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Mosbyu2019s Textbook for Long-Term Care Nursing Assistants 8th Edition
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Contents
Foreword by Professor John Barrett, vii
Foreword by Professor John Goldman, viii
List of Contributors, ix
Section 1 Late effects concepts, 1
1 Introduction to long‐term survivorship after hematopoietic cell transplantation, 3
Bipin N. Savani and André Tichelli
2 International Blood and Marrow Registries: trends on long‐term data collection, 6
Rachel Phelan, Jakob R. Passweg, Helen Baldomero, Minako Iida, Yoshiko Atsuta, Shinichiro Okamoto, Mahmoud Aljurf, Feras Alfraih, and Bronwen E. Shaw
3 Long‐term follow‐up program and transplant clinic setup, 14 André Tichelli, Bipin N. Savani, Shahrukh K. Hashmi, Navneet S. Majhail, and Alicia Rovó
4 Telemedicine in patient care of long‐term transplant survivors, 25 Catherine J. Lee, Mihkaila Wickline, and Mary E.D. Flowers
5 Long‐term follow‐up calendar, 33 André Tichelli, Bipin N. Savani, Shahrukh K. Hashmi, Navneet S. Majhail, and Alicia Rovó
6 Late effects post‐allogeneic hematopoietic stem cell transplantation, 38 Shahrukh K. Hashmi and Yoshihiro Inamoto
7 Late effects post‐autologous hematopoietic stem cell transplantation, 47
Rajshekhar Chakraborty and Betty K. Hamilton
8 Long‐term follow‐up of children, 58 Paul A. Carpenter
9 Graft‐versus‐host disease and late effects after hematopoietic stem cell transplantation, 73 David Michonneau, Aurélien Sutra del Galy, and Gérard Socié
10 Screening and prevention guidelines for hematopoietic cell transplant survivors, 80 Neel S. Bhatt, J. Douglas Rizzo, and Navneet S. Majhail
11 Biology of survivorship after blood or marrow transplantation, 92 Smita Bhatia
Section 2 Specific late effects, 101
12 Second malignancies, 103 Aurélien Sutra del Galy, David Michonneau, and Gérard Socié
13 Anti‐infective prophylaxis, immunization and prevention of late infectious complications, 112 Per Ljungman
14 Seasonal respiratory viral infections, 119 Nosha Farhadfar, Zeina Al‐Mansour, and John R. Wingard
15 Monitoring and management of hepatitis B, C, and HIV infection before and after transplantation, 132 Enric Carreras and Montserrat Rovira
16 Skin chronic GVHD, 140 Attilio Olivieri, Anna Campanati, Gaia Goteri, and Andrea Bacigalupo
17 Ocular complications, 166 Alicia Rovó, André Tichelli, and Yoshihiro Inamoto
18 Management of oral and dental complications, 176 Hildegard T. Greinix
19 Thyroid disease: monitoring and management guidelines, 183 Juliana Matthews, Leslee Matheny, and Shubhuda Jagasia
20 Pretransplant considerations in gender, reproductive, and sexual health, 189 Dana Shanis, Jeanne Murphy, Kate Debiec, Betty K. Hamilton, Shawna Boyle, and Pamela Stratton
21 Posttransplant Considerations in Gender, Reproductive, and Sexual Health, 198
Jeanne Murphy, Dana Shanis, Kate Debiec, Betty K. Hamilton, Shawna Boyle, and Pamela Stratton
22 Fertility issues, fertility preservation, and pregnancy outcome in long‐term survivors, 211 Alicia Rovó, Alison W. Loren, André Tichelli, and Nina Salooja
23 Sexual Dysfunction in Long‐Term Survivors, 221
Rebecca L. Hunter, Sarah Thilges, Janna Gordon, Kristy Luke, Karla Cavazos, Emilee Moeke, Colleen Bruen, and Sunita Nathan
24 Late non‐infectious pulmonary complications, 231 Ayman O. Soubani
25 Cardiac and arterial complications, 241 Alicia Rovó and André Tichelli
26 Cardiovascular risk factors, 251 Kimberley Doucette and Minoo Battiwalla
27 Gastrointestinal complications, 260 Sumona Bhattacharya, Steven Pavletic, and Theo Heller
28 Hepatic Complications, 271
Christy Ann L. Gilman, Christopher Koh, Steven Pavletic, and Theo Heller
29 Renal complications, 278
Insara Jaffer Sathick and Sangeeta Hingorani
30 Posttransplantation bone disease: prevalence, surveillance, prevention, and management, 287 Christine N. Duncan
31 Late neurologic complications, 300 Enrico Maffini
32 Neurocognitive dysfunction, 312 David Buchbinder and Angela Scherwath
33 Psychological Distress, 330 Anna Barata, Aasha I. Hoogland, and Heather S. L. Jim
34 Evaluation and management of fatigue in survivors of allogeneic hematopoietic stem cell transplantation, 337 Sandra A. Mitchell
35 Social Issues, 349 Sanghee Hong and Navneet S. Majhail
36 Health‐related quality of life in adult and pediatric survivors, 355
Sandra A. Mitchell, Lori Wiener, Jenny Hoag, Abigail Fry, and Margaret F. Bevans
Section 3 Supportive care and patients reported outcomes, 381
37 Immunosuppressive agents and monitoring in long‐term survivors, 383
Kathryn A. Culos and Katie S. Gatwood
38 Nutritional support and nutritional supplementation, 393 Shigeo Fuji
39 Daily routines and healthy lifestyle guidelines, 397 Melissa Logue
40 Prevalent psychosocial adjustment issues and solutions: lifestyle and social challenges, 402 Katrina M. Stokes
41 Complementary and alternative medicine in HSCT, 406 Ibrahim N. Muhsen, Bipin N. Savani , and Shahrukh K. Hashmi
42 Impact of adherence in outcome of long‐term survivors, 413 Corien Eeltink and Annika Kisch
43 Prominent role of allied health professionals, 418 Catherine E. Lucid
45 Caregivers of long‐term survivors, 428 Angela Moreschi Woods
46 Patient’s perspective: memoir of a recovered lymphomaniac, 434 Michael Brown
APPENDIX 1 Commonly used transplant‐related medications in long‐term survivors, 442
Kathryn A. Culos and Katie S. Gatwood
APPENDIX 2 The eGVHD App, 445 Hélène Schoemans
Index, 448
Foreword to the Second Edition
by Professor John Barrett
Since 2013 when the publication of the first edition of Savani’s Blood and Marrow Transplantation Long Term Management: Prevention and Complications the accelerated pace of stem cell transplant activity worldwide since the beginning of this century, together with the continuing trend to reduced early mortality from the procedure has translated into an almost exponential expansion in the number of long term survivors which must now number well beyond half a million individuals surviving more than five years. More than ever, to serve our patients we need this authoritative guide for the management of our long-term survivors as well as a comprehensive and contemporaneous account of the causative factors of long-term complications that can inform us of better ways to do stem cell transplants.
What have we learned in the last few years? Chronic graft-versushost disease (C-GVHD) is increasingly recognized as a cause of late effects not hitherto ascribed to this common post-transplant event. It is now clear that human papilloma virus (HPV) contributes to a significant proportion of the second malignancies which relentlessly increase over time after transplant. Understanding the impact of these two risk factors is important in focusing efforts to avoid C-GVHD, and by using post-transplant HPV vaccination to reduce second malignancies. As observational studies of long-term survivors accumulate, we are discovering new late effects extending beyond the familiar territories of GVHD and second tumors. In this newest edition, the section of organ-specific late effects is greatly expanded. In particular delayed cardiovascular events are being defined, as well as a much clearer idea of the psychosocial and economic burden that long-term survivors and their carers may
experience. Finally, we are beginning to distinguish different trajectories of late effects due to particular transplant approaches. Over and above the well characterized differences on late outcomes after autologous versus allogeneic SCT databases are extensive enough to identify the impact of different and newer transplant approaches for example haplo-identical donor transplants.
All this new information and increased competence in managing as well as preventing transplant late effects could not have been possible without a concerted effort from all the major transplant registries and societies to concentrate on the problem. This has led to the development of useful guidelines, dedicated multidisciplinary late effect clinics, and a gratifyingly broader knowledge base among transplant physicians and primary caregivers, which in turn leads to better patient management. The first section of this book captures the contribution by the world’s registries as well as provides a helpful guide to establishing a comprehensive long-term follow-up program including the application of telemedicine to this discipline.
The editors Dr. Bipin Savani and Dr. Andre Tichelli are pioneers in the field of transplant late effects and they have selected contributing authors from a worldwide elite of experts in late effects of transplantation. They have amply addressed all the new advances in biology and prevention of late effects and have authoritatively covered all aspects of management of the long-term transplant survivor. This book should stand as the definitive and most current text on late effects following stem cell transplantation, a field that is now an established specialty in its own right.
John Barrett
Foreword (from first edition)
by Professor John Goldman (1938–2013)
Though sadly, there has been little progress in recent years in some areas of medicine, the clinical use of hematopoietic stem cell transplantation is not one of them. If 50 years ago, one had suggested to an experienced hematologist that one could collect nucleated cells from the marrow or indeed from the blood of normal persons and infuse them in relatively small numbers into a suitably “prepared” patient with leukemia or another hematologic or immunologic disorder and thereby cure the disease, the suggestion would have been greeted with incredulity. In reality, the pioneering preclinical work of many laboratory scientists, the increased understanding of histocompatibility antigen, and the dedicated commitment of clinicians such as Georges Mathé, Robert Good, and Don Thomas laid the foundations for the first successful bone marrow transplant in the 1970s. It is difficult today to appreciate the scepticism or, indeed, formal opposition with which the initial work of these enthusiasts was met.
In the beginning of the 21st century, stem cell transplantation in some form or another is practised in 60 to 70 countries of the world and there is no aspiring hematologist who does not learn early that there are certain diseases for which allogenic or autologous stem cell transplantation offers a real chance of cure or, at worst, just useful palliation. This means that the number of persons surviving and, in many cases, cured of a serious and usually life‐threatening disease has increased enormously in recent years. This collection of
papers, written by experts in the field of stem cell transplantation, could not have been contemplated by earlier researchers in the field for the simple reason that the number of patients who had survived long term would have been very few. Today, clinical data on transplant recipients are carefully collected and analysed by two very valuable organizations: on a global scale by the International Center for Blood and Bone Marrow Research and by the European Group for Blood and Marrow Transplantation, which focuses mainly on Europe. Data collated by these two agencies and the multiplicity of individual publications covering many aspects of health in patients alive at 5, 10 or more years after a transplant procedure show clearly that some long‐term survivors do still have specific problems associated with their original transplant procedures, but most of these are relatively minor and eminently treatable. The fact that there are so many “ex‐patients” alive today is a truly impressive testament to the progress that has been made in this field since the 1960s.
Professor John Goldman DM, FRCP, FRCPath, FMedSci Hammersmith Hospital Imperial College London Centre for Haematology Du Cane Road London, UK
Feras Alfraih MD Oncology Center
List of Contributors
King Faisal Specialist Hospital & Research Center Riyadh, Saudi Arabia
Mahmoud Aljurf MD Oncology Center
King Faisal Specialist Hospital & Research Center Riyadh, Saudi Arabia
Zeina Al‐Mansour MD
Division of Hematology & Oncology University of Florida College of Medicine Gainesville, FL, USA
Yoshiko Atsuta MD, PhD Japanese Data Center for Hematopoietic Cell Transplantation (JDCHCT) Nagoya, Japan
Andrea Bacigalupo MD Department of Hematology Università Cattolica Roma, Italy
Anna Barata PhD Department of Health Outcomes and Behavior Moffitt Cancer Center Tampa, FL, USA
Helen Baldomero BMS Division of Hematology, University Hospital Basel Basel, Switzerland
Neel S. Bhatt MBBS MPH
Fred Hutchinson Cancer Research Center and University of Washington Seattle, WA, USA
Minoo Battiwalla MD Sarah Cannon Blood Cancer Center Network
Margaret F. Bevans RN PhD AOCN
United States Public Health Service National Institutes of Health, Clinical Center Bethesda, MD, USA
Smita Bhatia MD
Institute for Cancer Outcomes and Survivorship University of Alabama at Birmingham Birmingham, AL, USA
Sumona Bhattacharya MD Digestive Disease Branch
National Institute of Diabetes and Digestive and Kidney Diseases National Institutes of Health Bethesda, MD, USA
Shawna Boyle MD University of Nebraska Medical Center Omaha, NE, USA
Michael Brown Transplant Patient Advocate
Colleen Bruen RN Section of Bone Marrow Transplant and Cellular Therapy
Rush University Medical Center Chicago, IL, USA
David Buchbinder MD Division of Hematology CHOC Children’s Hospital Orange, CA, USA
Anna Campanati MD Clinica Dermatologica Department of molecular and clinical sciences Ancona University Ancona, Italy
Paul A. Carpenter MD Clinical Research Division Fred Hutchinson Cancer Research Center Seattle, WA, USA
Karla Cavazos RN
Section of Bone Marrow Transplant and Cellular Therapy
Rush University Medical Center Chicago, IL, USA
Enric Carreras MD
Spanish Bone Marrow Donor Registry Josep Carreras Foundation and Research Institute Barcelona, Spain
Taussig Cancer Center Cleveland Clinic Cleveland, OH, USA
Kathryn A. Culos PharmD BCOP Pharmacy
Vanderbilt University Medical Center Nashville, TN, USA
Kate Debiec MD
University of Washington and Seattle Children’s Hospital Seattle, WA, USA
Kimberley Doucette MD, MSc
Medstar Georgetown University Hospital Washington, DC, USA
Christine N. Duncan MD
Division of Pediatric Stem Cell Transplant Dana‐Farber Cancer Institute Boston, MA, USA
Corien Eeltink RN, MA ANP Department of Hematology Cancer Center Amsterdam/ VU University Medical Center Amsterdam, The Netherlands
Nosha Farhadfar MD
Division of Hematology & Oncology
University of Florida College of Medicine Gainesville, FL, USA
Mary E.D. Flowers MD
Clinical Research Division
Fred Hutchinson Cancer Research Center and Department of Medicine Seattle, WA, USA
Abigail Fry BA Psychosocial Support and Research Program Center for Cancer Research
Pediatric Oncology Branch
NIH Bethesda, MD, USA
Shigeo Fuji MD
Department of Hematology
Osaka International Cancer Institute Osaka, Japan
Katie S. Gatwood, PharmD BCOP Pharmacy
Vanderbilt University Medical Center Nashville, TN, USA
Christy Ann L. Gilman MD Liver Disease Branch
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institutes of Health Bethesda, MD, USA
Janna Gordon PhD
Department of Population Health Sciences Huntsman Cancer Institute
University of Utah Salt Lake City, UT, USA
Gaia Goteri MD
Department of Pathology
Ancona University
Ancona, Italy
Hildegard T. Greinix MD
Medical University Graz
Division of Hematology Graz, Austria
Betty K. Hamilton MD
Blood and Marrow Transplant Program Taussig Cancer Institute Cleveland Clinic Cleveland, OH, USA
Shahrukh K. Hashmi MD, MPH
Division of Blood and Marrow Transplantation
William J. von Liebig Transplant Center
Mayo Clinic Rochester, MN, USA
Theo Heller MD
Translational Hepatology Unit Liver Disease Branch
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institutes of Health Bethesda, MD, USA
Sangeeta Hingorani MD University of Washington Children’s Hospital and Regional Medical Center Seattle, WA, USA
Jenny Hoag PhD
Medical College of Wisconsin Department of Pediatrics Division of Hematology/Oncology/Bone Marrow Transplant Milwaukee, WI, USA
Sanghee Hong MD
Blood and Marrow Transplant Program Cleveland Clinic Cleveland, OH, USA
Aasha I. Hoogland PhD
Department of Health Outcomes and Behavior Moffitt Cancer Center Tampa, FL, USA
Rebecca L. Hunter PhD Division of Hematology University of Colorado Anschutz Medical Center Aurora, CO, USA
Heather S. L. Jim PhD
Department of Health Outcomes and Behavior Moffitt Cancer Center Tampa, Florida, USA
Annika Kisch RN, PhD
Department of Haematology Skåne University Hospital Institute of Health Sciences at Lund University Lund, Sweden
Christopher Koh MD, MHS Liver Disease Branch
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institutes of Health Bethesda, MD, USA
Minako Iida MD
Department of Promotion for Blood and Marrow Transplantation
Aichi Medical University School of Medicine
Nagakute, Japan
Yoshihiro Inamoto MD
Department of Hematopoietic Stem Cell Transplantation
National Cancer Center Hospital Tokyo, Japan
Shubhuda Jagasia MD MMHC
Vanderbilt Eskind Diabetes Clinic
Inpatient diabetes and Endocrinology
Division of Diabetes, Endocrinology and Metabolism
Vanderbilt University Medical Center Nashville, TN, USA
Catherine J. Lee MD
Utah Blood and Marrow Transplant Program
Huntsman Cancer Institutet Salt Lake City, UT, USA
Per Ljungman MD, PhD
Department for Cellular Therapy and Allogeneic Stem Cell Transplantation
Karolinska University Hospital Huddinge
Division of Hematology
Department of Medicine Huddinge
Karolinska Institutet Stockholm, Sweden
Melissa Logue ANP‐BC
Hematology and Stem Cell Transplantation Section
Division of Hematology/Oncology
Department of Medicine
Vanderbilt University Medical Center Nashville, TN, USA
Alison W. Loren MD, MSCE
Blood & Marrow Transplantation
Abramson Cancer Center
University of Pennsylvania Pennsylvania, PA, USA
Catherine E. Lucid ACNP‐BC, MSN
Hematology and Stem Cell Transplantation Section
Division of Hematology/Oncology
Vanderbilt University Medical Center Nashville, TN, USA
Kristy Luke NP
Section of Bone Marrow Transplant and Cellular Therapy
Rush University Medical Center Chicago, IL, USA
Enrico Maffini MD
Department of Oncology
AOU Città della Salute e della Scienza di Torino
Department of Molecular Biotechnology and Health Sciences
University of Torino, Torino, Italy
Navneet S. Majhail MD, MS Blood and Marrow Transplant Program Cleveland Clinic Taussig Cancer Institute Cleveland, OH, USA
Leslee Matheny MD
Division of Diabetes, Endocrinology & Metabolism
Vanderbilt University Medical Center Nashville, TN, USA
Juliana Matthews MD
Division of Diabetes, Endocrinology & Metabolism
Vanderbilt University Medical Center Nashville, TN, USA
David Michonneau MD, PhD Hematology Transplantation
APHP Hospital Saint Louis and Université de Paris; Université de Paris & INSERM U976 Paris, France
Sandra A. Mitchell PhD, CRNP, AOCN Outcomes Research Branch
Healthcare Delivery Research Program Division of Cancer Control and Population Sciences
National Cancer Institute Bethesda, MD, USA
Emilee Moeke RN
Section of Bone Marrow Transplant and Cellular Therapy
Rush University Medical Center Chicago, IL, USA
Angela Moreschi Woods MSN APRN ACNP‐BC
National Marrow Donor Program Minneapolis, MN, USA
Ibrahim N. Muhsen MD
Department of Medicine
Houston Methodist Hospital and Weill Cornell Medical College Houston, TX, USA
Jeanne Murphy PhD, CNM, FACNM
The George Washington University Washington, DC, USA
Sunita Nathan MD
Section of Bone Marrow Transplant and Cellular Therapy
Rush University Medical Center Chicago, IL, USA
Shinichiro Okamoto MD, PhD Division of Hematology Department of Medicine Keio University School of Medicine Tokyo, Japan
Attilio Olivieri MD Clinica di Ematologia Department of molecular and clinical sciences Ancona University Ancona, Italy
Steven Pavletic MD
Immune Deficiency Cellular Therapy Program
Graft‐versus‐Host and Late Effects Section Center for Cancer Research
National Cancer Institute
National Institutes of Health Bethesda, MD, USA
Rachel Phelan
Center of International Blood and Marrow Transplant Research; Department of Medicine
Medical College of Wisconsin Milwaukee, WI, USA
Jakob R. Passweg MD Division of Hematology
University Hospital Basel Basel, Switzerland
J. Douglas Rizzo MD, MS
Medical College of Wisconsin and Center for International Blood and Marrow Transplant Research Milwaukee, WI, USA
Montserrat Rovira MD, PhD Hospital Clinic
Hematopoietic Cell Transplantation Program Barcelona, Spain
Alicia Rovó MD
Department of Hematology and Central Hematology Laboratory Inselspital, Bern University Hospital Bern, Switzerland
Nina Salooja FRCPath MD Department of Medicine Imperial College London Hammersmith Hospital London, UK
Insara Jaffer Sathick MD Renal Service, Division of Medicine Memorial Sloan Kettering Cancer Center New York, NY, USA
Bipin N. Savani MD
Long Term Transplant Clinic (LTTC), Hematology, Stem Cell Transplantation and Cellular Therapy Section, Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center and Veterans Affairs Medical Center, Nashville, TN, USA
Angela Scherwath PhD Department and Outpatient Clinic of Medical Psychology University Medical Center Hamburg – Eppendorf Hamburg, Germany
Hélène Schoemans MD, PhD Department of Hematology University Hospitals Leuven and KU Leuven Leuven, Belgium
Dana Shanis MD, FACOG VHealth & Wellness Philadelphia, PA, USA
Bronwen E. Shaw MD, PhD Center of International Blood and Marrow Transplant Research; Department of Medicine Medical College of Wisconsin Milwaukee, WI, USA
Gérard Socié MD, PhD
Hematology Transplantation
APHP Hospital Saint Louis and Université de Paris; Université de Paris & INSERM U976 Paris, France
Ayman O. Soubani MD
Division of Pulmonary, Critical Care and Sleep Medicine
Wayne State University School of Medicine Detroit, MI, USA
Katrina M. Stokes MSSW LCSW Tennessee Valley Healthcare System Nashville, TN, USA
Pamela Stratton MD Office of the Clinical Director National Institute for Neurological Disorders and Stroke Bethesda, MD, USA
Aurélien Sutra del Galy MD Hematology Transplantation
APHP Hospital Saint Louis and Université de Paris; Université de Paris & INSERM U976 Paris; France
Sarah Thilges PhD
Section of Psychosocial Oncology Loyola University Medical Center Maywood, IL, USA
André Tichelli MD Division of Hematology University Hospital Basel Basel, Switzerland
Mihkaila Wickline MD Seattle Cancer Care Alliance Fred Hutchinson Cancer Research Center Seattle, WA, USA
Lori Wiener, PhD, DCSW, LCSW-C Psychosocial Support and Research Program Center for Cancer Research Pediatric Oncology Branch NIH Bethesda, MD, USA
John R. Wingard MD
Division of Hematology & Oncology University of Florida College of Medicine Gainesville, FL, USA
SECTION 1 Late effects concepts 1
CHAPTER 1 1
Introduction to long‐term survivorship after hematopoietic cell transplantation
Bipin N. Savani1 and André Tichelli2
1Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
2Division of Hematology, University Hospital Basel, Basel, Switzerland
Background
Hematopoietic cell transplantation (HCT) provides curative ther apy for a variety of diseases. Over the past several decades, signifi cant advances have been made in the field of HCT and now HCT has become an integral part of treatment modality for a variety of hematologic malignancies and some nonmalignant diseases. HCT remains an important treatment option for a wide variety of hema tologic and nonhematologic disorders, despite recent advances in the field of immunologic therapies. Factors driving this growth include expanded disease indications, greater donor options (expanding unrelated donor registries and haploidentical HCT), and accommodation of older and less fit recipients [1,2‑4].
The development of less toxic pretransplant conditioning regimens, more effective prophylaxis of graft‐versus‐host disease (GVHD), improved infection control, and other advances in transplant technol ogy have resulted in a rapidly growing number of transplant recipients surviving long‐term free of the disease for which they were trans planted. The changes over decades in the transplant recipient popula tion and in the practice of HCT will have almost inevitably altered the composition of the long‐term survivor population over time. Apart from an increasingly older transplant recipient cohort, the pattern of transplant indications has shifted from the 1990s when chronic mye loid leukemia made up a significant proportion of allo‐HCT indica tions. Changes in cell source, donor types, conditioning regimens, GVHD prophylaxis, and supportive care have all occurred, with ongo ing reductions in both relapse and non‐relapse mortality (NRM) have been demonstrated [5‑10].
These patients have increased risks for a variety of late complica tions, which can cause morbidity and mortality (Figure 1.1). Most long‐term survivors return to the care of their local hematologists/ oncologists or primary care physicians, who may not be familiar with specialized monitoring and management of long‐term compli cations after HCT for this patient population. As HCT survivorship
increases, the focus of care has shifted to the identification and treatment of long‐term complications that may affect quality of life and long‐term morbidity and mortality [11‑13].
Preventive care, as well as early detection and treatments, are important aspects to reducing morbidity and mortality in long‐term survivors after allo‐HCT [4,14‑17]. The second edition of the book Blood and Marrow Transplantation Long‐Term Management: Prevention and Complications updates our knowledge on diagnosis, screening, treatment, and long‐term surveillance of long‐term sur vivors after HCT and shall meet the long‐term follow‐up standard operative practice (SOP) requirement of Foundation for the Accreditation of Cellular Therapy (FACT)/ Joint Accreditation Committee of ISCT‐EBMT (JACIE) standards [17].
Rapidly rising numbers of long‐term transplant survivors
Since the first three cases of successful allo‐HCT in 1968, the num ber of HCTs performed annually has increased steadily over the past several decades and continues to do so each year [1‑3]. Advances in HCT practice and supportive care have led to improved outcomes and an increasing number of long‐term HCT survivors.
Historically, the limitation of allo‐HCT has been transplant‐related mortality (TRM) and the availability of a compatible donor. In order to offer the curative allo‐HCT treatment option in most patients, safer regimens with acceptable GVHD‐associated morbidity and TRM are preferred, and donor availability have been expanded. In this era, a stem cell source can be found for virtually all patients who have an indication to receive allo‐SCT. All of these advances result in steadily increasing numbers of long‐term survivors after HCT, creat ing an expanding pool of children, and young and mature adults who are at risk of long‐term complications of HCT [18].
Blood and Marrow Transplantation Long Term Management: Survivorship after Transplant, Second Edition. Edited by Bipin N. Savani and André
Timelines for post HCT late effects (courtesy - Dr John Barrett)
Years1 35 10 15 20
Long‐term issues in long‐term survivors
For long‐term survivors (beyond 2 years post‐HSCT), the prospect for long‐term survival is excellent (85% at 10 years after HSCT). Yet, among long‐term survivors, mortality rates are four‐ to nine‐fold higher than observed in an age‐adjusted general population for at least 30 years after HCT, yielding an estimated 20–30% lower life expectancy compared with someone who has not been transplanted [19.20]. The most common causes of excess deaths, other than recurrent malignancy, are chronic GVHD (cGVHD), infections, second malignancies, respiratory diseases, and cardiovascular dis ease and many other late effects reviewed in this book.
cGVHD is a multisystem chronic alloimmune and autoimmune disorder that occurs later after allo‐HCT. It is characterized by immunosuppression, immune dysregulation, decreased organ function, significant morbidity, and impaired survival. A number of patients require continued immunosuppressive treatment beyond 5 years from the initial diagnosis of cGVHD. Therefore, it is not sur prising that corticosteroid and other immunosuppressive therapies are major contributors of late complications after allo‐HCT. If not treated adequately, and in severe cases, cGVHD can result in major disability related to keratoconjunctivitis sicca, pulmonary insuffi ciency due to bronchiolitis obliterans, or restrictive lung disease related to scleroderma or fasciitis, as well as joint contractures, skin ulcers, esophageal and vaginal stenosis, and many other long‐term complications [4.21].
Several factors impact on recovery from and late effects of HCT, including previous therapy for the underlying disease, pretrans plant co‐morbidities and psychosocial status, intensity of the trans plant conditioning regimen and, most importantly, duration of cGVHD and immunosuppressive therapy [18,22]. Other complica tions are related to the prolonged use of glucocorticoids and other immunosuppressive drugs, and many are multifactorial in etiology. Side effects of the treatment of acute complications early after HCT (e.g., the use of corticosteroids) may also contribute to long‐term complications. Nearly all organ systems can be affected by late effects of HCT. However, the burden of late effects can greatly differ among long‐term survivors, primarily depending on patient‐ and transplant‐related risk factors.
Developing resources and a guide for long‐term survivors
Ongoing research is focused on better understanding of late effect issues and prediction of posttransplant long‐term complications, which allows transplant‐eligible patients to incorporate this knowl edge into more informative decision making [18,23]. Therefore, significant resources should be focused on the better implementa tion of how patients and physicians use extensive data regarding posttransplant late complications in clinical care.
Figure 1.1 Timelines for post‐HCT late effects. (Source: Courtesy of Prof. John Barrett.)
With survivorship, a shift in care occurs from large transplant centers to community healthcare providers. As a result, many hema tologist/oncologist and primary care physicians are assuming the posttransplant care of long‐term survivors. Preventive measures, as well as early detection and treatments, are important aspects to reducing morbidity and mortality in long‐term survivors after HCT. This book [17] offers the updated practical advice and outlines late effect experts’ personal approaches in managing long‐term survi vors after HCT. The management of late HCT effects is important to improve long‐term survival of HCT recipients but should be tailored to the risks specific to the primary disease and transplant type. Future planning should account for the impact of the expected increase in transplant activity and number of survivors on resource utilization.
We also recommend early referral or discussion with a transplant center for enrolment of patients in available late effect studies and for management guidelines. A better understanding of the patho genesis of late effects will allow for more effective screening to iden tify patients at risk prior to the HCT procedure, and allow more effective monitoring to detect early evolution of the late effects after HCT. This may, in turn, allow for improved therapeutic decision making while evaluating patients for HCT, and early institution of treatments directed at preventing and treating late effects in patients at risk after HCT. To better inform the needs of the contemporary HCT survivor generation and guide the delivery of late effects ser vices, periodic analysis of new survivor cohorts is needed.
Declaration of commercial interest
None.
References
1. D’Souza A, Fretham C, Lee SJ, et al. Current use of and trends in hemat opoietic cell transplantation in the United States. Biol Blood Marrow Transplant, 2020.
2. Blume KGT, E. D. Chapter 1: A history of allogeneic and autologous hematopoietic cell transplantation (ed Fifth). Oxford, UK, John Wiley & Sons, Ltd, 2015 pp. 1–11
3. Horowitz MM. Chapter 2: Uses and Growth of Hematopoietic Cell Transplantation (ed Fifth). Oxford, UK, John Wiley & Sons, Ltd, 2015 pp. 8–17.
4. Savani BM (Editor). Blood and marrow transplantation long‐term man agement: prevention and complications (ed First). Oxford, UK, John Wiley & Sons, Ltd, 2013.
5. Shah NN, Ahn KW, Litovich C, et al. Allogeneic transplantation in elderly patients >/=65 years with non‐Hodgkin lymphoma: a time‐trend analysis. Blood Cancer J 9:97, 2019.
6. Cooper JP, Storer BE, Granot N, et al. Allogeneic hematopoietic cell transplantation with non‐myeloablative conditioning for patients with
hematologic malignancies: Improved outcomes over two decades. Haematologica, 2020.
7. Canaani J, Beohou E, Labopin M, et al. Trends in patient outcome over the past two decades following allogeneic stem cell transplantation for acute myeloid leukaemia: an ALWP/EBMT analysis. J Intern Med 285:407–418, 2019.
8. Bakhtiar S, Salzmann‐Manrique E, Hutter M, et al. AlloHSCT in paedi atric ALL and AML in complete remission: improvement over time impacted by accreditation? Bone Marrow Transplant 54:737–745, 2019
9. Khoury HJ, Wang T, Hemmer MT, et al. Improved survival after acute graft‐versus‐host disease diagnosis in the modern era. Haematologica 102:958–966, 2017.
10. Kanate AS, Majhail NS, Savani BN, et al. Indications for Hematopoietic Cell Transplantation and Immune Effector Cell Therapy: guidelines from the American Society for Transplantation and Cellular Therapy. Biol Blood Marrow Transplant 26:1247–1256, 2020.
11. Hashmi S, Carpenter P, Khera N, et al. Lost in transition: the essential need for long‐term follow‐up clinic for blood and marrow transplanta tion survivors. Biol Blood Marrow Transplant 21:225–232, 2015.
12. Hashmi SK, Lee SJ, Savani BN, et al: ASBMT Practice Guidelines Committee Survey on Long‐Term Follow‐Up Clinics for Hematopoietic Cell Transplant Survivors. Biol Blood Marrow Transplant 24: 1119–1124, 2018.
13. Savani BN, Griffith ML, Jagasia S, et al. How I treat late effects in adults after allogeneic stem cell transplantation. Blood 117:3002–3009, 2011.
14. Majhail NS, Rizzo JD, Lee SJ, et al. Recommended screening and pre ventive practices for long‐term survivors after hematopoietic cell trans plantation. Biol Blood Marrow Transplant 18:348–371, 2012.
15. Bhatia S, Armenian SH, Landier W. How I monitor long‐term and late effects after blood or marrow transplantation. Blood 130:1302–1314, 2017.
16. Inamoto Y, Lee SJ. Late effects of blood and marrow transplantation. Haematologica 102:614–625, 2017.
17. Savani BN, Tichelli A (Editors). Blood and marrow transplantation long‐term management: prevention and complications (ed Second). Oxford, UK, John Wiley & Sons, Ltd, 2020.
18. Battiwalla M, Hashmi S, Majhail N, et al. National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: developing recommendations to improve survivorship and long‐term outcomes. Biol Blood Marrow Transplant 23:6–9, 2017.
19. Martin PJ, Counts GW, Jr., Appelbaum FR, et al. Life expectancy in patients surviving more than 5 years after hematopoietic cell transplan tation. J Clin Oncol 28:1011–1016, 2010.
20. Bhatia S, Francisco L, Carter A, et al: Late mortality after allogeneic hematopoietic cell transplantation and functional status of long‐term survivors: report from the Bone Marrow Transplant Survivor Study. Blood 110:3784–3792, 2007.
21. Palmer J, Chai X, Pidala J, et al: Predictors of survival, nonrelapse mortality, and failure‐free survival in patients treated for chronic graft‐versus‐host disease. Blood 127:160–166, 2016.
22. Sun CL, Francisco L, Kawashima T, et al: Prevalence and predictors of chronic health conditions after hematopoietic cell transplantation: a report from the Bone Marrow Transplant Survivor Study. Blood 116:3129–3139; quiz 3377, 2010.
23. Battiwalla M, Tichelli A, Majhail NS. Long‐term survivorship after hematopoietic cell transplantation: roadmap for research and care. Biol Blood Marrow Transplant 23:184–192, 2017.
CHAPTER 2 2
International Blood and Marrow Registries: trends on long‐term data collection
Rachel Phelan1, Jakob R. Passweg2, Helen Baldomero2, Minako Iida3, Yoshiko Atsuta4, Shinichiro Okamoto5, Mahmoud Aljurf 6, Feras Alfraih6, and Bronwen E. Shaw1
1Center for International Blood and Marrow Transplant Research; Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA
2Division of Hematology, University Hospital Basel, Basel, Switzerland
3Department of Promotion for Blood and Marrow Transplantation, Aichi Medical University School of Medicine, Nagakute, Japan
4Japanese Data Center for Hematopoietic Cell Transplantation (JDCHCT), Nagoya, Japan
5Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan
6Oncology Center, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia
Overview of the Role of Registries in HCT
Registries focused on data collection specific to hematopoietic cell transplant (HCT) recipients have been in place since the late 1960s. These databases are instrumental in research efforts to understand outcomes over time for those receiving an HCT [1,2]. They allow analyses based on pre‐ and posttransplant variables, including his tocompatibility, choice of conditioning regimen, donor sources, disease type and the development of transplant‐related complica tions. These databases have been used in a multitude of published retrospective studies, which have informed clinical practice over the years [3‑12]. Registry data has helped to inform numerous pro spective clinical trials in efforts to improve upon prior outcomes such as overall survival and the development of graft‐vs‐host‐disease (GVHD) and has also been used as a tool for developing prospective clinical trials by providing insight into areas of research need or estimates for potential patient accrual. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN), in collaboration with a well‐established registry, the Center for International Blood and Marrow Transplant Research (CIBMTR), is an example of how ongoing input of registry data can be utilized for this purpose. It is also notable that some registry data is linked to biorepositories, presenting the opportunity for studies focused on issues such as immune reconstitution or genetic predisposition to certain transplant‐related complications or disease relapse. Globally, HCT‐specific registries have continued to expand both in number and depth of data collection, and include the CIBMTR, the European Society for Blood and Marrow Transplantation
(EBMT), the Asia‐Pacific Blood and Marrow Transplantation Group (APBMT) and the Eastern Mediterranean Blood and Marrow Transplantation Registry (EMBMT) (Table 2.1.).
Overview of Late Effects Data Collection through Registries
Registry Strengths
With a growing population of survivors following HCT, the impor tance of registry‐based studies focused on this patient population has become increasingly apparent. Research focused on long‐term HCT survivors is complex due to several factors, including the fact that certain HCT‐specific late effects may be rare, have long laten cies, or occur more frequently in certain patient populations.
In order to overcome these research barriers, centralized and standardized data collection of large numbers of patients over extended periods of time is required. Recent studies evaluating risk factors for secondary neoplasms (SN), including central nervous system (CNS) tumor development in survivors of pediatric HCT and acute myeloid leukemia/myelodysplastic syndrome in survi vors of autologous HCT, are examples of the critical importance of registry data to explore rare events that occur many years following the HCT process itself [13,`4]. The study focused on CNS tumor development found the cumulative incidence of tumor develop ment to be 1.29% at 20 years following HCT. Though this equated to a total of 59 CNS tumors in 8720 patients, this was 33 times the
Table 2.1 Transplant Registries Collecting Data on HCT Survivors
Center for International Blood and Marrow Transplant Research (CIBMTR)
Population/ Region Included in Data
Over 320 centers. All US allograft centers (mandatory reporting for allogeneic transplants), various other regions in the world
European Society for Blood and Marrow Transplantation (EBMT)
Asia‐Pacific Blood and Marrow Transplantation Group (APBMT)
Over 500 centers in EuropeOver 600 centers in 20 Asia‐Pacific countries/regions
Eastern Mediterranean Blood and Marrow Transplantation Registry (EMBMT)
38 centers in the Eastern Mediterranean Region Year Data Collection Began
Patients in Registry
Transplant‐Related Data Collected
Late Effects‐Specific Data Collected
Transplant essential data (TED) for all patients includes Patient‐Disease‐Transplant related characteristics as well as several outcome data including disease status, aGVHD, cGVHD, cause of death and a number of infectious and noninfectious complications, such as second malignancies. Research level data on a subset (approximately 25%) of patients includes comprehensive disease history and late effects post‐transplant
Secondary malignancy and fertility outcomes for all patients.
Research level patients: extensive organ‐specific late effects
Patient‐Disease‐Transplant related characteristics as well as several outcome data including disease status, aGVHD, cGVHD, cause of death and a number of infectious and noninfectious complications
Least Minimum Dataset (LMD) for all patients includes disease information, conditioning regimen (agents/radiation types), GVHD prophylaxis, best disease status after HCT, details of relapse or progression of disease, aGVHD, cGVHD, and cause of death. LMD also includes donor information
Limited database is obtained from all participating centers which includes: type of transplant, indication, type of conditioning, donor type and source of stem cells
Few centers can provide outcome data on request.
Funding for Registry
Regulations (voluntary/ mandatory)
Research Opportunities
Funding sources include federal, National Institute of Health grants and corporations
Mandatory TED level reporting for all allogeneic transplants in the US
All other reporting is voluntary
Open to the entire community through a system of peer‐review
Secondary malignancy; Details of relapsed or persisting disease including treatment;
Pregnancy after HCT, Infectious and toxic complications are collected for the first 100‐day evaluation and subsequently for every yearly follow‐up on MED‐B forms (i.e. centers not reporting MED‐B forms do not report late effects except for secondary malignancy)
Through EBMT fundraising and locally paid data managers
Consent forms for patients, regulation for data collection; manuals for data management; regulation through JACIE accreditation which mandates data collection
Secondary malignancy and the main cause of death
Few centers can provide outcome and late effect data on request.
Late effects are addressed in few multicenter studies but not captured by the database.
Studies on late effects
performed (Y/N)
Through APBMT funding onlyThrough EMBMT fundraising and partial support from the hosting institution
In Japan, centers are obliged to make an effort to submit outcome data to the Japanese HCT registry. In all other countries or regions, reporting is voluntary.
Open for any EBMT memberOpen for any APBMT member from a country/region participating and submitting data to outcome registry
Y Y N
In some countries/regions with a long history of HCT, studies on late effects are performed by using their national registry data
Consent forms for patients, regulation for data collection. Few centers are JACIE accredited which mandates data collection
Open for any EMBMT member.
Few studies were done in partnership with CIBMTR and EBMT
Y One study at present
expected rate in the general population and highlights the impor tance of surveilling for rare events in survivors [14].
While pre‐HCT exposures, HCT‐related variables and demo graphic data have routinely been collected in most registries, the granularity and extent of late effects data collection has varied. SN development was the major long‐term complication captured by registries in their early stages of development. Though it differs depending on the specific registry, the late effects data obtained has now expanded to include long‐term outcomes such as fertility, car diovascular disease, diabetes, cataracts, chronic GVHD (cGHVD), socioeconomic status and late disease relapse.
Registry Challenges
Though data collection through registries can address several of the issues surrounding late effects research, there remain many chal lenges. The correct methodology to conduct such research often requires intensive protocol development and complex statistical approaches. A recent report by the National Institutes of Health (NIH) Hematopoietic Cell Transplantation Late Effects Initiative highlights the importance of collecting the correct amount and type of data, thoughtfully approaching study design, and having the expertise to conduct the analysis [15]. In order to collect registry data and conduct appropriate studies, significant infrastructure and funding is required. When collecting and evaluating data interna tionally, cultural/language difference, regulation variances around data collection, variability in organizational structure, and resource barriers need to be considered. One of the most notable challenges, regardless of geographic location, is that of patient attrition as they get further from the acute post‐HCT period and may be less likely to be followed by the transplant center.
Future of Data Collection in Survivorship
Efforts are being made to improve data collection for long‐term survivors. Growth of dedicated late effects‐focused clinics in both the pediatric and adult setting has the potential to improve patient engagement and decrease the number of patients lost to follow‐up in the years following HCT [16‑20]. The utilization of technology, such as mobile health (mhealth) platforms to track the health of survivors, electronic patient‐reported outcomes, and streamlined registry data ascertainment using electronic health record systems, is being investigated as an alternative means of data collection that may not require patients to return to their specific transplant cent ers [21‐23]. Sharing research findings with patients and caregivers through various forums (i.e. online webinars, in‐person confer ences) can demonstrate the importance of continued registry involvement and may result in improved patient follow‐up. Registries are also adapting and expanding to include outcomes related to various novel cellular therapies, such as chimeric antigen receptor T‐cell (CART) therapy, in addition to HCT. Though only short‐term data are available for novel cellular therapies at this time, the importance of following these patients long‐term to evaluate for potential late effects has been acknowledged and is already being discussed. Facilitating the merging of other disease and
treatment‐specific registries not centered on HCT alone (such as those focused on solid‐organ transplant, hematologic or solid‐tumor malig nancy therapies, and pediatric or adult cancer survivors) is another area of interest [24]. Though merging data from diverse registries represents another opportunity to compare patient populations and use registry data to its full extent, challenges exist since data collection methodology is seldom standardized, and the collection of uniform, unique identifiers is inconsistent. Most importantly, continued and increased future collaborations between the major HCT registries presented herein will be critical to enhance research endeavors focused on the growing population of HCT survivors.
Center for International Blood and Marrow Transplant Research (CIBMTR)
Rachel Phelan and Bronwen E Shaw
Introduction to the registry
The CIBMTR® (Center for International Blood and Marrow Transplant Research®) is a research collaboration between the National Marrow Donor Program® (NMDP)/Be The Match® and the Medical College of Wisconsin (MCW). This collaboration, agreed upon in 2004, brought together the strength of the two organizations and removed the need for centers to carry out dupli cate reporting to both the NMDP and International Bone Marrow Transplant Registry (IBMTR) for patients who received stem cells from an unrelated donor. The mission of the CIBMTR is to pro mote collaborative research to understand and improve access to, and outcomes of, cellular therapies for the people served. Though CIBMTR initially collected data only for Hematopoietic Cell Transplant (HCT) recipients, this has recently been expanded to include recipients of non‐HCT cellular therapies. CIBMTR works closely with other international registries to harmonize data collec tion variables and facilitate joint research efforts.
Data collection
CIBMTR has been collecting longitudinal patient outcome data for over 45 years. The complexity and volume of data collected has increased with time, as the field has progressed. In the US, reporting of all allogeneic transplants is mandatory to meet the requirements of the Stem Cell Therapeutic Outcomes Database (SCTOD) contract (which CIBMTR holds) for the Health Resources and Services Administration (HRSA)‐sponsored C.W. Bill Young Cell Trans plantation Program (CWBYCTP). This contract requires CIBMTR to produce an annual center‐specific survival analysis evaluating the one‐year survival rates among US centers. All patients participate at the “essential” level of data collection, which includes details related to patient, disease and transplant characteristics which impact trans plant outcomes. A subset of patients who consent to research (approx imately 25% of the registry) have more comprehensive data collected, which includes details of pretransplant disease course and therapy, as well as additional outcomes data such as infections and organ‐specific late effects. Data are collected for as long as the patient is followed clinically (lifelong if applicable).
Data quality is an essential aspect of the registry and multiple steps are in place to enhance this. These include: upfront data vali dations, automated cross‐form data validations, in‐system data queries, automated data quality checks performed by a dedicated data quality team and, finally, direct review by medical and scien tific staff of individual data elements at the time of data analyses. In addition, CIBMTR has a routine system to ensure the complete ness of form submission on a calendar basis, and an audit team who perform comprehensive on‐site data audits for participating sites every four years. There are ongoing challenges related to the burden of data entry at the transplant centers and laboratories, as well as challenges related to the need to regularly update the data variables collected on the forms to reflect changing transplant practice.
Late effects specific data collection
CIBMTR has made an effort to include collection of late‐effects data on patients for most of its history, however, the nature and completeness of these data has changed significantly over time. Data on subsequent neoplasms (SN) and fertility outcomes have been collected for many years on all patients. Centers are asked to provide pathology reports to CIBMTR to support the SN diagnosis and subsequent research studies in SNs, however, this can by logis tically challenging, especially when SNs are not diagnosed at the original transplant center.
Data on other organ‐specific late effects, including renal, cardiac, metabolic, endocrine, psychiatric and others are collected for patients for whom research level data are collected. These data are complex to collect due to the broad spectrum of late effects and the inability to collect extensive detail on individual events due to the nature of registry reporting. Another serious challenge relates to the fact that these late effects most frequently occur at a time when the patient is no longer regularly (or at all) attending their transplant center and thus under‐ascertainment is highly likely.
In 2018, CIBMTR convened a group of experts to form a late effects task force to develop a strategy for the focused collection of late effects in a subset of patients reporting to CIBMTR. The task force made recommendations in three main areas: subsequent neoplasms, organ‐specific late effects and the inclusion of Patient‐Reported Outcomes (PRO) in routine registry data collection. Many of the recommendations focus on assessing the quality and completeness of late‐effect reporting to CIBMTR and include pro posals to compare CIBMTR data to other disease or outcomes specific databases/registries. Enhancing the collection of risk fac tors, and correlative biologic material was also recommended in some circumstances. Finally, the value of adding assessments of quality of life by direct patient questioning (PROs) was strongly encouraged.
Most research on late effects in CIBMTR is performed in the Late Effects and Quality‐of‐Life (QOL) Working committee. Members of the community can propose studies to the committee which are then voted for through a peer‐review system at the annual meeting. The committee has performed studies addressing a diverse range of topics such as the incidence and risk factors for SN and other late effects after HCT, cardiovascular and metabolic complications, and return to work and QOL in HCT survivors [3,13,14,25‑31].
Future plans
CIBMTR is currently implementing the recommendations of the late effects task force. An IRB‐approved PRO protocol is in place (August 2019) to begin the collection of PROs. An important rec ommendation of the task force was to explore mechanisms to enhance patient engagement in later years following transplant, especially if they have left the care of the transplant center, to con tinue to understand the physical, emotional and social issues that they face. Such engagement, through direct patient contact, may also enhance the collection of late effects such as SN and fertility outcomes. Finally, CIBMTR is also transforming the way in which medical record/electronic data are collected to reduce the burden on transplant center staff and maximize the benefits of advances in IT systems and electronic data records.
The Registry of the European Society for Blood and Marrow Transplantation (EBMT)
Jakob R. Passweg and Helen Baldomero
Introduction to the registry
The EBMT Registry, established in 1974, is the backbone of the EBMT’s research and educational activities. More than half a million patients having received a hematopoietic stem cell transplantation (HSCT) procedure are included and cellular therapies now consti tute a rapidly expanding field. The purpose of the Registry is to pro vide a pool of data to EBMT members to perform studies, assess epidemiologic trends, and ultimately improve patient outcome.
The EBMT is a voluntary organization comprising more than 600 transplant centers mainly from Europe. Status as a member center requires submission of minimal essential data (MED‐A form) from all consecutive patients to a central registry in which patients may be identified by the diagnosis of underlying disease and type of transplantation.
Data collection
Completeness of data registration is checked at regular intervals in centers with accreditation by the Joint Accreditation Committee ISCT‐Europe (JACIE) & EBMT, Europe’s official accreditation body in the field of hematopoietic stem cell transplantation (HSCT) and cellular therapy, promoting high‐quality patient care and medi cal and laboratory practice through a profession‐led, voluntary accreditation scheme. Over 330 centers have been accredited at some point in time. Accreditation has been shown to be associated with improved outcome [32].
Informed consent for transplantation and data collection is obtained locally according to current regulations. Since 2003, all transplant centers are required to obtain written informed consent prior to data registration with the EBMT following the 1975 Helsinki Declaration.
Next to the MED‐A data with a restricted set of variables, MED‐B data, are collected by centers with the data management capacity to handle the burden of data management, a task with formidable challenges in a voluntary organization without remuneration for
the data management effort. Data initiatives are sometimes used to increase data coverage in a particular disease or field of inter est [33]. These data initiatives provide a tool in between routine data registration and specific cohort studies. Last, for some rare dis eases, e.g. aplastic anemia, data on transplantation are supple mented by routine collection of data on alternative treatment such as immunosuppressive treatment approaches [34].
In addition to the registry, the EBMT annual activity survey [35] compiles trends of the use of transplant technology in Europe and neighboring countries. This provides data on transplant indications in a timely manner for member centers of the EBMT and nonmem ber centers. At the same time, activity survey data collected inde pendently provides a source for checking completeness of reporting into the EBMT database. Information on almost 800,000 transplants has been accrued since 1990.
Benchmarking studies [36] are used to qualify the completeness of patient follow‐up across centers and to compare outcomes such as mortality among centers as a measure of patient selection and treatment quality.
Data from the registry are obviously among other things of major interest to describe outcomes of rare diseases [37] and even rare complications of rare diseases [38] and on impact of certain risk factors on early and long‐term outcome [39]. Data obtained through the registry provide a base to formulate guidelines and rec ommendations [40].
The Registry contains patient clinical data, including aspects of the diagnosis and disease, first‐line treatments, HSCT‐ or cell‐ther apy‐associated procedures, transplant type, donor type, stem‐cell source, complications and outcome. Patients are followed up indefi nitely. Basic donor information is included with these procedures and donor follow‐up data are entered. All Registry studies are per formed under the supervision of one of the EBMT Working Parties.
Late effects specific data collection
The Transplant Complications Working Party (TCWP) leads efforts focused on complications and long‐term survivorship. The aim of the Transplant Complications Working Party is to conduct research as well as to provide education and expertise on the subject of non‐infectious complications after HCT. The major fields of interest of the TCWP include the following:
Early complications e.g. graft failure, VOD/SOS, transplant‐asso ciated microangiopathy (TAM), other endothelial syndromes, impact of co‐morbidities, toxicity of conditioning regimen and sup portive care; Acute and cGVHD – all aspects from risk factors through diagnosis to treatment; Late effects – e.g. infertility, sexual dysfunction, secondary cancers, organ‐specific late complications, quality of life. Variables on late effects such as fertility and second ary cancers are collected in the MED‐B forms, while the MED‐A form contains a restricted set of variables. Cause of death is obvi ously recorded for every patients.
Issues of long‐term survivorship data collection are many. Obviously data quality depends on the quality of education for data managers, a task taken seriously by the EBMT where data managers take part at annual education conferences to facilitate quality collection. Follow‐up at each center also poses a challenge, especially in a continent with many different countries and types of healthcare systems.
Future plans
Future areas of focus for the EBMT include specific description and analysis of long‐term complications associated with GVHD, description of quality of life, including in comparison with other treatment approaches, and more precise definition of late toxicities and secondary tumors in patients treated by HCT.
Asia‐Pacific Blood and Marrow Transplant Group (APBMT)
Minako Iida, Yoshiko Atsuta, and Shinichiro Okamoto
Introduction of the registry
Asia‐Pacific Blood and Marrow Transplantation Group (APBMT) was initiated by transplant physicians from Australia, China, Hong Kong, India, Japan, Republic of Korea, Malaysia, and Taiwan in 1990 to share the information regarding hematopoietic cell trans plantation (HCT) and promote collaborative basic and clinical studies. As of August 2019, APBMT comprised 22 countries/ regions (Australia, Bangladesh, Cambodia, China, Hong Kong, India, Indonesia, Iran, Japan, Korea, Malaysia, Mongolia, Myanmar, Nepal, New Zealand, Pakistan, the Philippines, Singapore, Sri Lanka, Taiwan, Thailand, and Vietnam) and are leading a variety of issues regarding HCT in the Asia‐Pacific region.
APBMT established the Asian Blood and Marrow Transplantation registry (Asian BMT registry) at the 11th Annual Congress of APBMT in Nagoya, Japan in 2006.
Data collection
APBMT has a data center in Japan and has been collecting informa tion regarding the numbers of HCTs according to HCT type, donor type, stem‐cell source, and disease type in each country/region annually since 2007 (APBMT Activity Survey). Six countries/regions that have their own national registries (Australia, New Zealand, India, Republic of Korea, Japan, and Taiwan) submit data through their national registry annually. In China and Malaysia (until national registry systems were established), Iran, and the Philippines, one contact person from a major transplant center has collated the numbers and target diseases of HCTs performed in their countries each year and has submitted these data. Hospitals or centers in Bangladesh, Hong Kong, Myanmar, Pakistan, Singapore, Sri Lanka, Thailand, and Vietnam submit their data individually to APBMT Data Center, where data are combined as a national data of each country. At the end of 2017, APBMT Data Center had not yet received data from Cambodia, Indonesia, Mongolia, and Nepal, though certain HCT activities were known to have occurred in these countries. The total number of HCTs performed in the Asia‐Pacific (AP) region in 2015 was 17,572, and the annual number of HCTs performed in the AP region has continued to increase, exceeding 10,000 each year since 2008, with over 200,000 total HCTs performed between 1986 and 2015 [41]. The total population of APBMT mem ber countries/regions comprised approximately 55% of the world’s
population in 2018 [42], thus, a continued increase in the numbers of HCTs in APBMT countries/regions is expected.
APBMT Data Center launched the APBMT Outcome Registry in 2009, and are collecting individual patient data using the Least Minimum Dataset (LMD). When data collection started, data were submitted on Excel spreadsheets in PDF (hard copy). The collec tion rate remained at approximately 40% of HCTs reported through the annual APBMT Activity Survey as of 2018. The APBMT Outcome Registry accepts data registered through national regis tries. The countries/regions with active national registries submit ting data to the APBMT Outcome Registry include Australia/New Zealand (Australasian Bone Marrow Transplant Recipient Registry [ABMTRR]), Japan (Japan Society for Hematopoietic Cell Transplantation [JSHCT] / Japanese Data Center for Hematopoietic Cell Transplantation [JDCHCT]), and Taiwan (Taiwan Society of Blood and Marrow Transplantation [TBMT]). APBMT encourages and assists with the establishment of national transplant outcome registries. Global collaboration in the HCT community has led to data sharing/transmission from the Center for International Blood and Marrow Transplant Research (CIBMTR) from the centers that agreed upon the data sharing. This approach has been working very well for some centers in India, Pakistan, and Singapore. To further improve data submission, APBMT Data Center developed and launched an electronic data capture system in August 2019. With this system, we can receive data from each center, and create national data for each country/region; therefore, the APBMT Data Center anticipates an increase in the number of outcome data collected.
Late effects specific data collection
APBMT countries/regions are characterized by its diversity in terms of the activity of HCT, social infrastructure, regulation for medical care and research, and the age of HCT. Thirteen countries/ regions started HCT prior to 2000, with Japan, Singapore, Taiwan, and the Republic of Korea starting in 1986 [43]. Bangladesh, Myanmar, Sri Lanka, and Nepal started HCT from 2014. Establishment and dissemination of HCT and improvement of short‐term survival outcomes tend to be listed as priority issues in countries with a short history of HCT. Several studies have been performed in countries or regions with a long HCT history, includ ing studies to address incidence and risk factors or outcomes of long‐term complications such as secondary malignancies after HCT, or long‐term effects of HCT for recipients in terms of quality of life and returning to work challenges [44–53].
Future plans
Within APBMT, there are still many countries/regions where long‐term follow‐up after HCT is not properly performed according to the recommended guidelines. The barriers that impede the imple mentation and promotion of the long‐term follow‐up are varied significantly among the countries/regions. APBMT will continue to work with multidisciplinary transplant team members including community resource to increase the awareness of long‐term survi vorship in HCT, and will solve the barriers by geographical‐based approaches. This effort will facilitate further data collection in regards to late effects within the APBMT registry.
The Registry of the Eastern Mediterranean Blood and Marrow Transplantation Group (EMBMT)
Mahmoud Aljurf and Feras Alfraih
Introduction to the registry
The Eastern Mediterranean Blood and Marrow Transplantation (EMBMT) Group was established in 2008 as a cooperative platform for physicians, scientists and healthcare workers from institutions in the WHO designated Eastern Mediterranean Region (EMRO) with the goal of sharing experience, initiation of cooperative trials and establishing common strategy to achieve optimization in the field of HCT. The group’s aim is to promote all aspects of patient care, academic and research activities associated with HCT in the region which includes knowledge of the trends, patterns and status of HCT in Eastern Mediterranean (EM) countries [54].
The registry has member centers from 14 countries in Gulf Cooperative Council, Levant, North Africa and Near East. These countries are Saudi Arabia, Kuwait, Oman, Qatar, Jordan, Syria, Lebanon, Iran, Iraq, Pakistan, Egypt, Tunisia, Algeria and Morocco [55].
The Head Office of the EMBMT is hosted at the King Faisal Specialist Hospital and Research Center in Riyadh, Saudi Arabia.
The organization is active in holding periodic workshops focus ing on data management, quality management and HCT‐related research in general. There is a very active collaboration between the institutions particularly in relation to patient care.
Data collection
EMBMT central office currently collects data from 38 centers in the EMRO region individually on an annual basis.
The data submitted from participating centers includes type of transplant, indication, type of conditioning, donor type and source of stem cells. The registry publishes HCT regional performance data every two years. Additionally, the registry does retrospective studies on rare diseases that are more prevalent in the EMRO such as bone marrow failure. During the last 10 years, EMBMT had made several publications related to HCT in the EMRO region. Great heterogeneity exists in the capabilities of the reporting center to collaborate on data [56].
At present, approximately 2500 HCT procedures are done in the EMRO region annually with the majority being of allogeneic type (55–60%). This is because of the wider availability of related donors with the large family size that exists in most of the countries and the young median age of the population leading to more pediatric cases, obviously with more allogeneic indications.
Late Effects Specific Data Collection
Approximately 30% of the reporting centers are capturing outcome data. These centers are also reporting data to other international registries like CIBMTR and EBMT.
At present, late effects and outcome data are not routinely requested or obtained by EMBMT from participating centers. Late effects are of particular importance in the EMRO region as a large
proportion of the patients are from pediatric ages with highly cur able malignancies and inherited disorders. Few studies have been conducted on long‐term outcome of bone marrow failure syn dromes including Fanconi Anemia and Dyskeratosis Congenita and more are being done.
Future plans
EMBMT registry is in the process of adding a few items that will capture limited but important information on outcomes and late effects data such as survival and GVHD.
If this demonstrates success and feasibility, the registry will con tinue to slowly but steadily increase the items to be included in reporting.
References
1. Aljurf M, Rizzo JD, Mohty M, et al. Challenges and opportunities for HSCT outcome registries: perspective from international HSCT regis tries experts. Bone Marrow Transplant. 2014;49(8):1016–1021.
2. Horowitz M. The role of registries in facilitating clinical research in BMT: examples from the Center for International Blood and Marrow Transplant Research. Bone Marrow Transplant. 2008;42 (Suppl 1):S1–S2.
3. Bhatt NS, Brazauskas R, Tecca HR, et al. Post‐transplantation employ ment status of adult survivors of childhood allogeneic hematopoietic cell transplant: A report from the Center for International Blood and Marrow Transplant Research (CIBMTR). Cancer. 2019;125(1): 144–152.
4. Eapen M, Raetz E, Zhang MJ, et al. Outcomes after HLA‐matched sib ling transplantation or chemotherapy in children with B‐precursor acute lymphoblastic leukemia in a second remission: a collaborative study of the Children’s Oncology Group and the Center for International Blood and Marrow Transplant Research. Blood. 2006;107(12): 4961–4967.
5. Eapen M, Rocha V, Sanz G, et al. Effect of graft source on unrelated donor haemopoietic stem‐cell transplantation in adults with acute leu kaemia: a retrospective analysis. Lancet Oncol. 2010;11(7):653–660.
6. Verneris MR, Eapen M, Duerst R, et al. Reduced‐intensity conditioning regimens for allogeneic transplantation in children with acute lympho blastic leukemia. Biol Blood Marrow Transplant. 2010;16(9): 1237–1244.
7. Zhang MJ, Davies SM, Camitta BM, et al. Comparison of outcomes after HLA‐matched sibling and unrelated donor transplantation for children with high‐risk acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2012;18(8):1204–1210.
8. Hussein AA, Hamidieh AA, Elhaddad A, et al. First report of pediatric hematopoietic stem cell transplantation activities in the eastern medi terranean region from 1984 to 2011: on behalf of the pediatric cancer working committee of the eastern mediterranean blood and marrow transplantation group. Bone Marrow Transplant. 2017;52(1):120–125.
9. Iida M, Kodera Y, Dodds A, et al. Advances in hematopoietic stem cell transplantation in the Asia‐Pacific region: the second report from APBMT 2005‐2015. Bone Marrow Transplant. 2019;54(12): 1973–1986.
10. Paulson K, Brazauskas R, Khera N, et al. Inferior access to allogeneic transplant in disadvantaged populations: a center for international blood and marrow transplant research analysis. Biol Blood Marrow Transplant. 2019;25(10):2086–2090.
11. Pavlů J, Labopin M, Niittyvuopio R, et al. Measurable residual disease at myeloablative allogeneic transplantation in adults with acute lympho blastic leukemia: a retrospective registry study on 2780 patients from the acute leukemia working party of the EBMT. J Hematol Oncol. 2019;12(1):108.
12. Teira P, Battiwalla M, Ramanathan M, et al. Early cytomegalovirus reactivation remains associated with increased transplant‐related mor tality in the current era: a CIBMTR analysis. Blood. 2016;127(20): 2427–2438.
13. Radivoyevitch T, Dean RM, Shaw BE, et al. Risk of acute myeloid leuke mia and myelodysplastic syndrome after autotransplants for lympho mas and plasma cell myeloma. Leuk Res. 2018;74:130–136.
14. Gabriel M, Shaw BE, Brazauskas R, et al. Risk factors for subsequent central nervous system tumors in pediatric allogeneic hematopoietic cell transplant: a study from the Center for International Blood and Marrow Transplant Research (CIBMTR). Biol Blood Marrow Transplant. 2017;23(8):1320–1326.
15. Shaw BE, Hahn T, Martin PJ, et al. National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Research Methodology and Study Design Working Group Report. Biol Blood Marrow Transplant. 2017;23(1):10–23.
16. Chow EJ, Anderson L, Baker KS, et al. Late Effects Surveillance Recommendations among Survivors of Childhood Hematopoietic Cell Transplantation: A Children’s Oncology Group Report. Biol Blood Marrow Transplant. 2016;22(5):782–795.
17. Gebauer J, Rieken S, Schuster S, et al. Multidisciplinary Late Effects Clinics for Childhood Cancer Survivors in Germany: A Two‐Center Study. Oncol Res Treat. 2018;41(7–8):430–436.
18. Signorelli C, Wakefield CE, McLoone JK, et al. Models of childhood cancer survivorship care in Australia and New Zealand: Strengths and challenges. Asia Pac J Clin Oncol. 2017;13(6):407–415.
19. Signorelli C, Wakefield CE, Fardell JE, et al. The impact of long‐term follow‐up care for childhood cancer survivors: A systematic review. Crit Rev Oncol Hematol. 2017;114:131–138.
20. Nathan PC, Agha M, Pole JD, et al. Predictors of attendance at special ized survivor clinics in a population‐based cohort of adult survivors of childhood cancer. J Cancer Surviv. 2016;10(4):611–618.
21. Groarke JM, Richmond J, Kelly MG, et al. Examining the Impact of a Personalized Self‐Management Lifestyle Program Using Mobile Technology on the Health and Well‐Being of Cancer Survivors: Protocol and Rationale for a Randomized Controlled Trial (The Moving On Study). JMIR Res Protoc. 2019;8(8):e13214.
22. O’Malley DM, Davis SN, Devine KA, et al. Development and usability testing of the e‐EXCELS tool to guide cancer survivorship follow‐up care. Psychooncology. 2019;29(1):123–131.
23. Quintiliani LM, Foster M, Oshry LJ. Preferences of mHealth app fea tures for weight management among breast cancer survivors from underserved populations. Psychooncology. 2019;28(10):2101–2104.
24. Zinter MS, Logan BR, Fretham C, et al. Comprehensive Prognostication in Critically Ill Pediatric Hematopoietic Cell Transplant Patients: Results from Merging the Center for International Blood and Marrow Transplant Research (CIBMTR) and Virtual Pediatric Systems (VPS) Registries. Biol Blood Marrow Transplant. 2020;26(2):333–342.
25. Herr MM, Curtis RE, Tucker MA, et al. Risk factors for the development of cutaneous melanoma after allogeneic hematopoietic cell transplanta tion. J Am Acad Dermatol. 2019;S1090–9622(19):32952–32954.
26. Duncan CN, Brazauskas R, Huang J, et al. Late cardiovascular morbidity and mortality following pediatric allogeneic hematopoietic cell trans plantation. Bone Marrow Transplant. 2018;53(10):1278–1287.
27. Vrooman LM, Millard HR, Brazauskas R, et al. Survival and late effects after allogeneic hematopoietic cell transplantation for hematologic
malignancy at less than three years of age. Biol Blood Marrow Transplant. 2017;23(8):1327–1334.
28. Bhatt NS, Brazauskas R, Tecca HR, et al. Female sex is associated with poor health‐related quality of life in children at 12 months post‐hemat opoietic cell transplantation. J Pediatr Hematol Oncol. 2019;41(3): 233–237.
29. D’Souza A, Millard H, Knight J, et al. Prevalence of self‐reported sleep dysfunction before allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2018;53(8):1079–1082.
30. Norkin M, Shaw BE, Brazauskas R, et al. Characteristics of late fatal infections after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2019;25(2):362–368.
31. Myers RM, Hill BT, Shaw BE, et al. Long‐term outcomes among 2‐year survivors of autologous hematopoietic cell transplantation for Hodgkin and diffuse large b‐cell lymphoma. Cancer. 2018;124(4):816–825.
32. Gratwohl A, Brand R, McGrath E, et al. Use of the quality management system “JACIE” and outcome after hematopoietic stem cell transplanta tion. Haematologica. 2014;99(5):908–915.
33. Schetelig J, Wreede LC, Andersen NS, et al. Center characteristics and procedure‐related factors have an impact on outcomes of allogeneic transplantation for patients with CLL: A retrospective Analysis from the European Society for Blood and Marrow Transplantation (EBMT). Br J Haematol. 2017;178(4):521–533.
34. Locasciulli A, Oneto R, Bacigalupo A, et al. Outcome of patients with acquired aplastic anemia given first line bone marrow transplantation or immunosuppressive treatment in the last decade: a report from the European Group for Blood and Marrow Transplantation (EBMT). Haematologica. 2007;92(1):11–18.
35. Passweg JR, Baldomero H, Chabannon C, et al. The EBMT activity sur vey on hematopoietic‐cell transplantation and cellular therapy 2018: CAR‐T’s come into focus. Bone Marrow Transplant. 2020;55(8): 1604–1613.
36. Snowden JA, Saccardi R, Orchard K, et al. Benchmarking of survival outcomes following haematopoietic stem cell transplantation: a review of existing processes and the introduction of an international system from the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE). Bone Marrow Transplant. 2020;55(4): 681–694.
37. Cesaro S, Pillon M, Sauer M, et al. Long‐term outcome after allogeneic hematopoietic stem cell transplantation for Shwachman‐Diamond syn drome: a retrospective analysis and a review of the literature by the Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation (SAAWP‐EBMT). Bone Marrow Transplant. 2020; doi: 10.1038/s41409‐020‐0863‐z. [Online ahead of print].
38. Giardino S, de Latour RP, Aljurf M, et al. Outcome of patients with Fanconi anemia developing myelodysplasia and acute leukemia who received allogeneic hematopoietic stem cell transplantation: a retro spective analysis on behalf of EBMT group. Am J Hematol. 202095(7):809–816.
39. Penack O, Peczynski C, van der Werf S, et al. Association of serum fer ritin levels before start of conditioning with mortality after alloSCT: A Prospective, Non‐interventional Study of the EBMT Transplant Complications Working Party. Front Immunol. 2020;11:586.
40. Penack O, Marchetti M, Ruutu T, et al. Prophylaxis and management of graft versus host disease after stem‐cell transplantation for haemato logical malignancies: updated consensus recommendations of the
European Society for Blood and Marrow Transplantation. Lancet Haematol. 2020;7(2):e157–e167.
41. Iida M, Kodera Y, Dodds A, et al. Advances in hematopoietic stem cell transplantation in the Asia‐Pacific region: the second report from APBMT 2005‐2015. Bone Marrow Transplant. 2019;54(12):1973–1986.
42. Nations U. World Population Prospects 2019. 2019.
43. Yoshimi A, Suzuki R, Atsuta Y, et al. Hematopoietic SCT activity in Asia: a report from the Asia‐Pacific Blood and Marrow Transplantation Group. Bone Marrow Transplant. 2010;45(12):1682–1691.
44. Ashton LJ, Le Marsney RE, Dodds AJ, et al. A population‐based cohort study of late mortality in adult autologous hematopoietic stem cell transplant recipients in Australia. Biol Blood Marrow Transplant. 2014;20(7):937–945.
45. Atsuta Y, Hirakawa A, Nakasone H, et al. Late mortality and causes of death among long‐term survivors after allogeneic stem cell transplanta tion. Biol Blood Marrow Transplant. 2016;22(9):1702–1709.
46. Atsuta Y, Suzuki R, Yamashita T, et al. Continuing increased risk of oral/ esophageal cancer after allogeneic hematopoietic stem cell transplanta tion in adults in association with chronic graft‐versus‐host disease. Ann Oncol. 2014;25(2):435–441.
47. Gifford G, Sim J, Horne A, Ma D. Health status, late effects and long‐term survivorship of allogeneic bone marrow transplantation: a retro spective study. Intern Med J. 2014;44(2):139–147.
48. Inamoto Y, Matsuda T, Tabuchi K, et al. Outcomes of patients who developed subsequent solid cancer after hematopoietic cell transplanta tion. Blood Adv. 2018;2(15):1901–1913.
49. Kurosawa S, Oshima K, Yamaguchi T, et al. Quality of life after alloge neichematopoietic cell transplantation according to affected organ and severity of chronic graft‐versus‐host disease. Biol Blood Marrow Transplant. 2017;23(10):1749–1758.
50. Kurosawa S, Yamaguchi T, Oshima K, et al. Employment status was highly associated with quality of life after allogeneic hematopoietic cell transplantation, and the association may differ according to patient age and graft‐versus‐host disease status: analysis of a nationwide QOL sur vey. Bone Marrow Transplant. 2019;54(4):611–615.
51. Kurosawa S, Yamaguchi T, Oshima K, et al. Resolved versus active chronic graft‐versus‐host disease: impact on post‐transplantation qual ity of life. Biol Blood Marrow Transplant. 2019;25(9):1851–1858.
52. Nelson AS, Vajdic CM, Ashton LJ, et al. Incident cancers and late mortal ity in Australian children treated by allogeneic stem cell transplantation for non‐malignant diseases. Pediatr Blood Cancer. 2017;64(1):197–202.
53. Vajdic CM, Mayson E, Dodds AJ, et al. Second Cancer Risk and Late Mortality in Adult Australians Receiving Allogeneic Hematopoietic Stem Cell Transplantation: A Population‐Based Cohort Study. Biol Blood Marrow Transplant. 2016;22(5):949–956.
54. Aljurf MD, Zaidi SZ, El Solh H, et al. Special issues related to hemat opoietic SCT in the Eastern Mediterranean region and the first regional activity report. Bone Marrow Transplant. 2009;43(1):1–12.
55. Al‐Hazzouri A, Cao Q, Burns LJ, et al. Similar risks for chronic kidney disease in long‐term survivors of myeloablative and reduced‐intensity allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2008;14(6):658–663.
56. Rasheed W, Ghavamzadeh A, Hamladji R, et al. Hematopoietic stem cell transplantation practice variation among centers in the Eastern Mediterranean Region (EMRO): Eastern Mediterranean Bone Marrow Transplantation (EMBMT) group survey. Hematol Oncol Stem Cell Ther. 2013;6(1):14–19.
Long‐term follow‐up program and transplant clinic setup
5Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, Bern, Switzerland CHAPTER 3 3
André Tichelli1, Bipin N. Savani2, Shahrukh K. Hashmi3, Navneet S. Majhail4, and Alicia Rovó5
1Division of Hematology, University Hospital Basel, Basel, Switzerland
2Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
3Division of Blood and Marrow Transplantation, William J. von Liebig Transplant Center, Mayo Clinic, Rochester, MN, USA
4Blood and Marrow Transplant Program, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA
Introduction
With the increasing number of hematopoietic stem cell transplants (HSCT) performed yearly worldwide, and the improvement of survival, the number of patients surviving ≥2 years after transplantation is continuously increasing. By 2030, the projected number of long‐term survivors after HSCT in the US will increase up to 500,000, and worldwide probably to more than one million [1–3]. However, many of the long‐term recipients who have overcome the acute phase of HSCT and are in remission from their primary disease do not return to prediagnosis status [4]; about two‐thirds of them will experience at least one late effect that is a direct or indirect consequence of the cancer treatment or the transplant procedure [5]. Therefore, transplant survivors will have different healthcare needs. Late effects may impact multiple domains of health, quality of life (QoL), and social reintegration. During the early post‐HSCT period, acute medical problems such as infection, acute GVHD, toxicity or endothelial damage syndromes are the most frequent, often life‐threatening concerns, and are the center of attention. With longer follow‐up, the management of survivors increasingly focuses on detection, prevention, and treatment of late complications, improvement of QoL and social reintegration. Patients, having survived the acute phase of HSCT, may develop a series of later complications, some of them presenting in a slow and silent, but no less harmful way. The transition from the early outpatient phase to long‐term healthcare is critical. Survivors are at risk being lost in transition, either because they feel cured of the disease, or have been insufficiently informed about the long‐term consequences of HSCT, or because of psychological, social, financial or geographical issues [6].
Today, internationally approved guidelines on screening, prevention, and management of late effects after HSCT are available [7]. More
recently, the National Institutes of Health BMT Late Effects Initiative has recognized the value of lifelong follow‐up of HSCT‐survivors [8]. There is, however, less clarity on how to implement these recommendations and the roles among the involved healthcare providers in long‐term management. The relevant components allowing implementing recommendations of the long‐term health care after HSCT are a robust long‐term follow‐up (LTFU) program, appropriate infrastructures and facilities, specialized human resources covering all aspects of the long‐term care, and administrative and technical support. Additionally, a successful LTFU program needs the active involvement of the long‐term survivor and their primary care physician, as well as the support of the national authorities, to ensure the establishment of a dedicated LTFU clinic and complete insurance coverage.
Post‐HSCT long‐term follow‐up programs emerged with some delay, compared to cancer survivorship care. A good example is, for instance, survivorship programs for Hodgkin lymphoma, which were established about 20 years before HSCT programs. The HSCT‐survivorship programs have adopted much from the experience of cancer survivorship programs. However, HSCT has its long‐term particularities due to the type and intensity of the conditioning regimen, and in the allogeneic setting, the prolonged immune incompetence, and the complications due to graft‐versus‐host disease (GVHD) and its treatment. Survivorship programs and LTFU clinics will, therefore, share many characteristics with cancer survivorship programs, but also present some features of their own. Setting up an LTFU clinic is a challenging but rewarding experience. When starting a transplantation program, the HSCT team is initially confronted with immediate survival and disease control. The major focus is placed on patient and donor selection, the choice of stem‐cell source and problems related to acute toxicity, relapse, GVHD, and infectious complications. With advancing time, the
number of long‐term survivors in the HSCT center is increasing. The needs and expectations of long‐term survivors shift to further concerns. They require less acute medical interventions and immediate care but have increasing expectations of good physical and mental health, of recovery of QoL and social reintegration. In the long‐term, the focus lies on careful screening, prevention, and early treatment of possible late effects that interfere with health conditions. The setup of an LTFU clinic is part of the LTFU program chosen by the transplant center. There are different models of long‐term transplantation clinics, all of them with their advantages and their drawbacks. However, to provide optimal LTFU care to the long‐term survivors, they must all fulfill some minimal characteristics. A common outpatient HSCT clinic, where acute care and long‐term follow‐up are mixed, allows continuity in the care but faces the risk that the particular needs of long‐term survivors are left behind the daily care of the new post‐transplant patients.
In this chapter, the setup of a long‐term transplant clinic and the essential functions and components of an LTFU care program will be outlined. Different models of survivorship programs and LTFU clinics will be considered, and barriers, as well as the minimal requirements, discussed. There are many similarities between LTFU of cancer and of HSCT recipients. Therefore, in this chapter, studies of cancer survivorship are included; similarities and differences between both are discussed.
Concept of long‐term survivorship
The concept of survivorship in cancer patients was created by the National Coalition for Cancer Survivorship (NCCS) in 1986 [9]. According to the Institute of Medicine, cancer survivorship is the phase of care that follows primary treatment. However, this definition allows a wide range of interpretations, depending on the time of diagnosis, the completion of treatment, and the time interval between the diagnosis and the end of treatment of cancer. The Institute of Medicine and leaders in cancer survivorship have recommended cancer centers to examine and evaluate the setup of services for survivors. In a first step, general recommendations and the development of guidelines have been assessed for pediatric and young adult cancer survivors [10,11]. The Institute of Medicine provided a template for the four essential elements of survivorship care: prevention and detection of late effects, surveillance, interventions to manage side effects, and coordination of care and information [12]. Meanwhile, awareness for needs of HSCT survivorship care has risen, and was addressed in a workshop from the National Academies of Science, Engineering, and Medicine. The participants of the Workshop suggested to include issues on education and training, employment and work‐related concerns, financial toxicity and insurance concerns, as well as research needs [13].
Late effects after HSCT
Late mortality is increased in long‐term survivors of allogeneic HSCT when compared with an age‐ and gender‐matched general population. More than 25 years after transplantation there is still a
two‐fold excess in death rate [14]. Life expectancy among 5‐year survivors after HCT is reduced by approximately 30% compared to the general population, regardless of current age or time from transplantation [15]. A variety of pre‐ and posttransplant factors can contribute to the risk of late complications. They include patient‐related factors (e.g. age, gender), lifestyle factors (smoking, physical inactivity, unhealthy diet), pretransplant co‐morbidity (particularly in elderly patients), chemotherapy and radiotherapy applied before transplantation or as conditioning regimen, and posttransplant complications (GVHD and its treatment) [16]. Some of the late complications, such as secondary malignancies and vascular complications are expected very late after HSCT. Even three decades after allogeneic HSCT, the cumulative incidence for secondary solid tumors or vascular complications continues to increase, with no indication of a plateau developing [17,18]. Other late effects appear early after HSCT but have relevant consequences on the long‐term health condition and quality of life. A typical example is bronchiolitis obliterans syndrome often occurring within the first year after allogeneic HSCT, with respiratory consequences in the long‐term. Infertility is also an early consequence of pretransplant treatment and the conditioning regimen used for HSCT. However, this complication worries survivors many years after HSCT, frequently at a time when they have overcome acute toxicity and the phase of early complications. These data demonstrate that individuals undergoing HSCT, even when cured of their primary disease, will mandatorily need a lifelong commitment for posttransplant survivorship care.
Timing and transition to long‐term survivorship care
When does survivorship care start? Most studies on late effects after HSCT include recipients surviving two years or longer after transplantation when they are in remission of their primary disease. However, in daily routine, the precise timing of long‐term survivorship care is not stringent. In cancer patients, it is usually defined by the time the primary treatment ends. In many HSCT centers, the posttransplant survivorship begins when the patient no longer needs regular posttransplant care. At that time, annual survivorship visits are considered as a standard for long‐term follow‐up. With growing numbers of long‐term survivors after HSCT, many centers refer their patients back to the primary care provider or to the referring hemato‐oncology center. However, some long‐term follow‐up may need to be conducted by the transplant center or a specialized LTFU clinic, especially if patients present transplant‐related complications such as chronic GVHD (cGVHD) [16]. The transition to long‐term follow‐up care from the HSCT team to another set of providers, ensuring optimal care of long‐term survivors is a vulnerable period. This transition may result in fragmentation of care and poor communication between the different care providers and for some groups of patients represent a risk being lost in transition. Continuity of care implicates an adapted model of LTFU clinic, but also optimal coordination between the LTHU clinic, the primary care provider and the long‐term survivor, with a clear definition of
the responsibilities of each part. An HSCT long‐term survivorship care lasts until the recurrence of the primary disease, development of a subsequent cancer, or death of the patient. In the case of relapse or secondary cancer, survivors become cancer patients again, reentering possibly in the acute phase of cancer treatment [12]. Some of the controversial issues of a survivorship program concern the type and frequency of optimal follow‐up care, the increased expenses caused, as well as the extra time and the physical space needed to run such a program. In many countries, insurances that cover expenses of the HSCT, will not cover the costs of the follow‐up care.
The transition from pediatric to adult long‐term care
Survivors of childhood cancer have a high rate of illness due to the occurrence of chronic health conditions [19]. Despite long‐term late effects and care impact on all age groups, there is a paucity of data on the transition to adult healthcare from young adults transplanted during childhood. There are some specific issues for this subpopulation [20]. Several modes of cancer survivor care are applied, mainly depending on the size of the pediatric HSCT center and the center’s preferences: HSCT center‐based model (I) without a referral, where adult survivors are kept indefinitely at the treating institution; community referral model (II), where survivors are transitioned at adulthood to their primary care professionals; hybrid model (III), where the survivors are transitioned to community healthcare providers who collaborate closely with the treating institution for all questions concerning long‐term survivorship; adult HSCT LTFU model (IV), where the survivors are transitioned definitively to an LTFU‐clinic or HSCT center [21]. Independent of the selected model, there is the need to identify healthcare professionals with experience in childhood and adult HSCT, expertise in long‐term follow‐up and able to coordinate healthcare transition and future planning. During the childhood of the young cancer patient, the parents or other adult family members took the responsibility and the decisions for the child’s healthcare. In the preparation for the transition phase, the young adult survivor has to be motivated to become responsible for his survivorship care. Furthermore, it must be ensured that the healthcare insurance will continue to cover for all HSCT‐related complication through the adulthood [21,22].
Barriers to successful healthcare transition included the survivor’s psychological condition and knowledge about their primary disease, the attitude of pediatric and adult health‐providers, and the health system itself. Unlike their adult counterparts, childhood HSCT survivors have often limited access to information on the diagnosis and treatment of their malignancy, as well as on adverse effects that can occur later in life. They may have been too young to understand and their parents may have decided to shield them from details of their disease. In a cross‐sectional survey on 635 consecutive adult survivors of childhood cancer, 72% accurately reported their diagnosis with precision. Most of the participants correctly reported their treatment history for chemotherapy and
radiation therapy. However, knowledge deficits existed about basic facts of their medical history, such as the use and dose of anthracycline and site of radiation [23].
Despite a significant risk of late effects after cancer treatment, adult survivors of childhood cancer often do not receive regular medical care focused on their long‐term risk. Only 17.8% of a large cohort of 8522 long‐term survivors reported a specific medical follow‐up visit within the previous two years. Medical care was not a barrier for most since nearly 90% of the survivors had at least one medical visit during this period. Rather, the care that they received did not focus on their specific long‐term risk and strategies to ameliorate them [24]. These results correspond to another large cohort from the Childhood Cancer Survivor Study: most of the survivors reported some contact with a medical system. The likelihood of a medical visit decreased as survivors aged and the interval from diagnosis increased. Less than 20% of survivors were seen in a cancer center, and risk‐based healthcare of adult survivors of childhood cancer was very uncommon [25]. Very limited resources have been developed to help the care team to manage successfully the transition.
The transition from childhood HSCT to adult long‐term survivorship care is a long and difficult process. There is not one single way to proceed; however, an important step is to provide complete data on disease, treatment, and complications that occurred during the period before the transition, and to elaborate a personalized risk‐based follow‐up program. The transition to adult care has to be planned and started enough time before the patient is transferred. During this transition phase, certain health professionals, such as social workers, psychologists, physical therapists, and nurses, could maintain the continuity of the care [26]. A recent publication, based on real cases, provides a guide for the transition to adult long‐term follow‐up care teams to manage late effects and cGVHD in young adult survivors of childhood HSCT [22].
Long‐term follow‐up program
A long‐term follow‐up survivorship program is intended to provide specialized care to HSCT survivors who are in remission after having completed their treatment, usually for at least 1 or 2 years or longer. Such a program aims to prevent and to detect late complications after HSCT that will interfere later with physical and mental health, QoL and social reintegration. The introduction of risk‐adapted screening procedures allows early detection and promotes healthy behaviors. Special attention has to be brought to QoL, including physical and psychological functioning, sexuality, and fertility issues of long‐term survivors. The long‐term follow‐up program has also to be concerned about the collateral damage caused by the HSCT, such as financial embarrassments, limitations in insurance coverage, and obstacles encountered to reintegrate into society (employment and school) [27]. An LTFU program consists of guidelines for screening and management of late effects and long‐term issues (I), an LTFU clinic with appropriate rooms, dedicated personal and necessary infrastructure (II), and a structured follow‐up visit of the long‐term survivors with defined repartition of the roles involved in the LTFU care (III).
A study, including eight centers from the LIVESTRONG Survivorship Center of Excellence Network, evaluated survivorship models and aimed to identify barriers and facilitators influencing survivorship care [28]. According to this study, the most important prerequisite for the development and the support of a survivorship care program included an organization and leadership commitment as well as the existence of a well‐trained staff dedicated to survivorship. To succeed, the survivorship care model not only has to be supported from the top‐down but also from bottom‐up by the long‐term follow‐up team. Lack of dedicated workspace and personnel resources was often mentioned as the major barrier for a survivorship care center. The lack of financial support for salaries and research, as well as reimbursement for clinical services, remained a key issue for the centers. Finally, an appropriate clinical information system was, in most centers, either not existing or not adapted for the long‐term follow‐up care of cancer patients.
Education of survivors, the healthcare providers, and the LTFU team plays a central role in the setup of a LEFU program [29]. Educating healthcare professionals on long‐term follow‐up may produce institutional changes and improve survivorship care and communication between the healthcare providers involved. Within a National Cancer Institute funded educational program, 204 multidisciplinary teams from the US participated in four annual courses on education for quality of survivorship cancer care. The course participants included administrators, social workers, nurse practitioners, physicians, and others and were followed up at 6, 12, and 18 months after the course for goal achievement and institutional evaluations. The institutional assessments increased significantly from baseline to 18 months. Psychological and emotional standards, which were deficient for most cancer survivors, improved over time. Also, the communication domain improved significantly [30].
The Children’s Oncology Group described survivorship services and, based on their findings, discussed the models of care that are in use for childhood cancer survivors and adult survivors of childhood cancer. Of the 220 institutions, 175 completed an Internet‐based survey [21]. According to this survey, late effects services were available in 87% of the responding centers and 59% of these institutions provided a specialized care program for their pediatric population. This represented an increase compared to a survey done about 10 years previously. The main barriers in caring for pediatric cancer survivors were the lack of time to devote to the program (29% of responses), not enough funding to support the program (20%), deficits in knowledge about cancer survivorship (17%), lack of healthcare insurance or insurance limitations (12.7%), lack of survivor desire to be followed by the late effects team (7%), and no perceived need to support a late effects program (6.7%).
Long‐term follow‐up Clinic
A variety of models of LTFU clinic have been proposed for long‐term cancer care. The models can either be defined geographically or according to the provider of survivorship care [31]. A follow‐up
program can be built upon a cancer center‐based model, a community‐based model, or a combination of both models [32]. Each of these models has its advantages and disadvantages, in respect of continuity of care, education, resources and cost‐effectiveness, convenience for the survivor and their family members, opportunities for research on long‐term survivorship and late effects, and risk of loss to follow‐up an HSCT survivor. A combination of a specialized LTFU clinic and community model, where the role of each part has been predefined, appears to appealing. An emerging concept in combining community and cancer center follow‐up is to involve a virtual or Web‐based follow‐up program, which could be designed to bridge the two models of follow‐up [10].
There is a limited number of publications on LEFU clinic setup and long‐term follow‐up program for the transplant setting [16]. A lot of information used for cancer survivorship applies to transplant survivorship care. There are, however, some basic differences that affect the setup of an LTFU transplant clinic and the posttransplant survivorship care program. The follow‐up of cancer survivors is mainly concentrated on the cancer specificity and the treatment applied. In contrast, posttransplant long‐term follow‐up focuses on late effects due to the conditioning toxicity, the delayed immune reconstitution, and the consequences of chronic GVHD and its prolonged immunosuppressive treatment. The Children’s Oncology Group Late Effects Committee provided a comprehensive Long‐Term Follow‐Up Resource Guide describing the entire process required to establish the infrastructure for a long‐term follow‐up clinic [33]. This resource guide is based on the expertise of individuals who have successfully established such centers at their institution. This guide addresses all issues needed to set up a long‐term transplant clinic: various models of long‐term follow‐up care; transition issues; challenges and barriers; survivorship program development; multidisciplinary team composition; recommendations for the annual follow‐up visit; billing and financial issues; integration of survivorship research.
Japan recently evaluated the present status and needs of LTFU clinics for HSCT survivors [34]. A nationwide questionnaire survey showed that 62% of 188 participating centers had an established LTFU clinic. The most frequent reason no operating an LTFU clinic was lack of human resources, especially nurses. About half of the centers recommended that survivorship care at the LTFU clinic should go beyond 5‐years post‐HSCT. Still, a relevant number of HSCT centers did not yet set a LTFU clinic. However, when compared to a survey performed in 2008, there was a significant increase in the nationwide rate of establishing the LTFU clinic, from 7% in 2008, up to 69% in 2019.
There is no one best model of LTFU clinic for all transplant centers and, for a given center, the model may change over time. The development of a definitive model can be the result of different attempts until the optimal structure has been obtained. Considerations for the choice of a model include factors such as available resources in personnel and workspace. Other factors that play an important role are the commitment of the head of the transplant center and the team to support a late effects program, the size and type of transplant center (allogeneic, autologous), the geographic area covered by the transplant center, the level of education of the primary care providers in
Model Advantages
Integrated Care Model:
Outpatients long‐term follow‐up clinic is integrated into the outpatient clinic of the transplant center
Specialized long‐term follow‐up clinic integrated within the transplant center
Community‐based care:
The primary care provider or the hematologist‐oncologist is responsible for the long‐term follow‐up
Shared Care Model:
Combined approach between transplant center and community‐based care
Comfortable for patients and family because of the continuity of the care
Continuity of care ensured
Knowledge in transplant related problems and particularly in chronic GVHD
Network with other specialties usually available (dermatologist, gynecologist, endocrinologist, ophthalmologist etc.)
Providers with expertise in long‐term care
Risk‐based screening and follow‐up care
Emphasis on improving knowledge on long‐term survivorship after HSCT
Health education of the survivors and caregivers
Opportunity to train healthcare professionals
Structured research of late effects
Most advantages of the independent specialized long‐term follow‐up clinic, without loss of continuity
Convenience for the survivor and caregivers
Promotes independence and reintegration into primary care
May improve adherence to treatment and healthy life style recommendations from the LTFU‐clinic
Combined advantages of specialized care and community‐based care
Higher cost‐effectiveness
Effective implementation of the recommendations from the LTFU clinic
May improve adherence to treatment and healthy life style recommendations from the LTFU‐clinic
survivorship after HSCT, and the national system of insurance covering long‐term follow‐up care. Independent of the chosen model, all HSCT survivors should maintain life‐long regular contact with the care provider who knows the potential long‐term survivorship and the causal relationship between transplantation and late effects. Some models of long‐term follow‐up clinics are shown in Table 3.1, and Table 3.2 shows the significant aspects that need to be considered when setting up a long‐term transplant clinic.
The essential responsibilities of a LTFU clinic are to assess the health condition, screen for and prevent late effects, detect and treat as early as possible the late complications after HSCT, estimate the quality of life, and counsel the long‐term survivors after HSCT. Figure 3.1 presents the most relevant tasks of a LTFU clinic. Ideally, the posttransplant long‐term clinic not only assures medical and psychological care, but also considers financial aspects, insurance issues, and re‐adaption back into the social life, and approaches problems related to school and employment. The follow‐up clinic
Risks
Main attention brought to the acute medical problems of the post‐transplant care
Focus set on illness and not wellness
Potential lack of interest, knowledge and skills in late effects and long‐term healthcare
Research in late effects and long‐term survivorship becomes of second rank
Requires multiples resources of personnel and work space
Requires time
In the case of an independent center, loss of expertise of the transplant center
Continuity of care can get lost if the transition is not well done
Requires multiples resources of personnel and work space
Limited provider knowledge and training regarding late effects
Lack of time to devote to special physical and psychological needs of long‐term survivors
Lack of sub‐specialist resources with survivorship expertise
Difficult to coordinate research
Difficult to update survivors regarding new information as it becomes available
Difficult to update survivorship database
Risk of insufficient predefined role of each part
Risk of poor communication between each part
needs space and personnel resources to meet the requirements of survivorship care. It is also a time‐consuming issue. The minimum time required for initial and annual survivorship visits has been estimated to be approximately 120 min and 90 min, respectively [21]. The amount of time includes preparation, scheduling tests, clinical face‐to‐face time, gathering, interpreting and compiling results, post‐clinical conferencing and communication of the results.
Long‐term transplant team and the annual LTFU visit
A well‐functioning follow‐up program requires a multidisciplinary approach. The composition of the long‐term transplant team is crucial (Figure 3.2). There is usually a core team, including physicians and nurses specialized in HSCT, GVHD, and long‐term
Table 3.1 Different models of long‐term transplant clinics
Table 3.2 Significant aspects to consider when building up a long‐term follow‐up transplant clinic
1. Commitment of the head of the HSCT center to have a long‐term follow‐up clinic
a. Convince the core team of physicians and nurses that this needs to be done
b. Define the resources required to start the program
2. Decision on the type of model to be chosen
• This model can change with time for a given center
• Define what will be the consequences on the transplant center
3. Define the team of the long‐term clinic
• The core team composition
• The multidisciplinary network with the most important specialists involved in the long‐term follow‐up
4. Define the space needed for the long‐term follow‐up clinic
• Room for administrative work (preparation of the follow‐up visit)
• Room for blood sample taking
• Rooms for clinic visit and counseling
• Room to isolate patients with communicable infectious diseases
5. Define the follow‐up program for the survivor
• Define the process of a follow‐up visit (preparation; visit; post‐visit follow‐up)
• Determining program parameters
• Organize post‐visit follow‐up (tracking results; interpretation of the findings)
• Organize the documentation of the follow‐up care
• Define how to assure all long‐term follow‐up and to deal with lost to follow‐up
6. Define transition of survivors
• From regular posttransplant care to long‐term survivorship care
• From pediatric to adult care
• From long‐term follow‐up clinic to primary health‐care providers
7. Define reimbursement and financial issue
8. Define education and research issues on the long term
• Continuous education of the core team
• Education of the primary care providers and hemato‐oncologists
• Links with patients/family organizations
• Research on long‐term survivorship
• Assessment of relapse
• Management of chronic GVHD
• Long-term consequences of chronic GVHD
• Consequences of prolonged immunosuppression
• Immune reconstitution and late infectious complications Chronic GVHD
Prevention
• Prevention of cardiovascular complications
• Prevention of loss of bone density
• Oral health practices to prevent dental disease
• Physical rehabilitation to prevent progressive contractures
• Prevention of skin cancers
• Recommended screening for all patients (hypertension, diabetes, depression, colorectal cancer etc.
• Additional risk adapted screening for late effects
• Quality of life evaluation Screening
Coordination of long-term survivorship
• Communication management among patients, transplant clinic, general healthcare providers
• Organization of the follow-up visits
• Treatment summary of the survivor
• Treatment plan of the survivor
Counceling
• Self controls
• Healthy lifestyle behavior
– Regular physical activity
– Smoking and drug cessation
– Sun protection
– Healthy diet
– Sexuality
– Fertility preservation methods
– Insurance coverage, problems with employment or school, financial difficulties
• Early treatment of late effects
• Treatment of cardiovascular risk factors
• Physical therapy
• Psychological intervention Intervention
• Define research research focus on late effects
• Regular education of the follow-up team
• Education of the primary health care providers Research and education
Figure 3.1 Components of different long‐term follow‐up survivorship care.
