, et al. EHA 2016: abstract LB2238.

Checkpoint inhibitors – antibodies blocking the immune

2. Palumbo A, et al. EHA 2016: abstract LB2236.

checkpoint PD-1 or its ligand PD-L1 – have been a major focus of

3. Abe M, et al. EHA 2016: abstract S451.

research in solid tumors, with over 600 ongoing clinical studies.

4. Topp MS, et al. Lancet Oncol 2015;16(1):57-66.

Recently, encouraging results from early trials have led to a wave

5. Topp MS, et al. EHA 2016: abstract S149.

of PD-1 trials in hematologic malignancies as well. In a plenary

6. Toft N, et al. EHA 2016: abstract LB173.

session, Dr Philippe Armand (Dana-Farber Cancer Institute,

7. Jones J, et al. EHA 2016: abstract S429.

Boston, USA) discussed the current status and challenges for the

8. Younes A, et al. EHA 2016: abstract S793.

future of checkpoint blockade in lymphomas.

9. Ansell SM, et al. N Engl J Med 2015;372(4):311-9.

PD-1 inhibitors have already been granted breakthrough and

10. Chen R, et al. EHA 2016: abstract S794.

SUMMER 2016 | hematopics | EHA

35


infographic 36

EHA | hematopics | SUMMER 2016


Report of the highlights of the 21st Congress of EHA

Transplantation & gene therapy

cells that were isolated from the blood of three high-risk AML patients who remained disease free for more than five years after ASCT. From these cell lines, they isolated seventeen monoclonal antibodies that specifically bind to AML cells.

In the field of transplantation and gene therapy, the EHA

Seven of these antibodies recognized the same target. “That

Congress, offered several intriguing presentations. A novel

target was very surprising: the U5 snRNP200 protein”, Hazenberg

phenomenon was the discovery of AML-specific antibodies

revealed. This large protein is part of the spliceosome complex

in the blood of AML patients who were cured after allogeneic

which is normally located inside the cell. “We found that in

stem cell transplantation. The first results of two gene

AML cells, this protein is actually expressed on the surface

therapy studies in hemophilia B demonstrated increased

and recognized by these antibodies.” They were able to

and sustained factor IX activity levels. Hematopoietic stem

detect 5S snRNP200 on the surface of four out of five AML

cell-based gene therapy has seen some interesting new

patients screened.

developments, as was summarized in a presentation during

Interaction of these antibodies with the 5S snRNP200 protein on

Plenary Session 1.

the cell surface killed leukemic cells, both in vitro and in a mouse model. The cells were killed by a non-apoptotic mechanism

Cured patients produce AML-specific antibodies

termed oncosis, which is characterized by the swelling of the cell.

AML patients can potentially be cured by an allogeneic stem

The investigators hope to develop these AML-specific cytotoxic

cell transplantation (ASCT) when the donor cells generate a

antibodies further into novel therapies.

strong graft-versus-leukemia (GvL) response. Dutch investigators collected B cells from the blood of cured patients, and identified

Gene therapy converts severe hemophilia B

specific AML-killing antibodies. “This is a form of immunotherapy,

to mild phenotype

but by nature”, said Dr Mette Hazenberg (Academic Medical

In hemophilia B, the level of coagulant factor IX determines the

Center, Amsterdam, The Netherlands), who presented the results.

severity of the phenotype. Severe hemophilia B (factor IX <1%)

The investigators established clonal B cell lines from memory B

is characterized by frequent spontaneous bleedings, especially

1

SUMMER 2016 | hematopics | EHA

37


Report of the highlights of the 21st Congress of EHA in the joints. Most severe patients receive prophylactic factor

SPK-9001 is a recombinant AAV vector that has been developed

IX replacement therapy to prevent spontaneous bleeding. Mild

by investigators at Spark Therapeutics (Philadelphia, USA). It has

hemophilia B is not associated with bleedings. The aim of gene

a novel bioengineered AAV capsid (Spark-100) and carries an

therapy has been to achieve sustained production of sufficient

expression cassette containing a factor IX variant gene with a high

factor IX to convert the disease phenotype from severe to mild.

specific activity.

The novel viral vector AMT-060 has an adeno-associated virus

The phase 1/2 study evaluated the safety and tolerability of

(AAV) 5 serotype, and contains a gene cassette that has shown

SPK-9001 in four men with severe hemophilia B, having factor IX

sustained expression of factor IX for up to four years in a

activity levels of <1% of normal. To date, the patients have been

previous study. A phase 1/2 dose escalating study evaluated

followed for 7 to 26 weeks after a single IV infusion with a low

the safety and efficacy of AMT-060 in adult patients with severe

initial dose of 5 x 1011 vector genomes/kg of body weight. The

2

or moderately severe hemophilia B. All patients were on factor

investigators observed a gradual rise in factor IX activity levels

IX prophylaxis and had experienced numerous spontaneous

into the range of 25-39% of normal, which is well above the level

bleedings in the preceding year. In Copenhagen, Dr Frank

of 12% of normal that is recommended to protect against joint

Leebeek (Erasmus MC, Rotterdam, The Netherlands) presented

bleeds. None of the subjects had an immune response that would

the results of the first cohort of five patients, receiving a dose of 5

require treatment, and all were able to discontinue factor IX

x 1012 genome copies per kg of body weight.

prophylaxis without any bleeding events occurring.

Four out of five patients achieved stable expression of factor

“I have been working in this field for about twenty years, and it

IX during the follow up period of 26 weeks, with activity

gives me great pleasure to say that I am finally happy with

levels ranging from 3.1 to 6.4%, and discontinued prophylaxis

where the results are”, said lead author Dr Katherine High

treatment. As expected, all patients developed anti-AAV5

(Children’s Hospital of Philadelphia and Spark Therapeutics,

antibodies, but no patient developed factor IX inhibitors. “The

Philadelphia, USA).

3

single treatment was generally well tolerated, with manageable severe adverse events”, said Leebeek. In the ongoing study, five

New developments in hematopoietic stem cell-based

additional patients were recently treated with a higher dose.

gene therapy

Leebeek remarked that there were no exclusions due to pre-

Genetically modified hematopoietic stem cells (HSC) can

existing neutralizing AAV5 antibodies, suggesting that many

be transplanted back into the patient and steadily produce

patients will be eligible for treatment with AMT-060.

lineages of corrected cells for the treatment of several immunohematological diseases. The challenges have been to achieve

Low dose gene therapy resulting in high factor IX levels

efficient HSC gene transfer, to avoid unregulated expression

Patients with hemophilia B require infusions with factor IX

that may cause toxicity, and to minimize the risk of insertional

concentrates once to thrice a week for the rest of their lives. Gene

mutagenesis. Pioneering work was done with γ-retroviral vectors.

therapy approaches have thus far failed to achieve sufficiently

Lentiviral vectors have now brought more efficient gene transfer

high and sustained levels of factor IX without evoking an immune

and lower concerns for genotoxicity. As each vector inserts at a

response. In a phase 1/2 study, the novel gene transfer product

unique site, each clone can be followed separately.

SPK-9001 produced high factor IX activity levels without requiring

Prof Dr Luigi Naldini (San Rafaele Telethon Institute for Gene

immune suppression in individuals with severe and moderately-

Therapy, Milan, Italy) and colleagues have developed lentiviral

severe hemophilia B.

vector based HSC gene therapy for the treatment of Wiskott

4

Aldrich Syndrome and Metachromatic Leukodystrophy (MLD). Clinical trials demonstrated a highly polyclonal and stable reconstitution, without any dominant or expanding clones.5,6 Naldini suggested that in the future, HSC gene therapy may even become preferred to allogeneic HSC transplant in several diseases. Rather than replacing a mutated or lacking gene by random insertion, targeted gene editing is a more sophisticated way to correct inherited mutations in situ. This method can restore function and expression at endogenous levels, and abrogates the risk of random insertional mutagenesis. Artificial nucleases can be designed to target and cut a specific, predetermined sequence in the genome. The thus generated double strand break can be

38

EHA | hematopics | SUMMER 2016


repaired by Non Homologous End Joining (NHEJ), which can be used to disrupt a gene. It can also be repaired by Homology

Max Topp

Driven Repair (HDR), which can be exploited to introduce a specific sequence by providing an exogenous donor template. The genome editing machinery, including artificial nucleases and donor template DNA, can be delivered through a viral vector. Naldini and colleagues have been able to edit genes in human HSC in pre-clinical models. A new emerging strategy is targeting the epigenome by gene editing, with the aim to instruct a stable repressive state that can be passed on upon cell division. References 1. Hazenberg M, et al. EHA 2016: abstract S124. 2. Nathwani AC, et al. N Engl J Med 2014;371(21):1994-2004. 3. Leebeek FWG, et al. EHA 2016: abstract S467. 4. High KA, et al. EHA 2016; abstract LB771. 5. Aiuti A, et al. Science 2013;341(6148):1233151. 6. Sessa M, et al. Lancet 2016 Jun 8. pii: S01406736(16)30374-9. doi: 10.1016/S0140-6736(16)30374 [Epub ahead of print]

presidential symposium For the Presidential Symposium, the Program

(S148) ETV6-related thrombocytopenia (ETV6-RT): clinical and

Committee selected six of the best abstracts presenting

pathogenic characterization of an inherited thrombocytopenia

groundbreaking research in the field of hematology. This

(IT) predisposing to childhood acute lymphoblastic leukemia (ALL).

must-see session contained the following presentations.

Federica Melazzini (University of Pavia, Italy) demonstrated

(S145) Stopping tyrosine kinase inhibitors in a very large cohort of

that a new form of inherited thromobcytopenias associated

European chronic myeloid leukemia patients: results of the EURO-

with ETV6 mutations predisposes to the development of

SKI trial. Johan Richter (Sk책ne University Hospital, Lund, Sweden)

hematological malignancies.

presented trial results showing that patients with chronic

(S149) Blinatumomab improved overall survival in patients with

myeloid leukemia (CML) who have achieved deep molecular

relapsed or refractory Philadelphia negative B-cell precursor acute

response for at least a year can safely stop TKI treatment.

lymphoblastic leukemia in a randomized, open-label phase 3

(S146) Persistence of driver mutations during complete remission

study (TOWER). Max S. Topp (Universit채tsklinikum W체rzburg,

associates with shorter survival and contributes to the inferior

Germany) revealed that in adults with relapsed or refractory

outcomes of elderly patients with acute myeloid leukemia. Maja

acute lymphoid leukemia (ALL) blinatumomab treatment

Rothenberg-Thurley (Ludwig-Maximilians-Universit채t, Munich,

almost doubled overall survival.

Germany) used next generation sequencing to demonstrate

(LB2238) An open-label, randomized phase 3 study of

that elderly patients with acute myeloid leukemia (AML) more

daratumumab, lenalidomide, and dexamethasone (DRd)

often have persisting mutations at remission, indicating the

versus lenalidomide and dexamethasone (Rd) in relapsed or

persistence of a pre-leukemic clone.

refractory multiple myeloma (RRMM): POLLUX. Meletios A.

(S147) Dissecting the contribution of unregulated macrophage

Dimopoulos (National and Kapodistrian University of Athens,

iron recycling and dietary iron uptake in generating systemic iron

Greece) presented the first results of a randomized controlled

overload in hemochromatosis. Sandro Altamura (University

study with daratumumab in combination with standard

of Heidelberg, Germany) unraveled the pathobiology of iron

of care agents demonstrating impressive results in

overload in hemochromatosis.

multiple myeloma.

SUMMER 2016 | hematopics | EHA

39


Report of the highlights of the 21st Congress of EHA

Laboratory diagnostics

of the disease later on. Detection of minimal residual disease (MRD) provides a window of opportunity for early intervention in

In a Laboratory Diagnosis in Focus session, Dr Bruno Paiva

the subclinical phase of leukemia, potentially preventing clinical

(Universidad de Navarra, Pamplona, Spain) discussed the

relapse. At the EHA Annual Congress in Copenhagen, Dr Michael

detection of circulating tumor cells in the diagnosis of MM.

Heuser (Hannover Medical School, Germany) discussed the

Next generation sequencing may offer a new and sensitive

possibilities and challenges of next generation sequencing (NGS)

method for detection of minimal residual disease in leukemia

as a new and sensitive method for MRD detection.

patients, as was presented by Dr Michael Heuser (Hannover

In recent years, the sensitivity of different NGS systems has

Medical School, Germany).

improved. The sensitivity of NGS can be scaled up by increasing the read depth. In a dilution series of ALL samples, NGS had a

Circulating tumor cells in myeloma

linear detection range, reaching 10-5.

MM is preceded by the pre-malignant conditions monoclonal

However, the error rate of different NGS systems varies from

gammopathy of undetermined significance (MGUS) and

0.01%-1%. Heuser: “Thus, at each position you find some

smouldering MM (SMM). A small population of monoclonal

background. How can you tell what is MRD, and what is

plasma cells that produce a specific immunoglobulin, the

background? This background noise prohibits valid MRD

M-protein, usually without causing any symptoms, characterizes

detection of SNVs.” The variation can be caused by differences in

both. Approximately 1% of MGUS cases per year convert to

the fidelity of DNA polymerases, contamination of the instrument

SMM, and 10% of SMM cases per year progress to overt MM.

from the previous run, and deamination of cytosine to thymine

This process involves the accumulation of various cytogenetic

or uracil.

abnormalities and mutations, however it has been difficult to

NGS can be used for most MRD markers that are not suitable

predict which patients will progress due to the genetic diversity

for detection by quantitative PCR, potentially enabling MRD

of the disease.

detection in approximately 40% of AML patients. Heuser

Dr Bruno Paiva (Universidad de Navarra, Pamplona, Spain)

remarked that for clinical use, standardization of methods is

discussed recent developments involving circulating tumor cells

required, and that the clinical benefit still has to be proven.

(CTCs) as prognostic markers in MGUS and MM. Next generation flow cytometrie, a novel multiparameter, ultra-sensitive

Reference

technique using the Euroflow-IMF MM MRD panel, could detect

1. L. Sanoja-Flores et al. Blood 2015;126: abstract 4180

CTCs in virtually all MM patients, and in more than half of the

2. Mishima Y, et al. Blood 2015;126: abstract 23.

MGUS cases. The median absolute number of CTCs detected 1

in peripheral blood increased from 0.011/µl in MGUS to 0.14/ µl in SMM and 2.01/µl in MM. In subjects with MGUS or SMM, a low number of CTCs is related to a lower chance of progression and transformation. In MM, the number of CTCs appears to be a powerful prognostic marker for aggressive disease. Not all subclones in the bone marrow are able to egress into the peripheral blood. CTCs have less single nucleotide variants (SNVs) and are more quiescent compared to matched bone marrow plasmacells. Mutations in driver genes are mostly, but not completely the same, and in each cell type unique mutations can be detected as well.2 It remains unclear whether extramedullary disease in myeloma originates from CTCs. Determining the genetic fingerprint of CTCs may provide insight into the mechanisms of disease dissemination. Genetic characterization of CTCs may be of value as a non-invasive method for the prognostic and molecular profiling of MM patients. Sensitive MRD detection in acute leukemia with next generation sequencing Residual leukemic cells often remain present after initial treatment of patients with acute leukemia, resulting in relapse

40

EHA | hematopics | SUMMER 2016


Thrombosis and hemostasis

systemic embolism, and for the treatment and prophylaxis of venous thromboembolism. New, non-vitamin K antagonist oral

Several findings presented in Copenhagen may have their

anticoagulants (NOACs) have been introduced as alternatives

impact on the fields of thrombosis and hemostasis in the

to vitamin K antagonists (VKAs). In phase III studies, NOACs

years to come. An international study gathered real-life data

compared favorably to VKAs in terms of safety, with lower

from clinical practice on major bleeding events in patients

incidences of major bleeding. However, results from real-life

treated with traditional vitamin K antagonists compared to

clinical practice were lacking.

patients treated with new oral anticoagulants. Another study

A multicenter, Italian-German study collected data on clinical

called for caution when considering patients with inherited

presentation, management and outcome of 874 patients that

thromobcytopenias, as a new form associated with ETV6

were hospitalized for major bleeding while on treatment with

mutations predisposes to the development of hematological

NOAC (n=220) or VKA (n=654).1 Patients treated with NOACs

malignancies. And last but not least, the genomes of

significantly more often presented with gastrointestinal bleeding

thousands of patients were sequenced in a large effort

(46% compared to 24% with VKAs), whereas intracranial

to uncover the genetic basis of rare bleeding and

hemorrhage was more common among patients on VKA

platelet disorders.

treatment (52% compared to 22% with NOACs). â&#x20AC;&#x153;Thirty day mortality was significantly lower in NOAC than in

Anticoagulant treatment and major bleeding: real-life data

VKA patients, but the death rates were different across bleeding

Anticoagulants are mainly used for the prevention of stroke and

sitesâ&#x20AC;?, told Dr Laura Franco (University of Perugia, Italy). At day

SUMMER 2016 | hematopics | EHA

41


Report of the highlights of the 21st Congress of EHA recommend screening for ETV6 mutations in all patients with autosomal dominant forms of inherited thrombocytopenia with these characteristics”, concluded Melazzini. Determining the genetic basis of rare blood disorders There are many different types of rare bleeding, thrombotic and platelet disorders. Together they affect approximately three million people worldwide. For several of them, such as hemophilia, the genetic causes are known, but many more remain to be discovered. Small family sizes and variations in phenotype and penetrance have made it difficult to identify the driver mutations. In a large, international effort, investigators sequenced the genomes of more than 10,000 patients with rare diseases without a genetic diagnosis, including bleeding and platelet disorders.4 In addition, they systematically recorded detailed clinical features in 30, in-hospital death had occurred in 10% of the NOAC group,

a database. Using a novel clustering analysis and in order to

compared to 17% of the VKA group. However, this difference

discover novel causes of disease, the investigators then looked for

appeared to be related more to the bleeding site than to the

phenotypic commonalities between subgroups of patients who

anticoagulant treatment. In patients presenting with intracranial

also have similar genetic changes.

hemorrhage, the 30-day death rate was 25%, independent

Variants in the gene DIAPH1 were found to be linked to enlarged

of anticoagulant treatment, compared to 7-10% in patients

platelets (macrocytosis) and hearing loss. The investigators also

presenting with gastrointestinal bleeding.

found variants in the well-known cancer gene SRC, which were associated with fragile bones, scarring of bone marrow and

ETV6-related thrombocytopenia predisposes

low platelet count. TRPM7 was identified as a new genetic link

to malignant transformation

between platelet macrocytosis and heart rhythm problems. In

Inherited thrombocytopenias are familial disorders characterized

addition, novel variants in previously reported genes (e.g. ACTN1,

by low platelet counts. Patients often present with bleeding

ANKRD26 and STIM1) confirmed their involvement in these rare

complications, but usually only to a mild or moderate degree.

blood disorders.

Therefore this is generally considered to be a benign condition.

“Bringing together genetic and clinical data from hundreds of

“However, a new form of inherited thrombocytopenia is much

patients worldwide is essential to discover new variants”, said

more dangerous than it seems”, warned Dr Federica Melazzini

Dr Ernest Turro (University of Cambridge, UK), stressing the

(University of Pavia, Italy).

importance of worldwide collaboration. A better understanding

Germline mutations in the ETV6 gene lead to a new, autosomal

of platelet biology may also be of benefit for patients suffering

dominant form of inherited thrombocytopenia, as was described

from heart attacks or stroke, where platelets are known to have

by Melazzini and others last year.2 These patients appear to

a role as well. The genes can quickly be incorporated into a

have a high risk of developing hematological malignancies,

newly developed diagnostic platform, called ThromboGenomics.

especially ALL.

Patients can benefit from these findings within months of

In order to gain further information, Melazzini and colleagues

publication, according to Turro.

screened 130 patients with inherited thrombocytopenias, and identified 20 subjects with ETV6 mutations from seven

References

families.3 Four of them (20%) developed ALL during childhood.

1. Franco L, et al. EHA 2016; abstract S139.

“This confirms that early leukemic transformation is a major

2. Zhang MY, et al. Nat Genet 2015 Feb;47(2):180-5.

risk for these patients”, said Melazzini. One person developed

3. Melazzini F, et al. EHA 2016: abstract S148.

polycythemia vera (PV).

4. Turro E, et al. EHA 2016: abstract S518.

ETV6-related thrombocytopenia (ETV6-RT) was one of the most frequent forms of inherited thrombocytopenias. The incidence of ALL was 731.3 per 100,000 compared to 1.4 per 100,000 in the general population. ETV6-RT patients had no or only mild bleeding tendency, and did not show platelet macrocytosis. “We

42

EHA | hematopics | SUMMER 2016


infographic SUMMER 2016 | hematopics | EHA

43


Report of the highlights of the 21st Congress of EHA

Transfusion medicine

patients who received a platelet transfusion did worse and more often died than those receiving only the standard treatment.

This year’s education session focused on blood transfusions

The investigators observed no difference in hematoma growth.

for the management of coagulopathy in patients with chronic

Patients receiving platelet transfusion more often experienced

liver disease. Results from a late-breaking abstract warned

serious adverse events and complications of ICH. In a pre-planned

against using platelet transfusions to treat intracerebral

subgroup analysis, the type of antiplatelet therapy or hematoma

hemorrhage in patients taking antiplatelet drugs.

volume did not affect the outcome. Shortly after the EHA Congress, the results of this study were published in full in

Platelet transfusion harmful after antiplatelet-associated

The Lancet.2

intracerebral hemorrhage

“PATCH shows that platelet transfusions seem harmful for

Intracerebral hemorrhage (ICH) affects two million people

patients with antiplatelet-associated ICH”, concluded Dr Rianne

worldwide each year, of whom 40% dies in the first month.

Koopman (Sanquin Bloodbank, Amsterdam, The Netherlands),

More than a quarter of these patients are taking antiplatelet

who presented the results on behalf of the PATCH investigators.

drugs at the onset of ICH, which is associated with an elevated

“Pending further evidence, we think that platelet transfusions

risk of death. It is thought that antiplatelet therapy increases

should not be used in this patient group.”

hematoma growth. Therefore restoring platelet function may improve the outcome.

Transfusion management of coagulopathy in patients with

A randomized study (PATCH) conducted in The Netherlands,

chronic liver disease

UK and France evaluated the addition of platelet transfusion

Patients with chronic liver disease have a tendency to bleed,

to standard care in 190 patients with spontaneous ICH who

which has long been thought to be related to impaired synthesis

were on antiplatelet therapy. At three months, the mRS scores

of procoagulant factors and thrombocytopenia. This paradigm

representing functional outcome were lower, meaning that

is now shifting towards the idea that there is a ‘rebalance’ in

1

44

EHA | hematopics | SUMMER 2016


hemostasis in these patients, as alterations in both pro- and anticoagulant factors occur simultaneously. This idea questions the usefulness of traditional laboratory testing to assess bleeding

Patient Advocacy track and joint symposia

risk, and the use of pro-coagulant agents or platelet transfusions to control bleeding. In an education session, Prof Ton Lisman

The EHA Advocacy track consisted of four sessions, focusing

(University Medical Center Groningen, The Netherlands) and

on patient and policy related issues. The Patient Advocacy

Prof Armando Tripodi (University of Milan, Italy) introduced and

session discussed the establishment of European Reference

explained these concepts.

Networks from different points of view. A joint symposium

Dr Pratima Chowdary (Royal Free Hospital, London, UK) presented

organized in collaboration with the American Society of

an overview of current evidence for using transfusions to treat

Hematology (ASH) tackled issues of patents and licenses

coagulopathy in patients with chronic liver disease. “There

on biomarkers. Another session was dedicated to EU

is a good choice of therapeutic products that are efficacious

funded projects in hematology, where the speakers shared

and available”, she said. The most commonly used product,

their experiences and tips on how to apply for a European

fresh frozen plasma, can efficiently increase coagulation factor

research grant. Special attention was given to the Innovative

levels, but the correction is dependent on the infused volume.

Medicines Initiative IMI); a partnership between the EU

Prothrombin complex concentrates are also commonly used and

and the pharmaceutical industry for the development of

appear efficacious without an excess risk of thromboembolic

medicines in response to high unmet medical or social need.

complications. Treatment with recombinant factor VIIa is a lesser

EHA is one of the 44 public and 7 industry partners in the new,

option because of arterial thrombotic events, and is only offered

IMI-funded HARMONY project, which will develop a Big Data

to actively bleeding patients with severe liver dysfunction who

platform for the pooling and analysis of valuable knowledge

are not responding to conventional therapy. Platelet transfusion

on hematologic malignancies (HMs).

can be given prior to or during invasive procedures like liver

The last session addressed several topics linked to the theme

biopsy, and is mostly used in patients with bone marrow failure

of the year: ‘Innovation in hematology’, such as fast-track

or undergoing chemotherapy. In clinical studies, thrombopoietin

approval of drugs and the societal cost of blood disorders.

receptor agonists resulted in an excess of thrombotic events in

In addition, joint symposia were organized together with

patients with liver disease and thrombocytopenia.

well-known societies from around the world. In the joint

Although there appears to be a balance between anticoagulants

symposium organized together with the Japanese Society of

and procoagulants, coagulation abnormalities do worsen with

Hematology (JSH), two investigators presented the results

deteriorating liver function, remarked Chowdary. There are no

of the EHA-JSH exchange program. Targeted therapy for

agreed criteria to identify the small group of patients that will

chronic lymphocytic leukemia and the role of the tumor

experience spontaneous bleeding, therefore, overtreatment is the

microenvironment were discussed in the symposium

norm. Tests such as thromboelastography (TEG) may help guide

organized in collaboration with the Argentinean Society of

transfusions and reduce overtreatment, although conclusive

Hematology (SAH). The EHA-European School of Hematology

evidence is lacking and these tests should not be used outside

(ESH) joint symposium focused on patient-doctor

clinical trials.

communication based on a clinical case report.

References

European Reference Networks

1. Koopman M, et al. EHA 2016: abstract LB2234.

The goal of European Reference Networks (ERN), initiated by

2. Baharoglu MI, et al. Lancet 2016 Jun 25;387(10038):2605-

the European Commission (EC), is to join efforts in tackling rare

13.

or complex diseases in order to improve quality of and access to highly specialized healthcare, with a more efficient use of resources. Collaboration is needed for sharing and increasing expertise and knowledge, and for generating evidence for new treatments. “The main goal is not sending patients abroad, but getting the knowledge to treat patients as close as possible to their homes”, said Enrique Terol of the EC. The EC received approximately 20 network proposals, of which the first ones are planned to start in March 2017. One proposal, EuroBloodNet, concerns both non-malignant and malignant rare hematological diseases. Seventy-nine health care providers from

SUMMER 2016 | hematopics | EHA

45


Report of the highlights of the 21st Congress of EHA 19 member states have already expressed their interest to join. A

from the human body. The United States do not allow patenting

key feature of the ERNs is patient involvement in governance and

of a genomic sequence, which is regarded as a product of nature,

decision making. “The measurement of the impact of ERNs needs

though copy DNA can be patented as long as it is different from a

to take into account the patient’s perspective”, stressed Ananda

naturally occurring sequence.

Plate (Myeloma Patients Europe). A patient advisory group for

The jury is still out on whether genetic diagnostic tests for

EuroBloodNet was elected in May 2016 from more than 50

biomarkers should be patentable or not. In the past, novel

patient organizations.

diagnostic tests have been licensed to one or only a few diagnostic labs, which had consequences on the costs and

Patents and licenses on biomarkers

prevented the spread of knowledge. On the other hand, if

The possibility to patent DNA sequences may drive innovation

patenting were no longer allowed, it might not be worthwhile

and sometimes also generate funds for academia; however,

to invest in the development of genetic tests.

restrictive licensing may block research and optimal patient management. How to solve this paradoxical situation was the topic of discussion in the EHA-ASH joint symposium. In Europe, a DNA sequence is patentable as long as it is isolated

EHA Advocacy Session- Innovations in hematology: Cost and benefit, from a patient’s perspective

46

EHA | hematopics | SUMMER 2016


Pediatric hematology The cost of cure of childhood malignancies was the topic of the education session on pediatric hematology. A large Canadian study identified genetic variants that are associated with adverse drug reactions, including early and late effects of childhood cancer therapy. In order to improve the quality of survivorship, a new initiative has been started to develop international guidelines for long-term follow-up. Harmonization of long-term follow-up Genetic variants predict risk of late treatment effects

Many childhood cancer survivors experience important late

Adverse drug reactions caused by individual variations can have

effects of treatment, including cardiotoxicity and second

serious consequences. Clinical studies evaluate the efficacy and

malignancies. The recommendations for the long-term follow-

safety of a drug in quite homogenous populations, whereas in

up of childhood cancer patients are really different in different

daily practice, individual patients can vary widely in their response

countries, yet they are based on the same evidence, told Dr

to therapy. “Young children and elderly people are often not

Leontien Kremer (Academic Medical Center, Amsterdam, The

included in these populations, and yet they are treated”,

Netherlands). In order to combine efforts and recommendations,

said Dr Bruce Carleton (University of British Columbia,

she and others initiated the International Guideline

Vancouver, Canada).

Harmonization Group (IGHG), chaired by Kremer together with

He and his colleagues set up a large study to understand genetic

Dr Melissa Hudson from St. Jude Children’s Research Hospital

differences in drug response. Their hypothesis was that genetic

(Memphis, USA).

polymorphisms in drug biotransformation genes underlie a

The IGHG is a collaboration between guideline groups from

significant portion of concentration-dependent adverse drug

North America, the UK, Scotland, The Netherlands, the European

reactions in children. They collected DNA and detailed clinical

PanCareSurFup group and individuals from various countries

information from more than 8,000 children with adverse

around the world. The aim is to reduce duplication of effort and

drug reactions and more than 78,000 matched controls. The

optimize the use of expertise, with the goal to improve quality

investigators screened approximately 10,000 single nucleotide

of survivorship.

polymorphisms (SNPs) in genes known to be involved in drug

The first guideline developed by the IGHG was for surveillance

toxicity, including metabolizing enzymes, transporters and

of childhood cancer survivors for cardiomyopathy.3 Kremer:

transcription factors.

“We asked four main questions: Who needs surveillance? What

Variants in SLC28A3, UGT1A6 and RARG were found to be involved

surveillance modality should be used? When to start and how

in anthracycline-induced cardiotoxicity.1,2 Together with known

often? And what should be done when abnormalities are

clinical variables, these variants could assign patients to different

identified?” Based on the available evidence, the guideline

risk categories. Half of the patients had a low risk of cardiotoxicity.

strongly recommends screening patients treated with

“This may be helpful for patients with aggressive disease, as we

anthracyclines or radiotherapy by echocardiography every

may be able to push threshold doses much higher”, said Carleton.

five years.

In many of the high risk patients, cardiotoxicity occurred within

In clinical practice, shared decision-making is needed

the first year after treatment.

when evidence is lacking or when the interpretation is not

Carleton and colleagues set up a personalized medicine program

straightforward, according to Kremer. More international

and developed a risk prediction tool for pediatric anthracycline

guidelines have been completed or are underway, including

cardiotoxicity. For intermediate risk patients, the follow-up is

guidelines on screening for breast cancer, premature ovarian

intensified. High risk patients can be treated with ACE-inhibitors

insufficiency and male gonadotoxicity. In addition, a passport for

or beta-blockers to prevent further damage, or receive lower dose

the incorporation of individual care plans has been developed.

or even anthracycline-free treatment. “This provides further evidence for the need of a range of

References

therapeutic options, one drug is not ideal for all patients”,

1. Visscher H, et al. Pediatr Blood Cancer 2013;60(8):1375-81.

said Carleton.

2. Aminkeng F, et al. Nat Genet 2015 Sep;47(9):1079-84. 3. Armenian SH, et al. Lancet Oncol 2015 Mar;16(3):e123-36.

SUMMER 2016 | hematopics | EHA

47


Report of the highlights of the 21st Congress of EHA

Personalized medicine Research is focusing more and more on new biomarkers that

awards

may help to identify patients that require specific, tailored

Jean Bernard Lifetime Achievement Award

treatment. One presentation discussed the prognostic

Prof Clara Camaschella (San Raffaele Hospital, Milan, Italy)

potential of long non-coding RNAs in adult AML. The role of predictive biomarkers in treatment decisions was the subject

José Carreras Award

of a presentation in the education session on CLL.

Prof Eva Hellström Lindberg (Karolinska Institutet, Stockholm, Sweden)

Prognostic value of long non-coding RNAs Approximately 45% of adult AML patients have no known

Winners of the 2016 EHA Career Development

cytogenetic abnormalities (CN-AML). In these patients, gene

Program Fellowships

mutations as well as mRNA and microRNA expression have been

• H Poeck (Technical University of Munich, Germany;

identified as prognostic markers. Long non-coding RNA (lncRNA) expression has recently been shown to have prognostic value in older patients with CN-AML.1 A new study presented by Dr Dimitrios Papaioannou (Ohio State University, Columbus, USA) now demonstrates that lncRNA profiling provides prognostic information in young adults with CN-AML as well.

2

lncRNAs are regulatory RNA transcripts of approximately 200 nucleotides in length that do not encode for any protein. The investigators analyzed the total transcriptome of 377 patients aged between 17 and 59 years old. The cohort consisted of a training set of 263 patients, and a validation set of 114 patients.

winner John Goldman Clinical Research Fellowship) • G Jansen (Erasmus Medical Center, Rotterdam, The Netherlands) • D Passaro (The Francis Crick Institute London, United Kingdom) • A Nai (Vita-Salute San Raffaele University, Milan, Italy; winner José Carreras Non-Clinical Research Fellowship) • E Laurenti (Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, United Kingdom) • M Crisan (The Queen’s Medical Research Institute, Edinburgh, United Kingdom)

The investigators identified 24 lncRNAs that were related to EFS.

• R Marie (Hôpital Saint Louis, France)

Most of them were antisense or intergenic lncRNAs. Only six of

• I Hude (University Hospital Center Zagreb, Croatia)

them were associated with prognostic mutations in CEBPA and

• A Kozaric (University Clinical Center Sarajevo, Bosnia

FLT3-ITD.

and Herzegovina)

The investigators combined expression values of the 24 lncRNAs

• L Escriba Garcia (Hospital Sante Creu I Sant Pau, Spain)

to calculate a lncRNA score. A low score was associated with

• L Couronné (Hôpital Necker-Enfants malades, France)

longer disease-free and overall survival. This was confirmed in

• Y Sunami (Institute Juntendo University School of

the validation set, where 52% of patients with a low score were

Medicine, Japan)

alive at five years, compared to 26% of patients with high lncRNA scores. In a multivariable analysis, low lncRNA score was an

Clara Chamaschella, the Jean Bernard Lifetime Achievement Award

independent prognostic factor. “lncRNA measuring platforms for

winner and Tony Green, EHA President

the calculation of the prognostic lncRNA score in a fast, clinically applicable fashion are currently being developed and validated”, said Papaioannou. Treatment decisions informed by biomarkers in CLL Whereas prognostic biomarkers provide information on patient outcome independent of treatment, predictive biomarkers can predict whether patients are likely to benefit from a specific treatment. “The usefulness of biomarkers in CLL stems from the need for treatment tailoring in an era in which we have more and more treatment options”, said Dr Davide Rossi (Oncology Institute of Southern Switzerland, Bellinzona, Switzerland) in his presentation. TP53 abnormalities represent the first biomarker with predictive capacity in CLL. The TP53 gene can be mutated, deleted or both.

48

EHA | hematopics | SUMMER 2016


Andreas Engert, Chair of the Scientific Program Committee of the 21st Congress of EHA introduces the 2016 José Carreras Award winner; Eva Hellström-Lindberg

EHA-ASH Translational Research Training in Hematology (TRTH) Program – Trainees 2016 G Behbehani, USA

J Nangalia, United Kingdom

M Biernacki, USA

D Passaro, United Kingdom

C W Chen, USA

E Pronier, USA

K De Ceunynck, USA

S Sivapalaratnam, United Kingdom

C Y Fong, Australia

E Stieglitz, USA

A Höllein, Germany

E ten Hacken, USA

R Itzykson, France

I Uras, Austria

R Kridel, Canada

P Velasquez, USA

K Markey, Australia

J Woo, USA

M Murakami, USA

B Wouters, The Netherlands

SUMMER 2016 | hematopics | EHA

49


Report of the highlights of the 21st Congress of EHA

The prevalence of TP53 abnormalities increases with the stages

benefit from chemoimmunotherapy. Conversely, the response

of the disease. “Mutations may be acquired or selected during

to ibrutinib is not influenced by IGHV mutations. The most

progression”, according to Rossi. “This means you need to re-test

recent guideline from ESMO recommends IGHV analysis before

a patient if you want to apply a new treatment.” TP53-disrupted

treatment. Duration of remission and fitness of the patient are

patients do not respond to chemoimmunotherapy, yet they

other predictive factors in CLL.

respond as well as wild type cases to novel agents targeting BCRABL or BCL2. In all current guidelines, determining the TP53 status

References

is recommended for selecting treatment in the first or second line.

1. Garzon R, et al. Proc Natl Acad Sci U S A

The IGHV mutation status is the second important biomarker in CLL. Mutated cases are more common among newly diagnosed CLL, whereas unmutated cases are found mainly in relapsed or refractory disease. “The mutational status of IGHV represent the capability of the CLL cell to respond to micro-environmental interaction, and therefore the propensity of the disease to progress”, said Rossi. Patients with mutated IGHV particularly

50

EHA | hematopics | SUMMER 2016

2014;111(52):18679-84. 2. Papaioannou D, et al. EHA 2016; abstract S810.


Save the date

2016 September 14-17

EHA Scientific Conference on Bleeding Disorders: Increase your knowledge and improve patient care!

Barcelona, Spain

September 22-24

Hematology Society of Sri Lanka - Joint Symposium

Colombo, Sri Lanka

October 21

Turkish Society of Hematology – EHA-TSH Joint Symposium

October 27-28

ROHS International Conference on Malignant Lymphoma – EHA-ROHS Joint Symposium

October 27-29

Chinese Society of Hematology Congress - EHA Joint Symposium

November 11-12

EHA - Korean Society of Hematology Joint Symposium

November 10-13

EHA - Indian Society of Haematology & Blood Transfusion Joint Symposium

November 24-26

HSANZ Annual Meeting – EHA-HSANZ Joint Symposium

November 13-1

Highlights of Past EHA – Dubai 2016

Antalya, Turkey

Moscow, Russian Federation Suzhou, China

Daejeon, South Korea Jaipur, India

Melbourne, Australia Dubai, UAE

Dubai, United Arab Emirates

2017 February 2-4

EHA-SWG Scientific Meeting on Anemias: Diagnosis and Treatment in the Omics Era

February 23-24

EHA Hematology Tutorial – Sri Lanka Chairs to be announced

March 10-12

EHA-SWG Scientific Meeting on Advances in Biology and Treatment of B Cell Malignancies, with a Focus on Rare Lymphoma Subtypes

Barcelona, Spain

Colombo, Sri Lanka

Barcelona, Spain

For information and registration please visit: ehaweb.org

SUMMER 2016 | hematopics | EHA

51


EHA Corporate sponsors 2016 The European Hematology Association wishes to express its gratitude to the following sponsors

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