Palliative Care in Hematologic Malignancies and Serious Blood Disorders: A Clinical Guide 3031380576, 9783031380570

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Christina K. Ullrich Eric J. Roeland Editors

Palliative Care in Hematologic Malignancies and Serious Blood Disorders A Clinical Guide

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Palliative Care in Hematologic Malignancies and Serious Blood Disorders

Christina K. Ullrich  •  Eric J. Roeland Editors

Palliative Care in Hematologic Malignancies and Serious Blood Disorders A Clinical Guide

Editors Christina K. Ullrich Harvard Medical School Boston, MA, USA

Eric J. Roeland Oregon Health and Science University Portland, OR, USA

ISBN 978-3-031-38057-0    ISBN 978-3-031-38058-7 (eBook) https://doi.org/10.1007/978-3-031-38058-7 © Springer Nature Switzerland AG 2023 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Paper in this product is recyclable.

Preface

We are honored to share our colleagues’ cumulative work and collective wisdom in caring for patients with hematologic malignancies, including pediatric and adult clinicians. This textbook encapsulates years of relentless effort and dedication to improving the care of patients with hematologic malignancies and their caregivers. Moreover, it demonstrates how clinicians can effectively collaborate to share their expertise to optimize our care for patients with complex medical illness. We are proud of our colleagues who agreed to contribute to this work and demonstrated the fortitude to complete it during COVID. Emerging evidence—in conjunction with clinical experience—demonstrates that palliative care improves the well-being of seriously ill patients throughout their illness course. Through an interdisciplinary and holistic approach, palliative care improves patients’ and their caregivers’ physical, psychological, and spiritual distress. Moreover, palliative care promotes care aligned with patients’ values and preferences by facilitating effective and compassionate communication and supporting the delineation of treatment goals and informed decision-making. Regardless of prognosis or treatment, such outcomes are relevant throughout the illness trajectory. Individuals with hematologic malignancies and other serious blood disorders often undergo intensive therapies to find a cure. Others may experience years of chronic and debilitating illness. Both populations often face high uncertainty about the future, intense symptom burden, and impaired function and quality of life. Holistic care of individuals with hematologic malignancies and serious hematologic disorders is challenged by high prognostic uncertainty, wideranging ramifications of serious illness, and, at times, a focus on cure and disease-directed care. For example, stem cell and chimeric antigen receptor T cell (CAR-T) therapies now offer the possibility of a cure, even for individuals with advanced blood cancers. In addition, patients with nonmalignant blood disorders experience unmet palliative needs, such as uncontrolled pain among those with sickle cell disease and joint deformity among patients with hemophilia. Once thought to be the antithesis of hematologic/oncologic care, a palliative care approach, in fact, complements disease-directed therapies by attending to the multidimensional needs of patients and caregivers. While evidence and recognition of the benefit of palliative care in this population are mounting, important clinical and research questions surrounding palliative care integration have emerged. Moreover, there are few resources, and no textbooks, dedicated to the specific needs of individuals with blood cancers and other serious hematologic disorders, highlighting their palliative care needs and best clinical approaches. Likewise, interest in this topic among hematologists is greatly increasing, as evidenced by formal educational symposia at the annual meeting of the American Society of Hematology in 2013 and again in 2015. This textbook provides a comprehensive yet concise coverage of (1) the unique needs of patients with malignant and nonmalignant blood disorders and outlines specific strategies to optimize hematologist/hematologist-oncologist and palliative care collaboration; (2) issues salient to the provision of palliative care (e.g., communication, decision-making, advance care planning, symptom management, and ethics); (3) special populations (e.g., pediatrics, adolescents and young adults, geriatrics, and caregivers); and (4) issues on the care of patients with blood disorders at the end of life (e.g., care of the imminently dying patient). In keeping with v

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Preface

the interdisciplinary nature of palliative care, contributing authors for each chapter represent a range of disciplines, including medicine, nursing, psychology, social work, chaplaincy, pharmacy, and physical and occupational therapists, among others. We have designed this textbook to serve as a resource for several groups of clinicians. We envision it serving as a reference for hematology-oncology clinicians and trainees seeking to deepen their palliative care knowledge and skills while improving their understanding of the unique needs of patients with blood disorders. This text will also support and guide palliative care clinicians and trainees as they care for this population and their particular needs. Because palliative care is inherently interdisciplinary, covering an array of medical, nursing, and psychosocial topics, clinicians who will utilize this book extend beyond physicians and include advanced practice providers, nurses, social workers, psychologists, chaplains, and allied health professionals caring for this population. Boston, MA, USA Portland, OR, USA 

Christiana K. Ullrich Eric J. Roeland

Contents

1 Introduction�����������������������������������������������������������������������������������������������������������������   1 Christina K. Ullrich and Eric J. Roeland Part I Hematologic Malignancies and Serious Blood Disorders 2 Hematologic Malignancies�����������������������������������������������������������������������������������������   5 Daniel R. Richardson and Carolyn Mulroney 3 Hematopoietic Cell Transplantation�������������������������������������������������������������������������  23 Effie Wang Petersdorf 4 Serious  Blood Disorders: A Focus on Sickle Cell Disease and Hemophilia�����������  37 Sharl S. Azar and Srila Gopal 5 Cellular  Therapies: A Description of the Types of Existing Cellular Therapies and Associated Toxicities �������������������������������������������������������������������������  55 Gopi S. Mohan, Daniel J. Kats, Samantha D. Martin, and Pietro Miozzo Part II Palliative Care 6 Palliative  Care Approach for Patients with Hematologic Malignancies and Other Serious Blood Disorders��������������������������������������������������������������������������  71 Li Mo and David Hui 7 Hematology/Oncology  and Palliative Care Collaboration �������������������������������������  83 Courtney W. Johnson, Deborah A. Lafond, Steven J. Hardy, Elizabeth Hardesty, and Shana S. Jacobs 8 Hematologic  Malignancy and Palliative Care Integration in the Outpatient Setting���������������������������������������������������������������������������������������������������������������������������  93 Heather A. Carlson and Angela Sousa Part III The Intersection of Palliative Care and Hematologic Malignancies and Serious Blood Disorders: Key Issues 9 Communication Throughout the Illness Trajectory ����������������������������������������������� 105 Marc-Antoine Marquis, Monia Marzouki, and Lysanne Daoust 10 Decision-Making  Involvement Throughout the Illness Trajectory������������������������� 115 Maura A. Miglioretti, Emily M. Fredericks, and Melissa K. Cousino 11 Advance  Care Planning in Hematologic Malignancies and Other Serious Blood Disorders����������������������������������������������������������������������������������������������������������� 125 Vinay Rao and Dana Guyer 12 Measuring Quality of Life and Health-­Related Quality of Life����������������������������� 139 vii

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Susan Parsons, Nadine Linendoll, and Courtney Schroeder 13 Pain  Syndromes of Hematologic Malignancies ������������������������������������������������������� 153 Judith A. Paice and Jonathan Moreira 14 Symptoms  in Advanced Hematologic Malignancies and Other Serious Hematologic Conditions��������������������������������������������������������������������������������������������� 169 Mellar Davis, Carlos Fernandez, Nicki Vithalani, Lauren Elizabeth Nicholls, and Glen Digwood 15 Rehabilitation Medicine��������������������������������������������������������������������������������������������� 197 Jack B. Fu, George J. Francis, Shinichiro Morishita, and Julie K. Silver 16 Psychosocial  Considerations and Assessment of Patients with Hematological Malignancies and Serious Blood Disorders ����������������������������������� 205 Kristin Drouin, Nicholas Purol, Sarah J. Tarquini, Darcy E. Burgers, and Kristen Uhl 17 Multicultural  and Spiritual Considerations������������������������������������������������������������� 219 Allison Kestenbaum, Portia Howard, and Yuko Abbott 18 Ethical  Considerations in Palliative Care����������������������������������������������������������������� 229 Jonathan M. Marron and Melissa K. Uveges 19 Advancing  the Field through Research��������������������������������������������������������������������� 243 Oreofe O. Odejide Part IV The Intersection of Palliative Care and Hematologic Malignancies and Serious Blood Disorders: Special Populations 20 Palliative  Care for Special Populations: Pediatrics������������������������������������������������� 255 Danielle Faye Jonas, Angela Steineck, Joshua A. Johnson, Mallory Fossa, Julienne Brackett, Erica Carmen Kaye, and Deena R. Levine 21 Palliative  Care for Adolescents and Young Adults (AYAs) ������������������������������������� 273 Natalie Jewitt and Alisha Kassam 22 Caregivers  of Patients with Hematologic Malignancies ����������������������������������������� 285 Tara A. Albrecht, Shelby Langer, Marcia A. Winter, J. Nicholas Dionne-Odom, and Laura S. Porter Part V The Intersection of Palliative Care and Hematologic Malignancies and Serious Blood Disorders: Caring for Patients at End of Life 23 End-of-Life Considerations��������������������������������������������������������������������������������������� 301 Robert Macauley, Jessica Bordley, Lindsay Wooster-Halberg, and Paul Galchutt 24 Care  of the Imminently Dying Patient with a Hematologic Malignancy or Serious Blood Disorder ����������������������������������������������������������������������������������������� 315 Kevin Madden and Eduardo Bruera 25 Bereavement  in Hematologic Malignancies and Serious Blood Disorders ����������� 327 Sue E. Morris, Holly E. Barron, Kathleen A. Lee, Jennifer M. Snaman, and Sarah J. Tarquini Index������������������������������������������������������������������������������������������������������������������������������������� 345

Contributors

Yuko Abbott, DSW, LCSW, OSW-C  Moores Cancer Center Radiation Oncology, UC San Diego Health, La Jolla, CA, USA Tara  A.  Albrecht, PhD, ACNP-BC, ACHPN, RN School of Nursing, Duke University, Durham, NC, USA Sharl S. Azar, MD  Department of Medicine, Division of Hematology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA Holly  E.  Barron, MSW, LICSW Division of Social Work, Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, Boston, MA, USA Jessica Bordley, MD Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA Julienne  Brackett, MD, MS  Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine, Texas Children’s Cancer Center, Houston, TX, USA Eduardo  Bruera, MD Department of Palliative, Rehabilitation and Integrative Medicine, University of Texas, MD Anderson Cancer Center, Houston, TX, USA Darcy  E.  Burgers, PhD Division of Pediatric Psychosocial Oncology, Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, Boston, MA, USA Heather A. Carlson, MSN, ANP-BC, ACHPN  Department of Palliative Care, Massachusetts General Hospital, Boston, MA, USA Melissa  K.  Cousino, PhD Department of Pediatrics, C.S.  Mott Children’s Hospital, Ann Arbor, MI, USA Carlos  Fernandez  Cuartas, MD Department of Palliative Medicine, Geisinger Medical Center, Danville, PA, USA Lysanne  Daoust, MSN Department of Pediatric Palliative Care, Sainte-Justine Hospital, Montreal, QC, Canada Mellar  Davis, MD, FCCP, FAAHPM Department of Palliative Care, Geisinger Medical Center, Danville, PA, USA Glen  Digwood, DO, FACP Department of Palliative Medicine, Geisinger Community Medical Center, Scranton, PA, USA J. Nicholas Dionne-Odom, PhD, RN, ACHPN  School of Nursing, University of Alabama at Birmingham, Birmingham, AL, USA Kristin  Drouin, MSW, LICSW, APHSW-C The Wendt Center for Loss and Healing, Washington, DC, USA Mallory Fossa, MSN  Department of Pain and Palliative Medicine, Connecticut Children’s, Hartford, CT, USA ix

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George  J.  Francis, MD, FRCPC, CSCN (EMG)  Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Emily  M.  Fredericks, PhD Department of Pediatrics, C.S.  Mott Children’s Hospital, University of Michigan Medical School, Ann Arbor, MI, USA Jack B. Fu, MD  Department of Palliative, Rehabilitation and Integrative Medicine, University of Texas, MD Anderson Cancer Center, Houston, TX, USA Paul Galchutt, MPH, MDiv, BCC  University of Minnesota Medical Center, Minneapolis, MN, USA Srila Gopal, MBBS  Department of Medicine, Division of Hematology/Oncology, University of California San Diego, La Jolla, CA, USA Dana Guyer, MD  Division of Palliative Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USA Elizabeth Hardesty, MSW  Department of Oncology, Children’s National Medical Center, Washington, DC, USA Steven  J.  Hardy, PhD  Divisions of Hematology and Oncology, Department of Psychiatry and Behavioral Sciences, Children’s National Hospital, George Washington University School of Medicine and Health Sciences, Washington, DC, USA Portia Howard, MDIV  Volunteer and Spiritual Care Services, University of California, San Diego Health, San Diego, CA, USA David  Hui, MD Department of Palliative Care, Rehabilitation and Integrative Medicine, University of Texas, MD Anderson Cancer Center, Houston, TX, USA Shana S. Jacobs, MD  Department of Oncology, Children’s National Hospital, Washington, DC, USA Natalie Jewitt, MD  Paediatric Advanced Care Team (PACT), Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada Courtney W. Johnson, MD, MS  Department of Hospitalist Medicine, Children’s National Health System, Washington, DC, USA Joshua A. Johnson, M. Div.  Department of Spiritual Care, Carondelet St. Joseph’s Hospital, Tucson, AZ, USA Danielle Faye Jonas, MSW  Silver School of Social Work, New York University, New York, NY, USA Alisha  Kassam, MD, MPH Department of Pediatric Oncology and Palliative Medicine, Southlake Regional Health Centre, Newmarket, ON, Canada Daniel J. Kats, MD  Department of Pediatrics, Massachusetts General Hospital, Boston, MA, USA Erica  Carmen  Kaye, MD, MPH Hospice and Palliative Medicine Fellowship Program, Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA Allison  Kestenbaum, MA, MPA, BCC, ACPE Spiritual Care Services/Howell Palliative Care, UC San Diego Health, La Jolla, CA, USA Deborah A. Lafond, DNP  PANDA Education Consultants, PLLC, Lakeland, FL, USA Shelby Langer, PhD  Edson College of Nursing and Health Innovation, Phoenix, AZ, USA

Contributors

Contributors

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Kathleen A. Lee, MD  Section of Palliative Care, Division of General Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA Deena R. Levine, MD, FAAHPM  Department of Oncology, Division of Quality of Life and Palliative Care, St. Jude Children’s Research Hospital, Memphis, TN, USA Nadine  Linendoll, PhD, MDiv, GNP Division of Hematology/Oncology, Department of Medicine, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA Robert  Macauley, MD  Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA Kevin  Madden, MD Department of Palliative, Rehabilitation and Integrative Medicine, University of Texas, MD Anderson Cancer Center, Houston, TX, USA Marc-Antoine Marquis, MD, MSc, MA  Department of Pediatrics, Sainte-Justine Hospital, Montreal, QC, Canada Department of Pediatric Palliative Care, Sainte-Justine Hospital, Montreal, QC, Canada Jonathan M. Marron, MD, MPH  Department of Pediatric Oncology, Dana-Farber Cancer Institute and the Harvard Medical School Center for Bioethics, Boston, MA, USA Samantha D. Martin, MD  Department of Pediatrics, Boston, MA, USA Monia  Marzouki, MD Department of Pediatrics, Sainte-Justine Hospital, Montreal, QC, Canada Maura A. Miglioretti, PhD  Department of Pediatrics, C.S. Mott Children’s Hospital, Ann Arbor, MI, USA Pietro  Miozzo, BS, MD  Department of Pediatrics, Massachusetts General Hospital, Mass General for Children, Boston, MA, USA Li Mo, MD  The Center of Gerontology and Geriatrics, National Clinical Research Center of Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China Gopi S. Mohan, MD, PhD  Department of Pediatrics, Pediatric Critical Care, Massachusetts General Hospital, Boston, MA, USA Division of Hematology-Oncology, Boston Children’s Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA Department of Pediatrics, Pediatric Critical Care, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Jonathan  Moreira, MD Department of Medicine, Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA Shinichiro  Morishita, PhD Department of Physical Therapy, School of Health Sciences, Fukushima Medical University, Fukushima, Japan Sue E. Morris, PsyD  Division of Adult Psychosocial Oncology, Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, Boston, MA, USA Carolyn Mulroney  Department of Medicine, University of California San Diego, La Jolla, CA, USA Lauren  Elizabeth  Nicholls, MD Department of Palliative Care, Geisinger Community Medical Center, Scranton, PA, USA

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Oreofe  O.  Odejide, MD, MPH Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Judith A. Paice, PhD, RN  Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA Susan Parsons, MD, MRP  Department of Medicine, Tufts University School of Medicine, Boston, MA, USA Division of Hematology/Oncology, Department of Medicine, Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA, USA Effie  Wang  Petersdorf, MD Division of Hematology and Oncology, University of Washington, Seattle, WA, USA Division of Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA Laura S. Porter, PhD  Department of Psychiatry and Behavioral Sciences, Duke University Hospital, Durham, NC, USA Nicholas  Purol, MSW  Department of Psychosocial Oncology and Palliative Care, Boston Children’s Hospital and Dana-Farber Cancer Institute, Boston, MA, USA Vinay  Rao, DO Division of Palliative Medicine, Yale University School of Medicine, New Haven, CT, USA Daniel  R.  Richardson, MD, MA Department of Medicine, Division of Hematology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Eric  J.  Roeland, MD, FAAHPM  Division of Medical Oncology, Section Palliative Care, Department of Medicine,, Knight Cancer Institute, Oregon Health and Science University,, Portland, OR, USA Courtney  Schroeder, MD Division of Hematology/Oncology, Department of Medicine, Tufts Medical Center, Boston, MA, USA Julie K. Silver, MD  Department of Physical Medicine and Rehabilitation, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA Jennifer  M.  Snaman, MD, MS Pediatric Advanced Care Team, Department of Pediatric Oncology, Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, Boston, MA, USA Angela Sousa, MSN, ANP-BC, ACHPN  Department of Palliative Care, Newton-Wellesley Hospital, Newton, MA, USA Angela  Steineck, MD, MS  Department of Pediatrics, Seattle Children’s Hospital, Seattle, WA, USA Sarah J. Tarquini, PhD  Department of Psychosocial Oncology and Palliative Care, Dana-­ Farber Cancer Institute, Boston, MA, USA Division of Pediatric Psychosocial Oncology, Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, Boston, MA, USA Kristen Uhl, PhD  Department of Psychosocial Oncology and Palliative Care, Dana-Farber Cancer Institute, Boston, MA, USA Christina  K.  Ullrich, MD, MPH, FAAHPM Department of Psychosocial Oncology and Palliative Care, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA Division of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA Harvard Medical School, Boston, MA, USA

Contributors

Contributors

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Melissa  K.  Uveges, PhD, MA, RN  Boston College Connell School of Nursing, Chestnut Hill, MA, USA Nicki  Vithalani, MD Department of Palliative Medicine, Geisinger Lewistown Hospital, Lewistown, PA, USA Marcia  A.  Winter, PhD Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA Lindsay  Wooster-Halberg, LCSW, APHSW-C  Department of Pediatrics, Oregon Health and Science University, Portland, OR, USA

1

Introduction Christina K. Ullrich and Eric J. Roeland

Hematologists/oncologists and palliative care specialists have more in common than most think. Both medical fields are intensely focused on the exceptional care of patients with advanced illness. Clinicians gravitate toward these fields driven by “a calling” to engage in medically, emotionally, and psychosocially complex care. It is challenging but rewarding work. Clinicians in both fields provide a highly individualized approach to care, one based on disease risk factors and molecular markers and the other on specific symptoms and psychosocial factors. Neither field can treat a patient in isolation without assessing the whole patient as a person and considering the patient’s goals, resources, support, and coping. Both also rely on a multi -or interdisciplinary care model drawing on the strengths of other clinician colleagues, including nurses, social workers, pharmacists, spiritual counselors, case managers, psychologists, nutritionists, and physical therapists. As dual-trained oncologists and palliative care specialists, we have observed a shift in the interactions between hematologists/oncologists and palliative care specialists. Hematologists/oncologists increasingly welcome palliative care clinicians as active clinical team members. The outdated view that cancer-directed therapy and palliative care are mutually exclusive and opposing approaches to care has been replaced by strong evidence supporting the early integration of palliative care, including in the curative setting [1, 2]. Moreover, as trainees continue to gain access to palliative care education and clinical training, we see a generational shift toward increasing cooperation and collaboration.

C. K. Ullrich (*) Department of Psychosocial Oncology and Palliative Care, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA e-mail: [email protected] E. J. Roeland Division of Medical Oncology, Department of Medicine, Section Palliative Care, Knight Cancer Institute, Portland, OR, USA e-mail: [email protected]

As we look toward the future, we foresee ongoing uncertainty. As novel therapies become increasingly more effective and their use expands, we will require innovative approaches to predict and manage toxicity while supporting patients, caregivers, and one another. In addition, with patients living longer without a cure and instead with chronic illness, we must meet their needs to live as well as possible and as long as possible. With continued treatment success, we also anticipate that prognostic uncertainty [3] will become increasingly common, and we will have to shift away from historic prognostic trajectories to managing the unknown. In short, it will be as important as ever that palliative care be based on need, not prognosis. More specifically, it must not be reserved for the last moments of a patient’s life. Simultaneously, our world has become increasingly more complex. The challenges of delivering cutting-edge, high-­ quality, individualized care to patients with hematologic malignancies and nonmalignant hematologic conditions have also become increasingly complicated. The post-­ COVID era has further highlighted inequities in access to medical care in patients experiencing unemployment, housing insecurity, safety concerns, mental health challenges, and substance abuse, all impacting serious illness outcomes and experiences. Similarly, hematology/oncology and palliative care clinicians also share increasingly high rates of moral distress and burnout in caring for these patients in an increasingly fragmented medical system [4–6]. Consequently, we believe there is much we can continue to learn from each other and even more we can do to support one another as we strive to deliver high-quality, comprehensive care in the context of such inequities and challenges. The path forward is recognizing and supporting patients, caregivers, and clinicians in this uncertainty. This textbook has been structured as a resource for clinicians caring for individuals with a hematologic malignancy or nonmalignant hematologic condition, with both hematology/oncology and palliative care content. We hope this structure makes for a valuable reference for clinicians caring for patients with

© Springer Nature Switzerland AG 2023 C. K. Ullrich, E. J. Roeland (eds.), Palliative Care in Hematologic Malignancies and Serious Blood Disorders, https://doi.org/10.1007/978-3-031-38058-7_1

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hematologic malignancies and serious nonmalignant hematologic disorders while also serving as a call for continued inspiration, research, and collaboration in this critical space.

References 1. El-Jawahri A, LeBlanc T, VanDusen H, et  al. Effect of inpatient palliative care on quality of life 2 weeks after hematopoietic stem cell transplantation: a randomized clinical trial. JAMA. 2016;316(20):2094–103. https://doi.org/10.1001/jama.2016.16786. 2. El-Jawahri A, LeBlanc TW, Kavanaugh A, et  al. Effectiveness of integrated palliative and oncology care for patients with acute myeloid leukemia: a randomized clinical trial. JAMA Oncol. 2020;7(2):238–45. https://doi.org/10.1001/jamaoncol.2020.6343.

C. K. Ullrich and E. J. Roeland 3. Temel JS, Shaw AT, Greer JA.  Challenge of prognostic uncertainty in the modern era of cancer therapeutics. J Clin Oncol. 2016;34(30):3605–8. https://doi.org/10.1200/JCO.2016.67.8573. 4. Neumann JL, Mau L-W, Denzen EM, et  al. Hematopoietic cell transplantation multidisciplinary care teams: national survey of transplant provider burnout, moral distress and career satisfaction. Biol Blood Marrow Transplant. 2016;22(3):S29–30. 5. Neumann JL, Mau L-W, Virani S, et  al. Burnout, moral distress, work–life balance, and career satisfaction among hematopoietic cell transplantation professionals. Biol Blood Marrow Transplant. 2018;24(4):849–60. 6. Dijxhoorn A-FQ, Brom L, van der Linden YM, Leget C, Raijmakers NJ. Prevalence of burnout in healthcare professionals providing palliative care and the effect of interventions to reduce symptoms: a systematic literature review. Palliat Med. 2021;35(1):6–26.

Part I Hematologic Malignancies and Serious Blood Disorders

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Hematologic Malignancies Daniel R. Richardson and Carolyn Mulroney

Introduction Integrated palliative care within oncology has demonstrated improved outcomes for patients with advanced solid malignancies and, more recently, for those undergoing hematopoietic cell transplantation (HCT) and induction chemotherapy for hematologic malignancies. Historically, palliative care physicians were infrequently asked to see patients with hematologic malignancies; however, it is our hope and expectation that palliative care engagement will continue to improve in the upcoming years. As oncologic hematologists caring for patients with hematologic malignancies, we desire to highlight several unique aspects of caring for patients with hematologic malignancies that may differ from those patients with solid tumors. First, many hematologic malignancies are highly curable even when “metastatic” at diagnosis. Therefore, risk stratification and treatment intensity for these patients vary significantly from those patients with solid malignancies. There are three major categories of hematologic malignancies—leukemia, lymphoma, and myeloma. The prognosis of each varies widely by the maturity of the cell of origin. Diseases with immature cells of origin often lead to aggressive malignancies (e.g., acute myeloid leukemia [AML]) that can be treated and even cured with chemotherapy. Conversely, diseases with mature cells of origin often lead to more indolent diseases (e.g., multiple myeloma or chronic lymphocytic leukemia [CLL]) that are less aggressive and not generally curable. High-intensity chemotherapy for aggressive hematologic malignancies often results in disease response and functional improvement in many patients. This response can complicate D. R. Richardson (*) Department of Medicine, Division of Hematology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA e-mail: [email protected] C. Mulroney University of California San Diego, La Jolla, CA, USA e-mail: [email protected]

treatment decision-making for patients as high-risk, high-­ reward scenarios exist, leading to very poor outcomes for patients who experience complications. HCT is perhaps the quintessential high-risk, high-reward treatment offering a chance of cure for some patients while also carrying the risk of high morbidity and mortality. High-risk, high-reward treatment paradigms require a clear understanding of patient preferences and goals. Patients may fear that expressing their preferences, including worries about treatment and its toxicity, may impact the intensity of their treatment. Therefore, having a clinical team outside the HCT team can provide a space for patients and caregivers to express these concerns. Palliative care specialists working alongside the HCT team may substantially improve the patient-centeredness of care in these instances. Second, staging is different for hematologic malignancies than for patients with solid tumors. Diagnosis commonly involves a bone marrow biopsy where the morphology (i.e., what the cells look like under the microscope), immunophenotype (typically captured through various immunohistochemical stains or flow cytometry), and sometimes cytogenetic (i.e., karyotype abnormalities determined grossly or with fluorescent in situ hybridization [FISH]) or molecular features (i.e., specific mutations within individual genes) inform the final diagnosis. Imaging is uncommonly required for leukemia staging though lymphoma staging and treatment response rely on positron emission tomography (PET) scans. For example, imaging in multiple myeloma helps determine the extent of bony involvement, though prognosis depends mainly on treatment response. The cell of origin, along with genetic and cytogenetic features, predicts prognosis in most cases. Mutations in specific genes (particularly within TP53) may carry heavy prognostic value and may allow for a targeted-treatment approach (e.g., FLT3 targeted therapy in AML). While there are well-­ developed risk prediction models for some hematologic malignancies involving many of the above criteria, treatment response is the most important dynamic prognostic indicator.

© Springer Nature Switzerland AG 2023 C. K. Ullrich, E. J. Roeland (eds.), Palliative Care in Hematologic Malignancies and Serious Blood Disorders, https://doi.org/10.1007/978-3-031-38058-7_2

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Primary refractory disease (i.e., a disease that does not respond to initial treatment) portends a poor prognosis. Increasingly, the depth of response to treatment, including the presence or absence of minimal residual disease (MRD), is used to determine prognosis. Older patients generally fare substantially worse than younger patients as they often harbor more high-risk molecular and cytogenetic features and often are unable to tolerate high-intensity therapies. The most common toxicity of traditional cytotoxic chemotherapies is acute cytopenia, as would be expected. Many patients require infectious prophylaxis, hematopoietic stimulating factors (e.g., granulocyte-colony stimulating factor [GCSF]), and transfusions to complete therapy. Additionally, novel targeted agents have unique toxicities such as “differentiation syndrome,” where cells rapidly differentiate and infiltrate organs outside the bone marrow, and “tumor lysis syndrome,” where the rapid death of malignant cells can lead to renal and metabolic failure. The recent expansion of available therapies across hematologic malignancies (including some high-risk, high-reward therapies such as chimeric antigen receptor [CAR T]-cell therapy) has substantially increased the available options to patients. Yet, these therapies will likely complicate treatment decision-making and may expose patients to more toxicity. Because of the potential for good outcomes, even with advanced disease, many patients are treated aggressively near the end of life. Predicting who will respond to therapy and when they will respond is challenging. Even for patients with incurable diseases, prolonged survival and treatment response is possible despite multiple relapses. Unfortunately, these factors often lead to high healthcare utilization at the end of life. Integrated palliative care may improve these outcomes, though fundamental challenges in balancing potential benefits with known risks will likely remain. As palliative care teams are increasingly involved in patient care with hematologic malignancies, these specialists must be aware of their unique clinical aspects. To facilitate an improved understanding of established clinical and prognostic factors, we have summarized critical points regarding lymphoma, leukemia, myeloma, and HCT. We hope this chapter serves as a key reference for palliative care specialists to effectively engage and support patients with hematologic malignancies along with their caregivers and the clinical team.

Lymphoma The World Health Organization (WHO) bases the classification of lymphomas on morphology, immunophenotype, genetics, clinical features, postulated normal cell counterpart of the cell of origin, anatomic site, and age. Treatment and prognosis for patients with lymphoma depend on an accurate diagnosis. In 2016, the WHO updated the prior classification from 2008 based on additional genetic data and clinical

D. R. Richardson and C. Mulroney

behavior aspects [1]. In general, on presentation with suspected lymphoma, patients should undergo an excisional biopsy of lymph nodes because fine needle aspirate and core needle biopsies are limited in providing the tissue morphology required for an accurate diagnosis. Staging studies for lymphoma include computed tomography (CT) scans and PET/CT scans. Most cases will require bone marrow aspirate and biopsy. Additional biopsies and evaluation of the central nervous system (CNS) may be necessary depending on the clinical scenario. These same studies, including repeat biopsy, are frequently necessary at the time of relapse. Molecular testing has increasing relevance in the management of lymphoma with the identification of effective targeted therapies.

Low-Grade B-Cell Lymphoma Low-grade mature B-cell lymphomas are generally characterized by an indolent clinical course. These entities may not require immediate treatment, and treatment decisions are based on clinical characteristics and disease burden. Treatment for these diseases is non-curative; yet, treatment can lead to extended remissions. Patients with stage I and stage II may obtain long-term cures with radiation therapy alone. The most common form of low-grade lymphoma is follicular lymphoma. The overall survival for patients with follicular lymphoma is about two decades, and the median progression-free survival after front-line therapy is approximately 7  years. Relapse of follicular lymphoma within 2  years of first-line therapy is associated with a decreased overall survival (OS) [2–4]. The International Prognostic Index in first-line follicular lymphoma (FLIPI) is the most common clinical prognostic index used for follicular lymphoma and has been correlated with overall survival, time to treatment failure from diagnosis, risk of transformation to higher grade lymphoma, and 5-year survival from first progression [5]. Identified risk parameters in this scoring include age >60 years, stage III/ IV, hemoglobin 40% in association with BCL2 or BCL6 protein expression is associated with a more aggressive clinical course than standard DLBCL without molecular rearrangements or protein expression. High-grade B-cell lymphoma (HGBL) under the current WHO classification includes all large B-cell lymphomas with MYC and BCL2 and/or BCL6 rearrangements unless they otherwise meet the criteria for follicular lymphoma or lymphoblastic lymphoma. HGBL-NOS are morphologically similar to HGBL but lack rearrangements in MYC and BCL2/BCL6 rearrangements. Anthracycline-based chemotherapy is standard of care for the front-line treatment of large B-cell lymphomas and is curative unless a patient cannot tolerate multiagent chemotherapy. The most commonly used treatment for DLBCL and other aggressive B-cell lymphoma is R-CHOP (rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone). HGBL will frequently be treated with escalated regimens such as dose-adjusted R-EPOCH (rituximab, etoposide, prednisone, vincristine [Oncovin], cyclophosphamide, and doxorubicin [hydroxydaunorubicin]), R-CODOX-­M/R-IVAC (rituximab, cyclophosphamide, doxorubicin, vincristine, cytarabine, methotrexate/rituximab, ifosfamide, etoposide, cytarabine), and HyperCVAD/MTX-Cytarabine (cyclophosphamide, vincristine, doxorubicin, [Adriamycin], and dexamethasone). The International prognostic score (IPI) based on PET/CT response at diagnosis and longitudinally is useful in counseling patients regarding expectations [5]. For example, the R-IPI in DLBCL is associated with treatment outcomes and reflects the disease’s biological aggressiveness using available clinical markers.

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 rimary DLBCL of the Central Nervous System P Primary DLBCL of the central nervous system (PCNSL) is the most common form of lymphoma involving the CNS but represents only 4% of intracranial neoplasms and 4–6% of extranodal lymphomas [8]. The vast majority (>80%) of PCNSL are of the activated B-cell subtype of DLBCL.  A definitive diagnosis requires pathologic confirmation. The diagnostic procedure of choice is a stereotactic biopsy of the brain lesion, vitrectomy in the case of vitreoretinal disease, or cerebrospinal fluid (CSF) sampling. A patient may present with a wide variety of symptoms depending on the area of involvement of the CNS, including nonspecific neurocognitive abnormalities, signs of increased intracranial pressure, or neurocognitive deficits. Hematologic oncologists use two prognostic scoring systems when evaluating patients with PCNSL: (i) the International Extranodal Lymphoma Study Group (IELSG) score [9] and (ii) the Memorial Sloan Kettering Cancer Center (MSKCC) score [10]. The IELSG score includes ECOG performance score, age, CSF protein concentration, lactate dehydrogenase serum level, and deep brain involvement to determine prognosis. Two-year survival rates correlate with the presence of 0–1, 2–3, or 4–5 adverse-risk factors and are 80%, 48%, or 15%, respectively. The MSKCC scoring system identifies three prognostic groups based on the Karnofsky performance status (KPS) and age. Age ≤ 50 and KPS ≥ 70 correlate with and median overall survival of 5.2–8.5 years. A combination of age >50 and KPS ≥70 correlates with median overall survival of 2.1–3.2 years. Patients with age >50 and KPS 70 years and the presence of B symptoms. CD30 by IHC is an adverse and targetable prognostic factor. Treatment is similar to DLBCL with RCHOP used widely with a low complete response and decreased OS [16].  rimary Mediastinal (Thymic) Large B-Cell P Lymphoma Primary mediastinal (Thymic) large B-cell lymphoma (PMBL) represents about 2–3% of all NHL and 6–8%of LBCL. The median age is 36 years, and women are affected more frequently (ratio 2:1). This aggressive lymphoma presents with bulky anterior/superior mediastinal mass with 80% having stage I/II disease. Systemic symptoms occur in 20%. Patients may present with symptoms related to bulk and disease location including superior vena cava syndrome. Overall survival at 5 years is 70–85%. CD30 is expressed in approximately 80% of cases, PD-L1 and PD-L2 are positive in approximately 50–75%, and both CD30 and PD-L1/PD-L2 are targetable from a therapeutic perspective [17, 18]. It can be challenging to distinguish PMBL from DLBCL unless an adequate tissue sample is obtained. Initial therapy for curative intent includes dose-adjusted R-EPOCH with or without radiation therapy and RCHOP/radiation therapy. Plasmablastic Lymphoma Plasmablastic lymphoma is a rare B-cell lymphoma representing less than 1% of DLBCL.  This lymphoma is composed of immunoblastic or plasmablastic cells and is CD20-negative. EBV positivity is present in 50% to 80% of cases. This lymphoma occurs most commonly in the setting

2  Hematologic Malignancies

of immunodeficiency, especially human immunodeficiency virus (HIV) infection, and represents approximately 3% of HIV-related lymphoma. The median OS is 15 months.

 uman Herpesvirus-8-Positive Diffuse Large H B-Cell Lymphoma HHV8+ DLBCL is a rare disease and is one of the Human herpesvirus-8 (HHV8)/Kaposi sarcoma herpes virus-positive lymphoproliferative disorders, which also include germinotrophic lymphoproliferative disorder, multicentric Castleman disease (MCD), and primary effusion lymphoma (PEL). Approximately 50% of patients are HIV positive. This lymphoma commonly arises in a background of HHV8+ MCD in patients who are also HIV positive however can present de novo without evidence for MCD.  Pathology shows sheets and confluent clusters of plasmablasts and destruction of normal lymph node architecture, and in some cases, a leukemic component may be present. Neoplastic cells are negative for EBV. Patients have an aggressive course and poor prognosis [19, 20].  rimary Effusion Lymphoma P Primary effusion lymphoma (PEL) is a rare, aggressive B-cell lymphoma typically presenting with effusions without tumor mass, although it can present with solid variants. Reported to have near-universally associated with human herpesvirus-8 (HHV8) and can have concurrent EBV infection. Underlying immunodeficiency including HIV, increased age, and post-organ transplant immunodeficiency predispose to this lymphoma. These patients are most commonly present with symptoms related to effusions. Treatment is anthracycline based as for other high-grade lymphomas, but the prognosis is poor. Treatment of the underlying immunodeficiency is essential, if possible. The involvement of more than one body cavity is associated with OS of 4 months in comparison to 18 months in patients with only one cavity involved [21]. Burkitt Lymphoma Burkitt lymphoma is a rare, very aggressive lymphoma with endemic and sporadic variants. The sporadic variant occurs globally and has an increased incidence in HIV. The sporadic variant and HIV-associated form are associated with EBV in 25–40% of cases. The proliferative rate for this lymphoma is near 100%. MYC translocation is pathognomonic of the disease and is typically at 8q24. CNS disease with leptomeningeal involvement occasionally occurs at presentation. Treatment for this disease involves intensive multiagent chemotherapy with curative intent and is frequently complicated by tumor lysis syndrome due to the high-proliferative rate and bulk of disease. There is no validated prognostic score for Burkitt lymphoma. The outcome for relapsed and refractory disease is poor. Common regimens used at diagnosis are

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intensive multiagent regimens such as modified R-CODOX-M IVAC, reported to have 75% EFS at 3 years [22].

T-Cell Lymphoma T-cell lymphomas are a heterogeneous group of lymphomas that can develop within lymphoid tissues such as the spleen and lymph nodes or beyond lymphoid tissues (i.e., gastrointestinal tract, liver, nasal cavity, skin, and others). Natural killer (NK) cell shares many features with T cells and when they become cancerous, the cancer is called NK or NK/T-cell lymphoma. Overall, T-cell lymphomas account for approximately 7% of all lymphomas in the United States [23]. Peripheral T-cell lymphomas (PTCLs) are a group of clinically aggressive diseases associated with poor outcomes. Evaluating effective therapies in PTCL is challenging given its rarity. Types of PTCL include: • • • • • • • •

T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Aggressive NK-cell leukemia Indolent large granular NK-cell lymphoproliferative disorder Adult T-cell leukemia Extranodal NK-/T-cell lymphoma, nasal type Enteropathy-type T-cell lymphoma Hepatosplenic T-cell lymphoma

Unfortunately, treatment advances in PTCLs have been slow compared to other lymphomas. Therefore, PTCL patients frequently are treated with similar therapies used in B-cell lymphomas with generally poor outcomes. Relapse is common with currently available agents with few effective options available for salvage therapy [24]. Therefore, patients with PTCLs represent a patient population with high risk of relapse and death. In contrast to PTCLs, primary cutaneous T-cell lymphomas have a 5-year disease-specific survival of over 85–90% [25]. Primary cutaneous T-cell lymphomas included in the 2018 updates for the WHO-EORTC classification include the following: • • • •

Mycoses fungoides Mycoses fungoides variants Sezary syndrome Adult T-cell leukemia lymphoma

Primary cutaneous CD30+ lymphoproliferative disorders include: • Cutaneous anaplastic large-cell lymphoma and lymphomatoid papulosis (LyP) • Subcutaneous panniculitis-like T-cell lymphoma • Extranodal NK/T-cell lymphoma, nasal type

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• Chronic active Epstein–Barr Virus (EBV) infection • Primary cutaneous peripheral T-cell lymphoma, rare subtypes –– Primary cutaneous gamma/delta T-cell lymphoma –– CD8+ aggressive epidermotropic cytotoxic T-cell Lymphoma –– Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder –– Primary cutaneous acral CD8+ T-cell lymphoma • Primary cutaneous peripheral T-cell lymphoma, NOS

D. R. Richardson and C. Mulroney

pies and advancing treatment approaches, multiple myeloma is by definition incurable. Patients with multiple myeloma have a monoclonal protein >3 g/dL produced and secreted by malignant plasma cells that can be measured by serum-free light chain analysis and protein electrophoresis of the serum (SPEP) and/or urine (UPEP) as well as immunofixation. The most common monoclonal subtype is immunoglobulin G (IgG), followed by IgA, kappa or lambda light chain only (i.e., Bence Jones), IgD, and then IgM [28]. In patients with light chain multiple myeloma, the incidence of kidney failure is much higher. A diagnosis of multiple myeloma requires The 5-year disease-specific survival for folliculotropic a bone marrow biopsy with ≥10% clonal plasma cells or a mycosis fungoides and Sezary syndrome is 75% and 36%, biopsy-proven plasmacytoma, solitary tumors consisting of respectively [25]. Extranodal NK/T-cell lymphoma nasal plasma cells occurring outside the bone, and is  associated type involving the skin has a 5-year disease-specific survival with a worse prognosis. End-organ involvement (i.e., immuof 16%. Primary cutaneous gamma delta T-cell lymphoma nodeficiency, lytic bone disease, anemia, and renal failure) and CD8+ aggressive epidermotropic T-cell lymphoma have differentiates multiple myeloma from monoclonal gammopinferior disease-specific survival at 11% and 31%, respec- athy of undetermined significance (MGUS) and smoldering tively [25]. Primary cutaneous peripheral T-cell lymphoma multiple myeloma. 5-year disease-specific survival is only 15% [25]. Cutaneous MGUS has less than 10% plasma cells in the bone marT-cell lymphoma patients are frequently followed by a mul- row, serum M protein 8.5 g/dL and low levels of HbF have both independently been shown to increase the risk of frequent pain crises [11]. Change in humidity or temperature, dehydration, infection, initiation of menses, alcohol consumption, and psychosocial stressors have been demonstrated to induce a pain crisis. An average pain crisis will last between 2 and 7 days and affect any part of the body, but most patients note pain in their bones [9]. Approximately 50% of episodes are accompanied with an additional finding like fever, swelling, tenderness, hypertension, or nausea and vomiting. Notably, there is no lab test that can definitively diagnose a pain crisis. A peripheral blood smear may indicate sickle cells, but this is not diagnostic of a crisis. Similarly, increased levels of acute phase reactants and inflammatory markers like C-reactive protein, fibrinogen, and lactate dehydrogenase can be seen as well as intriguing research evaluating levels of interleukin-1 and TNF but there has been no conclusive correlation between these values and the manifestation of an event [12–14].

necrosis of the bones [7]. ACS refers to the collective acute pulmonary complications of SCD and occurs in 30–50% of patients with SCD, accounting for the second leading cause of hospitalization and the leading cause of death in adults [15]. Clinically, ACS is defined by the new appearance of an infiltrate on imaging with accompanying respiratory symptoms. This is often accompanied by fever, chest pain, cough, and hypoxia. ACS often will follow or occur in tandem with another VOC [16]. Patients with SCD are at an increased risk for infections, particularly by encapsulated organisms, due to functional asplenia from repeated splenic infarction [17, 18]. Augmenting this further is the inherent impact on the immune system itself with patients with SCD having irregular IgG and IgM antibody responses and defects in the alternative complement pathway. Bacteremia can be associated with aplastic or hypo-proliferative crises from marrow suppression or disseminated intravascular coagulopathy (DIC) leading to a mortality rate of 20–50% [19]. Approximately 24% of patients with SCD will experience a stroke by age 45, and 25% of children will have a silent ischemic lesion that may lead to impaired neurocognitive development [20–22]. Epilepsy is two to three times more common in individuals with SCD when compared to healthy controls and the development of dactylitis in childhood along with male sex have both been independently associated with an increased risk of developing a seizure syndrome [20]. As patients with SCD age, they are ultimately at an increased risk of neurocognitive decline and intracranial hemorrhage. Cardiac complications of the disease also remain a major cause of death in adult patients. Myocardial infarction can occur in patients with SCD even in the absence of atherosclerotic or obstructive disease and is driven by increased oxygen supply demand mismatch [23, 24]. Chronic anemia impacts the cardiovascular system and can cause cardiac compromise and cardiomyopathy. SCD can also cause nephropathy, causing chronic kidney disease and sometimes end-stage renal disease [25]. Painful erections, also known as priapism, can occur in young boys and men, causing significant pain and distress. Recurrent priapism can lead to infertility and sexual dysfunction [26, 27]. Microvascular thromboses can cause infarction of the bone trabeculae and marrow cells in patients with SCD resulting in osteonecrosis [28]. Bone infarcts are worsened by increased rates of vitamin D deficiency and osteoporosis in the population. Such osseous abnormalities can give rise to fractures or deformities of the vertebrae that can lead to spinal instability [28].

Overview of VOCs VOCs can affect any and all organ systems in SCD. Common complications include acute chest syndrome (ACS), acute hepatopathy, fat necrosis and more chronically, avascular

Treatment Options Despite recent advances, SCD has limited effective treatment options. From a historical and contemporary perspective, hydroxyurea remains the cornerstone for the

Vaso-occlusive Crises

4  Serious Blood Disorders: A Focus on Sickle Cell Disease and Hemophilia

management of the disease and is strongly recommended by the National Heart Lung and Blood Institute guidelines for management of SCD [29]. The Multicenter Study of Hydroxyurea was a 2-year, multicenter double-blind, randomized, placebo-controlled trial in 300 patients with SCD that demonstrated a 50% reduction in VOC and 40% reduction in mortality with the use of hydroxyurea [30]. Hydroxyurea stimulates the production of HbF, possibly by augmenting HbF mRNA synthesis [31]. It has also been posited to increase the release of nitric oxide which in turn modulates the genetic regulation of HbF transcription and translation [32]. In addition, hydroxyurea may have anti-­ inflammatory effects at the sites of VOC, possibly by decreasing neutrophil counts [29]. Hydroxyurea is indicated for patients with frequent painful episodes (≥3 episodes within a 12-month period), with a history of ACS, other severe VOCs, or in severe symptomatic anemia [33]. The therapy is continued as long as it remains well tolerated and the dose is titrated to achieve a HbF level of around 15%. Adherence can be measured using the RBC mean corpuscular volume (MCV), which typically rises upon treatment with hydroxyurea. Despite recommendations for use, hydroxyurea is often poorly tolerated in adult patients and therapy adherence, unfortunately, is low [34]. RBC transfusions also play a significant role in the treatment of SCD.  Transfusions have benefit both in the acute setting, in the treatment of life-threatening complications, and chronically, in prophylaxis [35]. Transfusions decrease HbS levels by dilution, decreasing blood viscosity, improving oxygen carrying capacity of the blood, and chronically by suppressing the hematopoietic drive and thereby decreasing the production of HbS. It must be stated that transfusions in SCD are not used to correct anemia in the absence of complications as this strategy poses more risks than benefits. In the acute setting, a clear benefit for transfusions has been seen in the management of acute strokes and severe ACS and to a lesser extent in multi-organ failure [36–38]. In the chronic setting, transfusions are effective in the secondary prevention of stroke and for prophylaxis against recurrent ACS and VOCs and in pregnancy [39]. The use of transfusions in the perioperative period has been shown to reduce the risk of surgery complications [40]. When available, automated or manual RBC exchange may be considered as an alternative to simple transfusions. Exchange transfusions, where a portion of the patient’s blood volume is removed and replaced with donor blood, can be done in the acute setting and also every 4–6 weeks to maintain a goal HbS percentage of less than 30%. This strategy helps decrease HbS levels more efficiently while keeping blood viscosity low and also decreases the risk for iron overload. Selecting an exchange transfusion over a simple transfusion can be a practical matter of resources; however, exchange transfusions are preferred over simple transfusions where available [36, 37].

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The risks and benefits of ongoing transfusion therapy should be reassessed frequently with the patient, especially given the high rates of transfusion-related complications, particularly RBC alloimmunization and iron overload. Iron overload is particularly problematic in this population as it threatens further organ damage [41]. Each unit of RBCs transfused introduces 200–250  mg of elemental iron to the patient and over time, this can lead to iron overload and deposition in the visceral organs. Iron chelation therapy is, thus, an important adjunct to any RBC transfusion program [42]. Liver biopsy or quantitative magnetic resonance imaging can be used to assess liver iron concentration, and chelation therapy should be considered when liver iron concentration is ≥7 mg Fe/g dry weight [43, 44]. Three iron chelators are currently commercially available in the US.  No head-to-head trial has been completed to compare the efficacy or safety of these medications but one of the three agents, deferoxamine requires a daily, slow, subcutaneous injection. As a result, the two oral agents, deferiprone and deferasirox are more easily administered but have adverse effects and need frequent monitoring resulting in poor adherence [42, 45]. In the last few years, recognizing the need for additional therapeutics in SCD, the Food and Drug Administration (FDA) has fast tracked and approved three new therapeutic agents: L-Glutamine, voxelotor, and crizanlizumab (Table 4.1). L-Glutamine has been shown to decrease hospitalizations in SCD, especially when used in combination with hydroxyurea and was approved by the FDA in 2017 [46]. In November 2019, the FDA also approved voxelotor as the first modulator of hemoglobin oxygen affinity and as a hemoglobin stabilizer. In the HOPE trial, a randomized, double-­blind, placebo-controlled study of 274 patients with SCD, voxelotor increased hemoglobin concentrations while reducing hemolysis but the trial failed to demonstrate an improvement in VOCs and this remains an area of future study [47]. The FDA also recently approved crizanlizumab for the prevention of VOCs in SCD [48]. Crizanlizumab is a P-selectin antagonist that reduces the adhesion of red cells to inflammatory cells and platelets during a VOC. In a phase 2 study of 198 patients with SCD and a history of VOCs, patients who received crizanlizumab experienced an average of 1.63 pain episodes annually with 35% of patients experiencing no episodes [49]. Patients in the placebo arm experienced 2.98 pain episodes annually while only 17% had no episodes at all [49]. The only potentially curative option in SCD is a hematopoietic cell transplant [50]. Several studies have demonstrated excellent results, even up to 80–90% sickle cell free 5-year survival coupled with a 90–97% overall survival. The complication rates of conditioning, post-transplant adverse events, and lack of matched donors, however, have markedly limited the wide use of hematopoietic stem cell transplants, especially in adult patients [51–53].

S. S. Azar and S. Gopal

40 Table 4.1  Therapeutic agents in sickle cell disease and their use Medication Hydroxyurea

Mechanism of action Exact mechanism unknown; increased HgF possibly through stimulation of HgF mRNA or regulation of transcription through nitric oxide release

L-Glutamine

Exact mechanism unknown; improved NAD redox potential preventing oxidative damage

Voxelotor

Indications ≥3 episodes within a 12-month period, history of ACS, history of other severe VOC, severe symptomatic anemia

Dose 15–35 mg/kg/ dose PO qd

If hydroxyurea is not well 65 kg: 15 g PO bid Binds to the alpha chain of HbS If hydroxyurea is not well 1500 mg PO increasing oxygen affinity and tolerated or VOCs persist qd reducing polymerization despite hydroxyurea

Crizanlizumab Inhibits P-selectin reducing Persistent VOCs interactions between endothelial unresponsive to cells and circulating blood cells hydroxyurea, L-Glutamine, or both

5 mg/kg IV on weeks 0 and 2; q4 weeks thereafter

Selected adverse reactions Myelosuppression Nail and skin hyperpigmentation Nail and skin atrophy Mucositis Hepatotoxicity Hypersplenism Constipation Chest and extremity Pain Hot Flashes Headache Diarrhea Abdominal pain Arthralgias Fever Infusion site reaction

Notes Reference Approved for [29, patients 31–33] 2 years and older

Approved for [46] patients 5 years and older

Approved for [47] patients 12 years and older Approved for [48, 49] patients 16 years and older

Fig. 4.1  Survival curves for SCD by genotype (a) and for HbSS/HbSB by number of hospitalizations (b). Adult patients with SCD (n = 712, 16–80  years of age) at King’s College Hospital (London, United

Kingdom) were observed over 10  years (2004–2013 inclusive) and mortality outcome was identified. Paulukonis S et al. [189]

Lastly, gene therapy offers tremendous promise in the management of SCD and may be a potential curative option for decades [54]. Currently, gene addition techniques, gene editing techniques, and induction of HbF synthesis are under investigation in pre-clinical models and in ongoing clinical trials. Gene therapy offers potential for cure and is an area of intense and rigorous study, but are yet to enter routine clinical practice [55].

and improved supportive care, the survivability of SCD has markedly improved over the last 10 years, but continues to be lower than that of the general population [4] (Fig. 4.1). However, in many parts of the world, particularly in sub-­ Saharan Africa, death in childhood remains an unfortunate reality. In the US, the greatest impact on mortality has occurred in pediatric patients with a steady decline in mortality rate over the last 20  years, particularly in children aged 0–3  years, where a 68% reduction in mortality has been observed [1]. It is now estimated that 94% of children with SCD in this country will survive into adulthood. Despite these improvements, patients with SCD die at a

 rognosis and Lifespan Considerations P As a result of newborn screening, immunizations, treatment of infections, disease-modifying agents like hydroxyurea,

4  Serious Blood Disorders: A Focus on Sickle Cell Disease and Hemophilia

younger age than matched peers. A recent study projected life expectancy of 54 years for patients with SCD vs 76 years for a matched non-SCD cohort [56]. Adults with SCD face complications that involve nearly every organ including pulmonary hypertension, congestive heart failure, sickle nephropathy, sickle retinopathy, and sickle hepatopathy. Recent population-­based studies suggest that SCD-related deaths in adults are more likely to be related to acute cardiac, pulmonary, and cerebrovascular complications; acute infections; and chronic cardiac and pulmonary complications and renal disorders [191].

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Acute and Chronic Pain Management

 pioid and Multimodality Therapy Plans O Pain management is an integral part of sickle cell therapy. Pain crises remain one of the costliest complications of SCD to both the patients and the healthcare systems [63]. Frequent hospital admissions are associated with school absenteeism and academic challenges in pediatric patients with similar occupational absenteeism as adults with diminished quality of life. Efforts to empower patients to live with their disease rather than live by the consequences of their disease are stifled by recurrent hospitalizations. An analysis in the US found that the lifetime cost of care for a patient with SCD Transitions of Care was $460,151 per patient with 80.5% of that cost associated with hospital admissions [64]. A similar evaluation in the Pediatric to Adult Transitions United Kingdom demonstrated that 91% of costs were dediAs described above, a comprehensive approach to the care of cated to hospitalizations [65]. patients with SCD is key to reduce morbidity and improve At the same time, VOCs can be extremely distressing to mortality in countries where such advances have been pos- patients and their families and even maximal efforts to mansible [57, 58]. As a result, the care of patients with SCD is age pain as an outpatient can falter requiring patients to seek best delivered through a multidisciplinary treatment center more intensive treatment. Ultimately, the approach to manwhere patients can be followed longitudinally. Comprehensive aging a patient with SCD’s pain, like all aspects of their care, SCD centers can help to empower and educate both the is best done through a comprehensive and multidisciplinary patients and their families while allowing them access to approach [66]. Individual pain management plans have been psychosocial and financial support [59]. Pediatric patients developed to tailor management to each patient’s needs. and their families can be followed by genetic counselors and These plans layout strategies for managing both acute and social workers during important developmental milestones chronic visceral and neuropathic pain, and not only provide while being educated on the importance of infection control, guidance to the patient and their caregivers at home, but also complication reduction, and administration of disease-­ standardize and normalize treatment when they present to modifying agents. As patients approach adulthood, adoles- the hospital for clinicians during an era when opioid precents can be given tools and resources to detect complications scribing has come under increased scrutiny [67–71]. of their disease early while learning to treat their symptoms Outpatient components of pain management plans can and seek care independently [60–62]. include the use of non-steroidal anti-inflammatory drugs along with long-acting and short-acting opioids. Inpatient Challenges in Providing Comprehensive plans can help direct clinicians to early initiation of opioids Adult Care at effective doses and set titration schedules via continuous As the prognosis of SCD has shifted within the last several infusion and bolus dosing. Additional neuropathic therapeuyears with the majority of patients now reaching adulthood, tics including ketamine and lidocaine infusions have also the emergence of adult treatment centers has not risen been studied for inpatient use and have demonstrated reduced quickly enough to absorb the new patients. Many patients opioid use during hospitalizations along with improved pain with SCD remain under the care of their pediatric hematolo- scores [72, 73]. gists or fail to transition to an adult clinician, simply because Data regarding the impact of individualized pain managethey are unable to find an adult-trained physician with expe- ment plans on hospitalizations is unfortunately limited but rience or expertise in SCD [57]. Despite the improvements in the use of such plans in the emergency department (ED) does mortality and morbidity, young adults in the second and third improve pain control [68]. One study demonstrated that a decade of life suffer higher rates of disease-related complica- coordinated multidisciplinary effort to develop individualtions and higher healthcare costs overall, possibly because of ized pain led to 88% of eligible patients having a plan in lack of access to standard measures such as transfusions and place with a concomitant reduction in ED visits for uncomtherapeutics [62]. Such findings stress the need for improved plicated SCD-related pain [74]. These plans can also help comprehensive adult care of patients with SCD and the overcome bias and discrimination that these patients often urgent need for adult hematology clinicians interested in the suffer when they access medical care, where they can often management of this disease. be mislabeled as “drug seekers” and denied appropriate pain

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control. For example, a 5-year quality improvement project at Yale New Haven Children’s Hospital demonstrated the value of incorporating multiple modalities for the treatment of pain. In their study published in 2019, the researchers explored the role of a multidisciplinary team with representatives from pediatric hematology, child psychology, child psychiatry, adolescent medicine, pain medicine, pediatric emergency medicine, nursing, social work, child life, and quality improvement [66]. Their coordinated interventions yielded a 61% reduction in hospitalizations, a decreased hospital stay, reduction in readmission rates from 33.9% to 19.4%, and decreased direct hospital costs [66]. The development and utilization of a “day hospital” has also been demonstrated to reduce admission rates and augment quality of life for patients. Day hospitals act as monitored units that allow patients’ pain crises to be managed with hydration, intravenous pain medications, and transfusions as needed over the course of several hours [75]. In one study, a 2-bed monitored day hospital that operated between the hours of 8 am and 5 pm 5 days per week for the evaluation and treatment of acute uncomplicated SCD-related pain demonstrated a marked reduction in hospital admissions [76]. Mean hospital cost and average length of stay for patients who ultimately did get admitted were also reduced with the day hospital [76–78]. Ultimately, improving the management of acute and chronic pain for patients with SCD requires buy in and education across the healthcare system. Teaching and empowering patients to care for their pain at home and recognizing when it is no longer safe to do so is only part of the solution. It is equally important to educate clinicians caring for patients with SCD long before the hematologist may be involved to assure that appropriate care is not delayed and that the patient is safe and comfortable.

 ptimizing Pain Management through O Technology As the electronic medical record (EMR) becomes a standard component of hospital systems and outpatient clinics across the US, utilization of the various systems to improve the care of patients with SCD has been of increasing interest. The development of individual pain management plans as described in the previous section is largely made possibly by EMR [74]. Some systems create alerts for clinicians in the ED that the patient has an individualized pain management plan in place and directs them to a location in the patient’s chart where this plan can be found. Other systems have integrated safeguards to assure that the outpatient hematology team is contacted and involved early in the patient’s care through the use of secure messaging or a virtual pager system. Order sets also standardize care across environments with curated options for pain control and symptom support along with preferred diagnostic lab and imaging choices

S. S. Azar and S. Gopal

[66]. While each patient’s symptoms and management are dictated by their individual disease manifestations, such standards allow a framework for clinicians who may not be comfortable with the management of the disease. Additionally, the use of smart phone apps has been explored as a secure means of communication between patients and their clinicians, as a reminder for patients to remain vigilant about their disease modifying and pain regimens as well as a record keeping tool to track pain crises, other symptoms, and barriers to care [79–83].

I ntegrative Medicine Approaches The use of complementary and alternative medicine for the support of patients with SCD has been of increasing interest with one study observing that 92% of patients with SCD use some form of integrative medicine approach [84]. Unfortunately, data on the efficacy of these treatments in the SCD population is limited. Small studies have demonstrated that acupuncture and massage therapy may be effective in reducing pain [85–88]. While patients have individually reported use of massage, relaxation techniques, prayer, and other modalities as part of their treatment, no comprehensive evaluations of these interventions have been done to date.

Considerations in Psychosocial Support  ental Health Considerations M As with any chronic disease starting in childhood, SCD is plagued with mental health issues. In addition, this disorder afflicts a minority population, often belonging to lower socio-economic strata which poses additional psychosocial challenges. In one study, 27.6% of patients with SCD had undiagnosed depression with 6.5% of patients having a previously undiagnosed anxiety disorder [89]. Patients noted to have depression recorded pain on significantly more days than non-depressed patients with higher distress from their pain and an increased interference in their activities of daily living. When assessed for overall functionality, patients with SCD and anxiety or depression had poorer overall function and anxious patients reported more opioid use [90–93]. Studies outside the US have demonstrated similar findings [94]. Moreover, the rise of the opioid epidemic in the US has made the management of SCD-related pain even more challenging for patients and clinicians alike. Adults with SCD report difficulties in obtaining prescriptions, inadequate dosing, and stigmatization that pose significant barriers in their treatment [95].  ognitive Impairment and the Impact of Silent C Cerebral Infarctions Patients with SCD can develop silent or overt cerebral infarctions, which over time, lead to neurocognitive impairment

4  Serious Blood Disorders: A Focus on Sickle Cell Disease and Hemophilia

[21]. SCD adults score worse than their healthy siblings on objective cognitive testing. Patients with SCD have reduced working memory, an integral component of language comprehension, learning, and reasoning [96]. Other studies show that these patients have reduced attention and selective visual scanning than age-matched healthy unrelated controls. These cognitive deficits can often impact their ability to care for themselves and their adherence with medications. Educating patients about these anticipated changes over time can allow identification and delivery of educational and occupational support in school and the workplace.

Quality of Life Estimation Tools  dult Sickle Cell Quality of Life Measurement A Information System The Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-Me) is a patient-reported outcome measurement system that evaluates the physical, social, and emotional impacts of living with SCD [97]. The questionnaire uses five items in each of six categories including emotional, pain episodes, pain impact, sleep impact, social functioning, and stiffness. It also incorporates nine questions about the patient’s individual medical history. The reliability of this tool has been well demonstrated, and patients can fill out the questions themselves, however, the length of questionnaire often precludes its routine use in the clinic setting [98–100].  atient-Reported Outcome Measurement P Information System The Patient-Reported Outcome Measurement Information System (PROMIS) is a comprehensive tool that evaluates the physical, mental, and social health of patients across multiple disease states including patients with SCD [101, 102]. Specific tools are directed for pediatric patients with accompanying parent or guardian questionnaires with a separate tool tailored for adult patients [101, 103]. With four to six item questionnaires across a variety of domains, the individual components of PROMIS can be used independently to evaluate a single domain or can be collectively used with a common metric score that has been weighed against the mean US general population. The PROMIS has also been studied in conjunction with other tools including the ASCQ-Me [100, 104].

Palliative Care and Sickle Cell Disease The utilization of the palliative care team as an advocate for the SCD patient or as a facilitator for improved communication around symptom management has been proposed [105,

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106]. Because of the physical, psychological, and emotional toll that the disease can take on patients and their families, initiating and building an open dialog that encourages and empowers patients to express how their disease plays into their daily activities and relationships can be an important tool in their treatment [107]. Palliative care providers can help young patients and their caregivers set goals and expectations while allowing them to revise these goals as they enter adulthood and become more independent. At the same time, integration of the palliative care team can help provide additional guidance on pain management and additional symptoms that can accompany VOCs. Finally, while advances in the disease are allowing patients to live a more full and robust life, the considerable morbidities of SCD along with its mortality warrant ongoing discussions about goals of care at the end of life and advance care planning. Our palliative care colleagues should be cognizant of the unique relationship that is forged between a patient and their medical team when they have faced a disease that has been present since childhood and that may impact other members of their families. Some patients have seen older family members suffer from comorbidities or die from the disease with those experiences playing a critical role in their own decision-­ making. At the same time, the fact that SCD primarily impacts people of color lends itself to important questions about health disparities and social determinants of health that call for an ongoing reevaluation of how we establish and build trust. These imperative discussions in the care of patients with SCD will only benefit further from the additional perspectives of our palliative care colleagues.

Hemophilia A and B Overview  pidemiology and Patterns of Inheritance E Hemophilia A and B are X-linked bleeding diatheses defined by the absence or reduced production of coagulation Factor VIII and Factor IX, respectively [108]. Hemophilia A occurs in 1 in every 5000 live male births, and Hemophilia B occurs in 1 in every 30,000 live male births [109]. A vast number of point mutations, frameshift mutations, or missense mutations in the factor VIII or factor IX genes have been identified. Being X-linked, hemophilia affects males predominantly, female carriers can have varying degrees of symptoms rarely augmented by lyonization [110].  isease Manifestations, Signs, and Symptoms D Hemophilia A and B are categorized as mild, moderate, or severe based on the degree to which factor activity is reduced. Patients with undetectable factor activity (5% have moderate or mild disease, respectively [108]. Patients with severe hemophilia bleed spontaneously into their joints and muscles, while mild and moderate hemophiliacs have less severe bleeding patterns. Repeated bleeding into joints leads to the development of “target joints” and hemophilic arthropathy (HA), characterized by synovial proliferation along with bone and cartilage destruction [111]. Arthropathy can occur during childhood, and joint status can worsen with increasing age. The primary manifestation of HA is pain, but many patients will also describe a sense of fullness or swelling in the joint along with overlying erythema. On physical examination, the joint may appear edematous or boggy or may have no outward signs of injury aside from pain to palpation or with passive or active motion. Similar to joint bleeds, muscle bleeds can occur spontaneously or with injury. In addition to pain and swelling in the muscle, compartment syndrome can occur if bleeding is unabated, especially if the bleed occurs in the muscles of the arm or leg [112]. While less prone to occur spontaneously, intracranial bleeds after a traumatic event can be potentially devastating as can bleeds in the thoracic or abdominal cavities after injury [113].

Treatment Options In 1973, the National Hemophilia Foundation launched a campaign aimed at providing comprehensive services to patients with bleeding disorders at a single site [114, 115]. The goal of these comprehensive Hemophilia Treatment Centers (HTCs) was to meet the medical, physical, psychological, emotional, and social needs of patients with hemophilia [116]. Today, there are 141 federally funded HTCs in the US which manage both acute and preventative aspects of this disease, where the patient is evaluated and treated by each member of the multidisciplinary team. A federally funded HTC mandates that patients have access to a hematologist with experience in the management of bleeding disorders in addition to nurses, social work, and physical therapists with special expertise with this patient population [116]. Some centers will manage patients from infancy into adulthood while others manage only pediatric patients and then transition them to nearest adult centers. Pediatric centers often provide patients and their families access to genetic counselors, child life specialists, educational counselors, and nutritionists. Whereas many adult centers have integrated pharmacists, dental care, and primary care providers into their teams. HTCs also allow patients access to ongoing national and international clinical trials focused on improving the diagnosis and treatment of hemophilia. HTCs remain the primary site for the acute treatment and prophylaxis of bleeding episodes. The treatment and prevention of bleeding episodes involve replacement of the missing clotting factor, which may be achieved using fresh frozen plasma (FFP), plasma derived or recombinant factor concen-

S. S. Azar and S. Gopal

trates, and other novel therapies. Administration of FFP at 20–40 mL/kg (the equivalent of 4–6 units in an adult) will raise the levels of deficient factor by approximately 20% [117]. FFP however also carries the risks associated with blood product transfusions coupled with the additional volume of 250 mL with each unit. The development of plasma-derived coagulation factor concentrates in the 1970s and 1980s allowed patients a treatment with markedly reduced fluid volume and the capacity to self-manage symptoms via an intravenous infusion at home [114]. Proprietary methods of viral inactivation have allowed these plasma-derived products to become increasingly safe. In 1992, the FDA approved the first recombinant factor VIII product and subsequently many recombinant factor VIII and factor IX products have been produced and are now standard of care in the management of hemophilia [115]. Modification of these recombinant products through PEGylation or the addition of an immunoglobulin chain (Fc) component has extended the product half-life allowing patients to dose less frequently or use lower doses [118]. Within the past 5 years, hemophilia management has dramatically shifted with the first introduction of non-factor treatment options [119]. In 2017, the FDA approved the bispecific monoclonal antibody, emicizumab for patients with hemophilia A. Emicizumab has binding sites for factor IX and activated factor X, and plays the role that factor VIII ordinarily would in the coagulation cascade [120]. The advantage of this medication over traditional factor replacement is that it can be injected subcutaneously rather than intravenously, sparing patients the need to access their own veins. After a weekly loading dose for 4 weeks, the medication can then be injected weekly, every 2  weeks, or even every 4 weeks, thus liberating patients from infusing factor two or three times weekly as is required in most prophylactic regimens. Additionally, the advent of molecularly directed nucleic acid-targeting therapies is poised to further revolutionize the management of hemophilia [120, 121]. Ribonucleic acid inhibitor (RNAi)-based treatments treat hemophilia without replacing the absent or reduced protein. By targeting anticoagulant proteins like tissue factor pathway inhibitor (TFPI) or activated protein C (APC), these treatments aim to adjust the “hemostatic teeter-totter” that is off-balance through the endogenous absence of clotting factor [119, 120, 122]. Gene therapy aimed at increasing endogenous production of factor via hepatotropic vectors poses a potentially exciting approach to the management of hemophilia [123]. While prior attempts gave rise to mild augmentation of native factor production at best, newer approaches currently in clinical trials aim to transition patients with severe hemophilia to moderate or mild disease [123, 124]. While early data in this field is very promising, the practical limitations in adopting this into routine clinical practice remain.

4  Serious Blood Disorders: A Focus on Sickle Cell Disease and Hemophilia

 isease Complications: Inhibitor Formation D and Treatment A considerable challenge in treating patients with hemophilia is the development of antibodies or “inhibitors” that neutralize infused clotting factor. These inhibitors are at greatest risk of occurring in the first 30–50 days after exposure to exogenous factor and as a result, are most often first detected in childhood [125, 126]. Eradication of an inhibitor can be achieved through use of immune tolerance induction (ITI) therapy [127]. This approach utilizes high doses of exogenous factor infused daily over several months in an effort to tolerize the immune system to the absent factor ­protein. This treatment is expensive and burdensome for patients, and the only has an efficacy of 50% [127]. The presence of an inhibitor not only prevents the continued use of exogenous factor but also necessitates a change in the treatment plan. Bypassing agents such as recombinant factor VIIa (rFVIIa), factor eight inhibitor bypassing agent (FEIBA), and emicizumab are potential treatment options for patients with inhibitors [127, 128]. Each of these approaches has its own limitations, rFVIIa and FEIBA are expensive, breakthrough bleeds can still occur, have unfavorable pharmacokinetics requiring more frequent dosing (every 2–4  h in the case of rFVIIa) for an active bleed, and lack a laboratory measure for monitoring their efficacy. In the absence of bypassing agents, plasma-derived or recombinant factor products can be used at two to four times standard dosing temporarily in the setting of an acute bleed [128]. This will likely augment the inhibitor titer but should be restricted to emergency settings. Emicizumab has been approved by the FDA to treat congenital hemophilia A with inhibitors based on favorable clinical trial data with a significant decrease in bleeds [121, 129]. Notably, the development of alloantibodies against exogenous factor in patients with congenital hemophilia is biologically different from the autoantibodies that can develop in otherwise healthy individuals and induce acquired hemophilia. The long-term management of the two phenomena is different even though similar medications can be employed to treat acute bleeding in both settings.  rognosis and Lifespan Considerations P Prior to the introduction of plasma-derived and recombinant factor products, most patients with hemophilia would struggle to survive into adulthood. With these developments and with the introduction of the HTC comprehensive care model described above, most patients with hemophilia are now able to lead a full life [130, 131]. Significant strides have been made in the improvement of disease mortality sparking new discussions about the management of hemophilia in the aging population, including management of complications such as heart disease and high blood pressure [130–132]. The approach to maintaining patients with hemophilia on

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anticoagulants or antiplatelet agents after suffering thrombotic events, myocardial infarctions, or cerebrovascular accidents poses significant clinical conundrums [133]. Likewise managing patients with hemophilia in the setting of platelet altering chemotherapeutic regimens has become an emerging challenge as these patients develop malignancies often seen only in the last decades of life. As the current generation of patients with hemophilia age, identification of the best practices is required in managing joint pathology that developed over a full lifespan of bleeds [132].

Transitions of Care Pediatric to Adult Transitions With patients with hemophilia now able to live well into adulthood, the transition from pediatric to adult care has become an important priority of national hemophilia organizations for the last several years [134, 135]. In childhood, patients will have the support of parents or guardians who can help them detect and treat a bleed, bring them to appointments at the HTC, and inform schools about management considerations. As they age and become more independent, patients must learn to acquire many of these disease-­ management skills [136]. Many HTCs have established formal transition programs to help patients achieve milestones on their way to adult care [137]. Transition programs often begin by introducing the patient to the adult clinician and her or his team, if separate from the team caring for the patient in the pediatric setting. Many lifespan centers who see patients from infancy into adulthood will have the same social workers, nurses, or physical therapists who can provide valuable continuity for these patients. Nursing and physician team members can coach patients on how to recognize the signs and symptoms of a bleed and how to reconstitute and infuse factor [135, 136]. Social workers are imperative in assisting patients with changes in insurance as they shift from their parents’ plans onto their own. At the same time, social work can provide vocational or education guidance as adolescent patients plan for their future [134, 136]. It is critical to assure patients that their bleeding disorder does not prevent them from attending college or starting a job and that the HTC can provide resources and support to assure that the symptoms of the disease do not impact the quality of their studying or work. Physical therapy and athletic training can help improve strengthening and balance while initiating healthy lifestyle habits that can support them for decades to come. Inpatient to Outpatient Transitions and Perioperative Management Despite the innovations in the management of patients with hemophilia, acute bleeds that necessitate inpatient manage-

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ment, and surgical interventions and procedures continue to occur. In the era of the aging hemophilia population with significant and debilitating arthropathy, joint replacement surgeries have become very common and require extensive coordination between the surgeons, anesthesiologists, inpatient and outpatient teams, physical therapists, social workers, and financial staff [138]. The HTC plays a central role in setting a factor support plan and coordinating care across specialties. HTCs also develop mechanisms to support patients who need help adjusting to a new and more vigorous factor infusion schedule after discharge, manage intravenous access, obtain insurance authorization for prescription ­coverage, and ensure access to clotting factor [139–141]. Efforts to improve and standardize these processes remain the subject of study and quality improvement interventions at HTCs across the country. At the center of all of this communication, it is imperative that the patient feel comfortable and confident that their hemophilia will not be a barrier to their safe and timely recovery.

 emophilic Arthropathy and Pain H Management

Mo st da ys

Integration of Physical Therapy The role of physical therapy in the acute and long-term management of patients with hemophilia cannot be overstated. Physical therapy has been shown to reduce pain in the setting of an acute bleed and more rapidly restore joint function after a bleed has resolved [147, 148]. Beyond this, the inte-

ys da e m So n now Unk

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Unknown

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Every da y

 verview and Factor Prophylaxis O As described above, HA remains one of the hallmarks of the disease and one of its most life-altering complications [111] (Fig.  4.2). Injury to the joint space through the recurrent

deposition of blood over time leads to changes in the architecture and integrity of the joint and can give rise to crippling pain, reduced mobility, and decreased function [142]. At the same time, factor VIII may play a role in bone health and development overall and thus the combination of factor deficiency and recurrent joint bleeds can cause long-term skeletal damage [143, 144]. In her seminal work, Dr. Marilyn Manco-Johnson and colleagues identified that the integration of routine prophylaxis with exogenous factor could slow the development of HA and reduce the number of bleeds overall [145]. This pediatric study paved the way for prophylaxis to become the standard of care in patients with frequent bleeds [146]. Today, patients with severe hemophilia A or B or patients with mild or moderate disease that still manifest frequent bleeds are initiated on factor prophylaxis. However, maintaining a strict prophylaxis regimen can be taxing for even the most diligent patient and even a flawlessly followed prophylactic regimen will still give rise to intermittent bleeds and hence these patients often need therapy managed closely by the HTC.

Fig. 4.2  According to data from Centers for Disease Control (CDC) Registry for Bleeding disorders, this figure describes the distribution of chronic pain due to bleeding disorder among participants in the hemophilia registry over 12 months. The data reveal that 24.46% of patients

with hemophilia reported chronic pain, of which a third reported that they had it every day. Registry data include unique participants enrolled since December 2013 as reported at the time of enrollment [190]

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Ev er y

da y

4  Serious Blood Disorders: A Focus on Sickle Cell Disease and Hemophilia

Unknown

Mos

ys t da

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e da ys

r ve n Ne now k Un Fig. 4.3  Frequency of opioid use in the treatment of chronic pain in patients with hemophilia per the CDC Community Counts registry over 12 months. Of the available responses, 10% of patients with hemophilia reported opioid use with most using opioids some days [190]

gration of physical therapy has been shown to improve balance and strength while improving overall joint outcomes as patients age [148–150]. The National Hemophilia Foundation’s Physical Therapy Working Group has developed guidelines specifically for physical therapy assessment and management of patients with hemophilia in various settings. Current recommendations suggest these patients be evaluated by a hemophilia-trained physical therapist at least once annually.

 onsteroidal Anti-inflammatory Drugs (NSAIDs) N and Opioids NSAIDs are commonly used for the management of arthritis; however, their use in HA has been limited because of the propensity to induce upper gastrointestinal bleeding, a risk made that much more challenging with an underlying bleeding diathesis [151]. The selective cyclooxengase-2 (COX-2) inhibitors offer a more promising alternative for patients with hemophilia [151–153]. While providing a comparable analgesic effect, these agents also offer a reduced risk of upper gastrointestinal bleeding. A multicenter case-control study in patients with hemophilia assessed rates of upper gastrointestinal bleeds and determined that the risk increased in the first month of NSAID use but did not increase in patients who were using a COX-2 inhibitor over the same period [154]. Current evaluations of the COX-2 inhibitor, rofecoxib for the treatment of HA are underway [155]. Limited data guide the use of opioids in the long-term pain management of patients with hemophilia [156]

(Fig.  4.3). In their 2005 recommendations, the World Federation of Hemophilia discouraged the use of opioids in the management of HA and subsequently, anecdotal data and expert advice have suggested approaching patient’s risks and benefits individually. In one small cohort of 183 adult patients from two HTCs, about half of the patients used chronic pain medication, defined as the use of analgesic drugs for more than 3 months consecutively [157]. Of those, 21% were on a opioid-­ containing regimen and severity of disease was a predictor of opioid exposure odds ratio 3.14 [95% CI, 1.6–6.2]; P 500/uL) to ensure efficient leukapheresis for product manufacture. Finally, the patient’s cancer must express the appropriate CAR-T cognate antigen (e.g., B-lymphoblasts from a patient with B-ALL must express CD-19 if the patient is being considered for Tisagenlecleucel [Kymriah®], an anti-CD-19 CAR construct). Antigen expression is generally confirmed by flow cytometry on blood/tissue specimens. From a palliative care perspective, CAR  T-cell therapy represents an exciting new option for patients with advanced malignant disease who may not previously have had further curative options. As palliative care clinicians, special attention should be paid to the prognostic uncertainty associated with these therapies. Although remission is possible, it is not guaranteed, nor is the long-term durability of these outcomes known [10, 11]. Thus, clinicians should seek to understand their patients’ expectations of this novel therapeutic approach and assist with contextualizing and framing their understanding. As with all novel and experimental therapeutics, careful consideration of a patient’s goals, the potential risks and benefits of a given therapy, and the expected disease trajectory should be discussed with patients and caregivers.

Indication Pediatric (