PracticeUpdate Conference Series ASH 2018

ISSN 2208-150X (Print) ISSN 2208-1518 (Online)

60 TH AMERICAN SOCIETY OF HEMATOLOGY ANNUAL MEETING 1–4 DECEMBER 2018 • SAN DIEGO, CALIFORNIA, USA

THE BEST OF ASH 2018 Shorter Course of CHOP + Rituximab Noninferior to Standard of Care in Younger Patients With DLBCL Combining CAR T-Cell Therapy With PD-1 Checkpoint Inhibitors Could Improve Response Persistence Luspatercept Reduces Need for Blood Transfusions Among Patients With Beta Thalassemia Ibrutinib-Based Therapy Beats Standard of Care as First-Line in Young Patients With CLL Daratumumab Improves Outcomes in Fragile Patients With Multiple Myeloma

RETHINK WHAT’S POSSIBLE... ZYDELIG ® (idelalisib)

PBS LISTED 1

ZYDELIG – a first-in-class oral PI3K δ inhibitor – is PBS listed for the treatment of:

Double-refractory FL * 2

*As monotherapy for the treatment of patients with FL which is refractory to at least two prior systemic therapies. The disease must be refractory to rituximab and an alkylating agent. 2

Relapsed CLL or SLL † 2

† In combination with rituximab for the treatment of adult patients with CLL or SLL upon relapse in patients for whom chemo-immunotherapy is not considered suitable. 2

FL: follicular lymphoma; CLL: chronic lymphocytic leukaemia; SLL: small lymphocytic lymphoma.

PLEASE REVIEW PRODUCT INFORMATION BEFORE PRESCRIBING. PLEASE REFER TO MINIMUM PRESCRIBING INFORMATION ON THE INSIDE BACK COVER. FOR FULL PBS LISTING PLEASE SEE PRIMARY ADVERTISEMENT ON INSIDE BACK COVER.

References: 1. Pharmaceutical Benefits Schedule. Available at: www.pbs.gov.au. Accessed December 2018. 2. Zydelig Product Information, 26 October 2017.

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Contents

ASH 2018 • 1–4 December 2018 • San Diego, California, USA BY THE PRACTICEUPDATE EDITORIAL TEAM

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4 Shorter Course of CHOP + Rituximab 5 Expedited Genetic Screening Feasible for Detecting Subtypes of Acute Myeloid Leukemia 6 Combining CAR T-Cell Therapy With PD-1 Checkpoint Inhibitors Could Improve Response Persistence 7 L-Glutamine Benefits Consistent Regardless of History of Sickle Cell Disease Crises 8 Microbiome Injury Prior to Hematopoietic Stem Cell Transplantation Predicts Survival Noninferior to Standard of Care in Younger Patients With DLBCL

10 Hydroxyurea a Feasible Sickle Cell Therapy in Sub-Saharan Africa 11 First Transplant Following CAR T-Cell Therapy Boosts Leukemia-Free Survival in ALL 12 Doctors Underestimate the Impact of Fatigue Related to Immune Thrombocytopenia 13 Smoking Linked With Poorer Outcomes In Newly Diagnosed ALL Treated With TKIs 14 Older Patients With CLL See Better Outcomes With Ibrutinib Than Chemoimmunotherapy

15 Luspatercept Reduces Need for Blood Transfusions Among Patients With Beta Thalassemia 16 Direct Oral Anticoagulants Safely Reduce Clotting Risk In Outpatient Cancer Setting 16 Ibrutinib-Based Therapy Beats Standard of Care as First-Line in Young Patients With CLL 18 Daratumumab Improves Outcomes in Fragile Patients With Multiple Myeloma 19 Emapalumab Safe and Effective in Pediatric Patients With Primary HLH 20 Tisagenlecleucel Effectively Treats ALL in Update of ELIANA Trial

The production and distribution of this publication is sponsored by Gilead Sciences. The provision of this information is not intended to advocate any use not covered by the Product Information. Please check that the product is approved for use and always consult the Product Information before prescribing.

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ASH 2018 • PRACTICEUPDATE CONFERENCE SERIES

PRACTICEUPDATE ONCOLOGY BOARDS AND CENTERS OF EXCELLENCE PracticeUpdate is guided by a world-renowned Editorial and Advisory Board that represents community practitioners and academic specialists with cross-disciplinary expertise. Our centers of excellence in the treatment of advanced prostate cancer, brain cancer, metastatic breast cancer and renal cell carcinoma leverage technology to create a collaborative and comprehensive way to improve patient care. These unique centers have the key advantage of a real world academic center as well as the features and enhancements that only PracticeUpdate and Elsevier can provide to foster an expert-led team approach that helps you stay ahead.

PracticeUpdate® is a registered trademark of Elsevier Inc. ©2019 Elsevier Inc. All rights reserved. ABOUT For a complete listing of disclosures for each board member and editorial contributor, please refer to their profile on PracticeUpdate.com PracticeUpdate ’smission istohelpmedicalprofessionals navigatethevastarrayofavailable literatureand focuson themostcritical informationfortheirpatientsandpractice. PracticeUpdate Conference Series is a collection of key research from leading international conferences, reviewed by the PracticeUpdate editorial and advisory board, made available in print format. These news highlights and more are also available online at PracticeUpdate.com PracticeUpdate and the PracticeUpdate Conference Series are commercially supported by advertising, sponsorship, and educational grants. Individual access to PracticeUpdate.com is free. Premium content is available to any user who registers with the site. While PracticeUpdate is a commercially-sponsored product, it maintains the highest level of academic rigour, objectivity, and fair balance associated with all Elsevier products. No editorial content is influenced in any way by commercial sponsors or content The PracticeUpdate Conference Series provides highlights of key international conferences for specialist medicalprofessionals.The ideasandopinionsexpressed in this publication do not necessarily reflect those of the Publisher. Elsevier will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made.Pleaseconsult the fullcurrentProduct Information before prescribing any medication mentioned in this publication. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer. The production and distribution of this publication is sponsored by Gilead Sciences. It contains content published in accordance with the editorial policies of Elsevier’s PracticeUpdate.com. Content was produced by Elsevier with no involvement by Gilead Sciences. All content printed in this publication can be found on PracticeUpdate.com SALES Matthew Buttsworth m.buttsworth@elsevier.com Linnea Mitchell-Taverner l.mitchell@elsevier.com PRODUCTION Content was originally published on PracticeUpdate.com Production of this issue was executed by: Editorial Manager A nne Neilson anne.neilson@elsevier.com Editorial Project Manager Carolyn Ng Designer Jana Sokolovskaja Cover: Destruction of leukemia cell/gettyimages.com ISSN 2208-150X (Print) • ISSN 2208-1518 (Online) contributors. DISCLAIMER

PRACTICEUPDATE ONCOLOGY BOARD Editor-in-Chief Lee Schwartzberg MD, FACP

Associate Editors

Isabel Cunningham MD Adjunct Associate Research Scientist, Division of Hematology Oncology, Columbia University College of Physicians and Surgeons, New York Axel Grothey MD Consultant, Division of Medical Oncology, Department of Oncology, Mayo Clinic; Professor of Oncology, Clinical and Translational Science, Mayo Graduate School, Rochester, Minnesota

Executive Director, West Cancer Center; Professor of Medicine and Division Chief of Hematology/ Oncology, The University of Tennessee Health Science Center, Tennessee

Advisory Board

Benjamin Anderson MD, FACS Professor of Surgery and Global Health-Medicine, University of Washington; Director, Breast Health Global Initiative, Fred Hutchinson Cancer Research

David Henry MD Clinical Professor of Medicine, Pennsylvania Hospital, Philadelphia, Pennsylvania

Center, Seattle, Washington Barbara Ann Burtness MD

Eric Jonasch MD Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine; Director, VHL Clinical Center, The University of Texas MD Anderson Cancer Center, Houston, Texas Jeffrey Kirshner MD, FACP Partner of Hematology Oncology Assoc of Central New York, East Syracuse; Director of Research, HOACNY Community Clinical Oncology Program, New York Howard Scher MD Chief, Genitourinary Oncology Service, Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan-Kettering Cancer Center, New York David Straus MD Attending Physician, Lymphoma Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York Roger Stupp MD Professor of Medicine, Neurology and Neurological Surgery, Northwestern University Feinberg School of Medicine; Co-Director, Northwestern Brain Tumor Institute; Associate Director for Strategic Initiatives, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, Illinois Sara M. Tolaney MD, MPH Assistant Professor of Medicine, Harvard Medical School; Associate Director of Clinical Research, Breast Oncology; Associate Director, Susan F. Smith Center for Women’s Cancers; Senior Physician, Dana-Farber Cancer Institute, Boston, Massachusetts

Professor of Medicine (Medical Oncology); Disease Aligned Research Team Leader, Head and Neck Cancers Program; Co-Director, Developmental Therapeutics Research Program, Yale Cancer Center, New Haven, Connecticut Roxana Dronca MD Assistant Professor of Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota Wilfried Eberhardt MD Associate Director, Regional Outreach West German Cancer Centre, University Hospital of University of Duisburg-Essen, Germany Wafiq S. El-Deiry MD, PhD, FACP Deputy Cancer Center Director, Translational Research Program; Co-Leader, Molecular Therapeutics Program; Professor of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania Rafael Fonseca MD Chair, Department of Internal Medicine; Getz Family Professor of Cancer, Mayo Clinic School of Medicine, Phoenix/Scottsdale, Arizona Andre Goy MD Chairman and Director, John Theurer Cancer Center; Chief of Lymphoma, John Theurer Cancer Center, Hackensack University Medical Center, New Jersey

Annette Hasenburg Prof.Dr.med Director, Obstetrics and Gynecology, Mainz University Medical Center, Mainz, Germany

ELSEVIER AUSTRALIA ABN 70 001 002 357 475 Victoria Avenue Chatswood NSW 2067 Australia Locked Bag 7500 Chatswood DC NSW 2067 Printed in Australia. EMCS021902

PRACTICEUPDATE BENIGN HEMATOLOGY BOARD Editor-in-Chief Michael H. Kroll MD Professor of Medicine, Chief of the Section of

Associate Editors

Rakhi Naik MD MHS Associate Director for Hematology,

Cristhiam M. Rojas Hernandez MD Assistant Professor of Hematology, MD Anderson Cancer Center, Houston, Texas

Benign Hematology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas

Hematology/Oncology Fellowship Program; Assistant Professor of Medicine, Hematology, Johns Hopkins Medicine, Baltimore, Maryland

PRACTICEUPDATE ONCOLOGY EDITORIAL CONTRIBUTORS Kelly N. Casteel MD Fellow in Hematology/Oncology, MD Anderson Cancer Center, Houston, Texas

Jarushka Naidoo MD Assistant Professor of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins, Baltimore, Maryland Moshe Ornstein MD Genitourinary Medical Oncologist, Cleveland Clinic Taussig Cancer Institute, Cleveland, Ohio

Erin Schenk MD, PhD Assistant Professor of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Denver, Colorado Jeffrey Wiisanen MD Hematology/Medical Oncology Fellow, Mayo Clinic School of Graduate Medical Education, Rochester, Minnesota

Eric Fountain MD, MA Fellow in Hematology/Oncology, MD Anderson Cancer Center, Houston, Texas

Neil Majithia MD Fellow in Hematology/Oncology, Mayo Clinic School of Graduate Medical Education, Rochester, Minnesota

ADVANCED PROSTATE CANCER CENTER OF EXCELLENCE Editors-in-Chief Thomas J. Guzzo MD, MPH

Associate Editors

Brian E. Lewis MD, MPH Assistant Professor of Clinical Medicine, Department of Hematology and Medical Oncology, Tulane University School of Medicine, New Orleans, Louisiana

Chief of Urology, Associate Program Director, University of Pennsylvania Perelman Center for Advanced Medicine, Philadelphia, Pennsylvania

Oliver A. Sartor MD Laborde Professor, Cancer Research, Medicine and Urology Departments, Tulane School of Medicine, New Orleans, Louisiana

Jonathan Silberstein MD, MBA Candidate 2018 Assistant Professor of Urology; Chief, Section of Urologic Oncology, Department of Urology, Tulane University School of Medicine; Chief of Urology Service, Department of Surgery, Southeast Louisiana Veterans Health Care Center, New Orleans, Louisiana

BRAIN CANCER CENTER OF EXCELLENCE Editors-in-Chief Minesh P. Mehta MD, FASTRO

Associate Editor

Patrick Y. Wen MD Director, Center for Neuro-Oncology, Dana-Farber Cancer Institute; Director, Division of Cancer Neurology, Department of Neurology, Brigham and Women’s Hospital; Professor of Neurology, Harvard Medical

Manmeet Ahluwalia MD, FACP Dean and Diane Miller Family Endowed Chair in Neuro-Oncology, Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Neurological Institute and Taussig Cancer Institute, Cleveland Clinic; Associate Professor,

Deputy Director, Chief of Radiation Oncology, Miami Cancer Institute, Miami, Florida

School, Boston, Massachusetts

Department of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio

METASTATIC BREAST CANCER CENTER OF EXCELLENCE Editor-in-Chief Lee Schwartzberg MD, FACP

Associate Editors

Reshma L. Mahtani DO Associate Professor, Division of Hematology/ Oncology, Sylvester Comprehensive Cancer Center, University of Miami Health System, Miami, Florida

Lillie D. Shockney RN, BS, MAS University Distinguished Service Professor of Breast Cancer, Administrative Director, Johns Hopkins Breast Center and Cancer Survivorship Programs, Baltimore, Maryland

Executive Director, West Cancer Center; Professor of Medicine and Division Chief of Hematology/Oncology, The University of Tennessee Health Science Center, Tennessee

RENAL CELL CARCINOMA CENTER OF EXCELLENCE Editors-in-Chief Sumanta K. Pal MD Associate Professor, Department of Medical Oncology & Therapeutics Research; Co-Director, Kidney Cancer Program, City of Hope, Duarte, California

Associate Editor

Advisory Board

Eric Jonasch MD Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine; Director, VHL Clinical Center, The University of Texas MD Anderson Cancer Center, Houston, Texas Oliver A. Sartor MD Laborde Professor, Cancer Research, Medicine and Urology Departments, Tulane School of Medicine, New Orleans, Louisiana

Heather R. Greene MSN, FNP, AOCNP Nurse Practitioner, The West Clinic, Memphis, Tennessee

Bradley G. Somer MD Medical Oncologist; Associate Professor of Hematology/Oncology, University of Tennessee Health Science Center; and Senior Partner, West Cancer Center, Memphis, Tennessee

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Shorter Course of CHOP + Rituximab Noninferior to Standard of Care in Younger Patients With DLBCL A shorter course of chemotherapymeans fewer adverse events and amore rapid return to normal activities.

Y ounger patients with diffuse large B-cell lymphoma (DLBCL) may not require a full six cycles of chemotherapy as guidelines currently recommend, according to results of the phase III Flyer Trial. The Flyer Trial investigators hypothesized that a lower-intensity therapeutic regimen of four cycles of CHOP (cyclophosphamide, doxorubicin, vin- cristine, and prednisone) plus six applications of rituximab would be non-inferior to the standard- of-care six cycles of CHOP in younger patients with DLBCL. To test their hypothesis, the investigators enrolled patients aged 18 to 60 years who had stage I or II DLBCL that was considered to be low-risk. A total of 592 patients were enrolled between December 2005 and October 2016: 295 patients were ran- domized to receive the six-cycle CHOP regimen, whereas 293 patients were randomized to receive four cycles of CHOP with rituximab. Patients were enrolled from multiple European centers in Germany, Denmark, Norway, Italy, and Israel. There were no significant differences in demographics (median age 48 years) or protocol adherence between study arms. After a median 66 months of follow-up, the inves- tigators found that the 3-year progression-free survival (PFS) rates in both study arms were not significantly different from each other (94% with the six-cycle regimen vs 96% with the four-cycle regimen plus rituximab, P = .760). The study met its primary endpoint, namely a less than 5.5% impairment in PFS with the four-cycle CHOP plus rituximab regimen relative to the six- cycle standard-of-care regimen (lower limit of 95% confidence interval in difference between treatment arms = 0%). The investigators found that the 3-year event-free survival rates were identical between treatment arms (both 89%), with events including progressive disease, relapse, or death.

Dr. Viola Poeschel

Overall survival (OS) also did not significantly differ between treatment arms. Whereas 3-year OS was 98% in patients receiving six cycles of CHOP, the 3-year overall survival rate in patients receiving four cycles of CHOP plus rituximab was 99%. “Chemotherapy can be reduced without compro- mising prognosis in this population,” concluded study presenter Viola Poeschel, MD, of Saarland University Medical School in Homburg/Saar, Germany. Under the shorter chemotherapy regimen used in this study, patients receive chemotherapy for a total of 84 days, compared with the standard six-cycle chemotherapeutic regimen of 126 days. Dr. Poeschel suggested that the shorter duration of chemotherapy would allow patients to resume their lives more rapidly, without side effects that constrain work and home activities. “Reducing chemotherapy to four cycles also resulted in a reduction of acute adverse events by about a third, which means a significant ben- efit for patients,” Dr. Poeschel told Elsevier’s PracticeUpdate . Whereas 1295 adverse events were observed among the 295 patients who received the longer chemotherapy course, 835 adverse events were observed among the 293 patients receiving the shorter course with rituximab. Dr. Poeschel said she believes that the shorter, non-inferior chemotherapy regimen used in this study will become the new standard of care for younger, low-risk DLBCL patients.

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Expedited Genetic Screening Feasible for Detecting Subtypes of AcuteMyeloid Leukemia Rapid turnaround of screening results translates to rapid initiation of the best targeted therapy. G enetic analysis, performed in 7 days or less, can be used to screen patients for particular subtypes of acute mye-

Of the 285 patients whowere diagnosedwith AML, the researchers were able to assign 273 to therapy within 7 calendar days of their samples arriving at the genomic provider, Foundation Medicine. “We’ve achieved our primary endpoint of assigning therapy within 7 days in over 95% of patients,” Dr. Burd said. “What got us to the 7-day turnaround time is mostly by [Foundation Medicine] prioritizing samples and changing the logistical flow of how they come in,” Dr. Burd told Elsevier’s PracticeUpdate . “And also, by a little bit of what I call ‘brute force’ by going to three shifts a day, so they are processing samples 24 hours a day.” “But the technology will continue to advance, and we’ll see timelines improve, and Foundation Medicine is looking to advance it even further to create shorter turnaround times,” she said, adding that next-genera- tion sequencing technology continues to advance at a rapid pace. Overall, 146 patients have moved on to the study’s second phase, in which they are being treated in 1 of 11 clinical trials for experi- mental AML therapies that are targeting their specific AML subtype. In commenting on the clinical significance of being able to turn around this genetic analy- sis within 7 days, Joseph Mikhael, MD, of the International Myeloma Foundation in Phoenix, Arizona, said, “One of the greatest challenges we face in the concept of personalized med- icine is that by the time you determine what is best for a patient with diseases like AML, in a sense the horse is already out of the barn, and you’ve had to start the patient on treat- ment already, or the disease will progress quite rapidly.” He recalled that when he was in training, he would send out genetic evaluations on AML patients and would not obtain results until patients had already completed their first month of therapy. “So, to be able to get these early is so very fundamental,” he said. “And I know the objec- tive is to reduce the timeframe even further, so we can have closer to real in-time results to influence that individual patient.”

loid leukemia (AML) before they have even begun treatment, according to research presented here at ASH 2018. “Acute myeloid leukemia is the most com- monly diagnosed adult leukemia,” said Amy Burd, PhD, of The Leukemia & Lymphoma Society in White Plains, New York, during her presentation of the study, “and it is also the most lethal.” According to the National Cancer Institute, there will be an estimated 19,520 new cases of AML this year, and the 5-year survival rate is 27.4%. The Beat AML Master Trial, led by the Leukemia & Lymphoma Society, is a col- laboration of researchers, pharmaceutical companies, a clinical research organization, and a genomic provider. “We know that it is a heterogeneous disease,” she added. “Coupled with the increasing evi- dence of efficacy for targeted therapy in AML, we hypothesized that we can improve out- comes by matching patients to the increasing numbers of available targeted therapies.” The primary question the trial addresses is whether a personalized therapy based on genomics can be safely assigned to an AML patient. Expediting this kind of genetic analysis so that it is received within 7 days will help doctors match their patients with the ther- apy best suited to their disease as quickly as possible, something which is critical in treating patients with AML. As explained by Dr. Burd, because AML pro- gresses rapidly, physicians prefer not to wait the 2 or 3 weeks it takes to do a genomic analysis before beginning treatment. Therefore, they are likely to start all of their patients on the same treatment regimen until they determine which subtype a patient has. The researchers enrolled 356 patients over 60 years of age with suspected or confirmed AML between 2016 and 2018. Using samples from these patients, the researchers applied three types of genetic analysis techniques – cytogenetics, polymerase chain reaction (PCR), and next-generation sequencing – to create a genetic profile of each patients.

“In this patient population, four cycles of CHOP in combination with six applica- tions of rituximab are equally effective in eradicating the malignant lymphoma clone,” she said. “This conclusion is confirmed by the observation of similar response and, importantly, identical relapse rates.” Although the relapse rates were similar between arms in the trial, Dr. Poeschel said that she was surprised to find that cumulative relapses appeared to be linear during follow-up. Based on the literature, it is expected that 70% of DLBCL relapses will occur within the first year from diagnosis, with a declining rate of relapse thereafter. Thus, Dr. Poeschel cautioned that the “patients relapsing in our trial might have a different biological background” than would be observed in an unselected population of patients with DLBCL. Because the Flyer trial was designed in the pre-PET era, patients included in the trial were not required to undergo an FDG-PET scan. Dr. Poeschel suggested future studies may investigate whether performing an early PET scanmight allow for clinicians to further de-escalate the chemotherapy regimen given to younger, lower-risk DLBCL patients.

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Combining CAR T-Cell Therapy With PD-1 Checkpoint Inhibitors Could Improve Response Persistence The approach appears to show themost promise in patients with B-lymphoblastic malignancies and early B cell recovery or bulky extramedullary disease.

T he use of checkpoint inhibitors to augment CD19- directed chimeric antigen receptor (CAR) T-cell therapy could both enhance and sustain the benefits of CAR T-cell therapy in patients with relapsed B-cell acute lymphoblastic leukemia (B-ALL), according to the results of a study presented at ASH 2018. Previous research has shown CD19-directed CAR T-cell therapy can induce complete remission in up to 90% of patients with relapsed or refractory B-ALL. However, according to Shannon Maude, MD, PhD of the Children’s Hospital of Philadelphia, who presented the study, relapse-free survival drops to 60% within 12 months due to both CD19-positive and negative relapses. These relapses occur during this time because of early CAR T-cell loss, said Dr. Maude. “Our hypothesis was that T cells, upon activation, may become exhausted through activation of immune checkpoint pathways, and that one such pathway – PD-1 – may be involved in early loss of CD-19 CAR T-cells,” said Dr. Maude during her presentation. “Therefore, the combination with PD-1 checkpoint blockade may improve the function of the CAR T cells and their persistence.” Dr. Maude and her colleagues reported on their experience at the Children’s Hospital of Philadelphia in using PD-1 inhibitors in patients with relapsed or refractory B-lymphoblastic malignancies treated with CD19-directed CAR T-cell therapy. Fourteen patients 4 to 17 years of age, treated with CD19-directed CAR T-cell therapy, and who had repeated CAR T cell loss or a partial/no response to the therapy received a PD-1 inhibitor as early as 14 days after CAR T cell infusion and after the resolution of cytokine release syndrome symptoms.

Of those 14 patients, 13 had relapsed B-ALL and the other had B lymphoblastic lymphoma. All were treated with CD19-directed CAR T-cell therapy in combination with the PD-1 inhibitors pembrolizumab (n=13) or nivolumab (n=1). Outcomes were reported in three settings. The first setting involved patients with partial or no response to CD19-directed CAR T cells, where Dr. Maude and colleagues hypothesized that the activation of the T cells may lead to activation of the checkpoint path- way and block a full response. “In that group of patients, we added PD-1 blockade and, unfortunately, did not see an effect in this small group, where 4 of 4 patients had progression of their disease with 1 patient’s progression marked by reduced CD190 progression, which was probably the mode of escape from CD19 CAR T cells,” Dr. Maude said. The second setting included 6 patients who responded to CAR T cells but had poor persistence marked by early B cell recovery. These patients were reinfused with a CAR T-cell product followed by infusion with PD-1 blockade. Of these patients, 3 had return of B-cell aplasia and sustained complete response with B-cell aplasia, showing continued persistence of their CAR T cells. “In the third situation, we had patients with bulky extramedullary disease and we hypothesized that the PD-1 checkpoint pathway may be activated though the microenvironment in that extramedullary situation,” she explained during her presentation. “We added PD-1 blockade and saw 2 of 4 patients had sustained complete response, and 2 of 4 had a partial response.”

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L-Glutamine Benefits Consistent Regardless of History of Sickle Cell Disease Crises But findings are limited by their dependence on post hoc

analyses in small subgroups. T herapy with Endari, a prescrip- tion-grade pharmaceutical form of L-glutamine, was consistently effective in reducing the frequency of pain episodes in both pediatric and adult sickle cell disease patients, irre- spective of their history of sickle cell crises. In 2017, the United States Food and Drug Administration (FDA) approved L-glutamine powder for oral administra- tion to reduce the acute complications of sickle cell disease in patients aged 5 years and older. The FDA approval was based on the results of a randomized, double-blind, placebo-controlled trial of L-glutamine in 230 patients aged 5 to 58 over 48 weeks. With that approval, L-glutamine became only the second therapy – along with hydroxyurea – for the prevention of acute vaso-occlusive pain events. Patients in the trial were randomly assigned in a 2:1 ratio to receive either L-glutamine (152 patients) or placebo (78 patients). L-glutamine, whether administered alone or with hydroxyurea, reduced the frequency of sickle cell pain episodes by 25% (a median of three sickle cell crises for the L-glutamine study arm compared with four in the placebo arm) and hospitalizations by 33% (a median of two hospitalizations in the L-glutamine group and three in the placebo group). These results were achieved with no serious adverse events in the treatment as compared with the placebo arm. Here, researchers led by Yutaka Nihara, MD, of Emmaus Medical, Inc. in Torrance, California, manufacturers of Endari, and the University of California in Los Angeles, further evaluated the trial data in order to examine any differences in the effect of L-glutamine on sickle cell patients depending on the frequency of their sickle cell crises prior to study screening. For this analysis Dr. Nihara and his colleagues divided patients into three

categories: those who had two sickle cell crises in the year previous to screening (low, n=79), those who expe- rienced three to five (moderate, n=112), and those who experienced six or more (high, n=38), using data collected from their medical records when they entered the trial. Of the patients in the low subgroup, those in the treatment arm had a mean of 2.57 crises, compared with 2.95 in the placebo arm. Of those patients in the moderate subgroup, those in the treat- ment arm had 3.19 crises, compared with 4.28 in the placebo arm. Finally, among those in the high subgroup, those in the treatment arm had 4.77 crises, while patients in the placebo arm had 5.85. The ratio of the rate of crises in the L-glutamine arm to the rate of crises on placebo was similar in all categories (low 0.87, moderate 0.74, and high 0.82, with a rate ratio < 1.0 favoring the L-glutamine treatment effect). “The apparent lower rate ratio in those that had 3 to 5 crises in the year prior to screening may be due to having the largest sample size of the three cate- gories,” Dr. Nihara and his colleagues observed, and concluded that the analysis “indicates that the benefit of L-glutamine treatment observed in the phase III trial is consistent regardless of the history (1 year) of crises prior to the initiation of L-glutamine therapy.” In commenting on this study, John J. Strouse, MD, PhD, of Duke Health in Durham, North Carolina, told Elsevier’s PracticeUpdate that while it shows similar relative risk reduction in the sub- groups, “all subgroup analyses should be interpreted carefully based on small numbers and post hoc analyses.” As for how he uses this new therapy in practice Dr. Strouse said, “I use L-glutamine in patients that cannot tolerate hydroxyurea, or I will add it to hydroxyurea if their response is inadequate to hydroxyurea alone.”

Fever and symptoms of cytokine release syndrome were seen in 3 patients within 2 days of starting pembrolizumab. Other adverse effects associated with PD-1 inhibition included a case each of acute pancreatitis, hypothyroidism, arthralgia, and urticaria, as well as 4 patients with grade 3 to 4 cytopenias, all of which were either tolerable or reversible upon dis- continuation of the treatment. No grade 5 toxicities occurred. Dr. Maude and her colleagues called the response to treatment with PD-1 inhibitors “promising” in the cases of patients with early B cell recovery and bulky extramed- ullary disease. However, they also pointed out that PD-1 inhibition had a partial, but no durable effect, in all 4 B-ALL patients with poor initial marrow response to CAR T-cell ther- apy alone. This suggests, they reported, “a different mechanism such as [activation induced CAR T death] may be responsi- ble for poor initial responses.” “We showed that PD-1 checkpoint inhib- itors can be safely combined with CD19 CAR T-cell therapy and that this mecha- nism may be useful to improve CAR T cell persistence,” Dr. Maude concluded. “This strategy may particularly benefit patients with poor persistence marked by early B cell recovery, as well as those with bulky extramedullary disease.”

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Microbiome Injury Prior to Hematopoietic Stem Cell Transplantation Predicts Survival Strategies that treat microbiome injury pre-transplant may lead to better patient outcomes.

P re-hematopoietic stem cell transplantation (HSCT) microbiota injury is prevalent across institutions and predicts poor overall patient survival, according to research presented at ASH 2018. “The intestinal microbiome harbors the highest density of bacteria in any location on the planet,” said Jonathan Peled, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York, during his presentation. “We have as many bacteria cells in and on our body as we have human cells. We are actual ecosystems walking around.” “Our immune systems are really maintaining homeostasis – or an equilibrium balance – with the bacteria that we co-evolved with,” he added. “You can interpret many immune reactions as perturbations from that equilibrium.” Dr. Peled pointed out that after allogeneic HSCT, there are four causes of death: relapse, infection, graft versus host disease, and organ toxicity. “Each of these outcomes has been associated with the composition of the gut microbiota,” he said. However, these observations have been based on single-center studies that characterized the micro- biota in the first weeks after transplantation. In this study, Dr. Peled and his colleagues hypothesized that microbiota configuration pre-HSCT could also be a predictor of post-transplantation outcomes.

Dr. Peled and his colleagues collected stool sam- ples from 991 adult allogeneic HSCT patients at four international transplant centers (two in the United States, one in Europe, and one in Japan). These patients varied with respect to underlying diagnosis, donor graft sources, conditioning inten- sity, and GVHD prophylaxis. Patients from all four centers had reduced micro- biota diversity pre-HSCT with inverse Simpson index (α-diversity) measurements that ranged from 1.7- to 2.5-fold lower than those values of healthy volunteers (P < .005). And the microbial communi- ties in the majority of patients’ guts went on to be dominated by a single bacterial species. When looking at these pre-HSCT communities across institutions, they found in the largest cohort of 753 patients (one of the transplantation centers in the United States) that pre-HSCT microbiota diversity is associated with patient survival. Those patients in the lowest quartile of pre-HSCT micro- biota diversity had lower overall survival than patients in the highest quartile (P < .009). The study findings demonstrated that HSCT patients across the four institutions in three continents had microbiota configurations that were similar to one another and different from healthy individuals, and

" … if we come up with a way to remediate microbiome injury, there might be time to implement it before the transplant. "

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PRACTICEUPDATE CONFERENCE SERIES • ASH 2018

that it is possible to predict outcomes pre-transplant, said Dr. Peled. “The impli- cation is that if we come up with a way to remediate microbiome injury, there might be time to implement it before the transplant.” What could be done to treat the microbi- ome before transplantation? According to Dr. Peled, strategies could include the use of probiotics, or a prebiotic approach in which patients are given food that promotes growth of beneficial bacteria. Alternatively, a postbiotic approach could be used that emphasizes the use of short- chain fatty acids and indole derivatives, and avoids foods that compromise the mucus barrier. “And we could think about a different anti- biotic strategy; to use or not use different kinds of antibiotics in a rational way," he said. "The bottom line is that these are different strategies that are in develop- ment. This is where many fields are going, and we are trying to take bone marrow transplantation in this direction, as well.”

In an interview with Elsevier’s PracticeUpdate , Dr. Peled emphasized the importance of collaboration with multiple sites in studies like this. For example, the fact that microbiota injury, and the association of diversity with overall survival, was prevalent across geography “is significant because it sug- gests that associations that are made in one center are probably applicable across geography, even though there are differences in clinical practice from center to center, and there are geographical dif- ferences in the natural history of the gut microbiota around the world.” “A lot of correlative research is done in retrospective, observational single-center studies, and we’ve certainly engaged in our share of those,” Dr. Peled added. “But I think it’s time for our field to move beyond that and do multicenter studies with central analysis of specimens. That’s a way to get over the batch effects and the biases that can be introduced with single-center studies.”

© ASH/Curtis Compton 2018

www.practiceupdate.com/c/77028

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ASH 2018 • PRACTICEUPDATE CONFERENCE SERIES

Hydroxyurea a Feasible Sickle Cell Therapy in Sub-SaharanAfrica But financial barriers to widespread use in Africa remain. T he use of hydroxyurea for sickle cell disease, which is the standard of care in the developed world, is also Congo, Kenya, and Uganda), and involves 635 children aged 1 to 10 years.

with patients and their families. In addition, the hydroxyurea, lab tests and transporta- tion to clinics were free of charge. As for safety, the primary safety endpoint was hematological dose-limiting toxici- ties in the first 133 children at each site. Dr. Tshilolo and his colleagues found that just 5.1% of the children in the study had a dose-limiting toxicity within the first 3 months of the study, which they reported was well below the predicted 20% to 30%. Overall, they reported that hydroxyurea was well tolerated with no excess lab toxicities. As for the clinical benefits of hydroxyurea in this study population, the rates of vaso- occlusive pain, acute chest syndrome and transfusions were all reduced by about 50% during the course of treatment. One of the concerns with hydroxyurea treatment is the effect it might have on the incidence of malaria, since sickle cell disease is known to provide its carrier with some protective advantage against that mosquito-borne disease. However, said Dr. Tshilolo during his presentation, “an unexpected result was a reduction in malaria.” Specifically, the rate and severity of malaria (grade 3 or above) decreased from 9.9 to 2.5 events per 100 patient years during treatment. The group of patients on hydroxyurea also saw all-cause mortality decrease from 3.6 deaths per 100 patient years during screening to 1.1 deaths per patient years while on treatment. “Hydroxyurea is feasible, safe and an effective treatment for African children with sickle cell [disease],” concluded Dr. Tshilolo. “Wider access to hydroxyurea [for sickle cell disease] has the potential to save millions of lives in Africa.” As for the possibility of making the drug more widely available in Africa, Dr. Tshilolo suggested that it will probably depend on the pharmaceutical industry’s ability to provide it at an affordable price. “There are companies in Africa that are manufacturing hydroxyurea, but it’s not cheap,” said Ify Osunkwo, MD, of Carolinas Healthcare System in Charlotte, North Carolina, who was moderating the session on sickle cell disease. “It’s prob- ably cheap by American standards, but not cheap by African standards. So, it will be part of efforts going forward to make it more available to a larger variety of patients in the continent.”

Of those 635 children, 4 died during a 2-month screening period before the treatment with hydroxyurea began, while another 25 withdrew from the trial for other reasons. The remaining 606 children began treatment with a modest daily dose of hydroxyurea (15–20 mg/kg/day), which was gradually adjusted based on weight and other criteria to a maximum tolerated dose. After month 6, the dose was esca- lated by 2.5 to 5.0 mg/kg/day every 8 weeks until mild marrow suppression was achieved, typically an absolute neutrophil count <4.0 x 10 9 /L or absolute reticulocyte count <150 x 10 9 /L. Since the trial began, 5% of patients have either died or dropped out of the trial. Of the remaining patients, retention and adherence rates were high, with 97% completing all study visits, while 94% com- pleted all required tests. During his presentation Dr. Tshilolo sug- gested there are several reasons for the high retention and adherence rates in this trial. For example, he said, the trial was well-organized and healthcare workers were able to develop good relationships

effective, safe, accepted, and feasible in children in sub-Saharan Africa, according to research presented at ASH 2018. Unfortunately, explained Leon Tshilolo, MD, of Centre Hospitalier Monkole in Kinshasa, Democratic Republic of the Congo, who presented the study, hydroxyurea is rarely available to sickle cell patients in Africa even though about 75% of the global burden of the disease occurs in sub-Saharan Africa. While data have long supported the use of hydroxyurea in sickle cell patients in areas like the United States, the United Kingdom, and Europe, there are few data regarding its use in sub-Saharan Africa, where not only is the sickle burden extremely high but the health of these patients is also complicated by malnutrition, poverty and other diseases like malaria. The REACH study, which is being coordi- nated by Cincinnati Children’s Hospital, is a phase I/II open-label trial designed to determine the feasibility, effectiveness and safety of hydroxyurea in sub-Saharan Africa. It is being conducted in four sites (Angola, the Democratic Republic of the

www.practiceupdate.com/c/77032

© ASH/Rodney White 2018

PRACTICEUPDATE CONFERENCE SERIES • ASH 2018 10

First Transplant Following CART-Cell Therapy Boosts Leukemia-Free Survival inALL But patients with a history of previous transplantation did not show similar benefits. P atients with acute lymphoblastic leukemia (ALL) who receive their first hematopoietic stem cell trans-

plantation (HSCT) after chimeric antigen receptor (CAR) T-cell therapy have improved leukemia-free survival. In the phase I/II PLAT-02 trial, research- ers analyzed 64 subjects with ALL who underwent CAR T-cell therapy in the form of infusions of SCRI-CAR19v1 in order to evaluate the benefits of consolidative HSCT. According to Corinne Summers, MD, of Seattle’s Children Hospital, who pre- sented results from the trial, while most ALL patients go into remission after CAR T-cell therapy, approximately one-half of patients recur. In the trial, 14 patients either died, relapsed, or did not respond to the CAR T-cell therapy. Of the remaining 50 evalu- able subjects, 34 had a history of at least one prior HSCT, while 16 had no history of HSCT. The 1-year leukemia-free survival for those subjects who were evaluated was 76%. Overall, there was a trend toward better rates of leukemia-free survival among patients who underwent HSCT following infusion with SCRI-CAR19v1, compared with those who did not (P = .076). However, Dr. Summers reported that she and her colleagues continued to see late relapses, including CD19+ relapses at 12 and 27 months, and CD19– relapses at 41 and 37 months after infusion with SCRI-CAR19v1. “Therefore, we aimed to evaluate the role of bone marrow transplant in maintaining leukemia-free survival and overall survival in subjects who gained leukemic remis- sion for more than 63 days after CD19 CAR T-cell therapy,” Dr. Summers said during her presentation. “And we com- pared leukemia-free survival and overall survival between subjects regarding the receipt of allogeneic HSCT following a sustained remission.” “Transplant appears to improve leu- kemia-free survival,” she reported, although she added that she and her colleagues found no difference in over- all survival between the two groups. “We hypothesized this was due to continued

response to therapy following post-CAR relapse,” she said. When evaluating the 16 patients without history of transplant, 13 underwent HSCT after CAR T-cell therapy, and only 1 of these patients relapsed. On the other hand, 2 of the 3 patients without a his- tory of transplant who did not undergo HSCT after CAR T-cell therapy relapsed. There was a trend toward improved leu- kemia-free survival with the use of a first HSCT (P = .057). “Though it’s a small number of subjects, the data suggest there is a leukemia-free survival benefit for those without a his- tory of transplant who pursue a transplant once in remission following CAR T-cell therapy,” Dr. Summers said. Previous studies have shown that patients with a short duration (≤63 days) of B cell aplasia are at an increased risk of relapse following infusion with SCRI-CAR19v1. HSCT was found to be particularly bene- ficial among patients with a short duration of B cell aplasia who attained a complete response and did not relapse prior to day 63. Of the 15 patients with a short duration of B cell aplasia, 6 did not undergo HSCT,

and all experienced recurrence. Among the 9 patients who did undergo HSCT, 1 died and 2 relapsed. The rate of leu- kemia-free survival was superior for those who underwent transplantation (P = .007). As for the 34 patients with a history of transplant prior to CAR T-cell therapy “there does not appear to be a clear benefit to pursue a transplant following CAR T cells,” Dr. Summers said. Of the 10 patients who underwent a second trans- plant, 1 died from transplant complications, while 4 others relapsed. And of the 24 who did not undergo a second procedure, 17 have relapsed. Thus, the role of transplant following CD19 CAR T-cell therapy for patients with a his- tory of transplant is unclear, Dr. Summers said, adding that larger studies are needed. “Despite initial remissions, late leukemic relapse remains a barrier to long-term efficacy following CAR T-cell therapy for B[-cell] ALL,” Dr. Summers said. “Patients without a history of HSCT who achieve a sustained [minimal residual disease]-neg- ative remission following CD19 CAR T-cell therapy may benefit from HSCT.”

www.practiceupdate.com/c/77041

ASH 2018 • PRACTICEUPDATE CONFERENCE SERIES 11

Doctors Underestimate the Impact of Fatigue Related to Immune Thrombocytopenia Patients repeatedly report that fatigue has a major impact on their quality of life.

W hile perceptions of patients with immune thrombocytopenia (ITP) and the physicians who treat them are in alignment when it comes to the effect the overall disease symptom burden has on patient quality of life, those perceptions diverge when it comes to the issue of patient fatigue, according to new research. Specifically, in an international survey of patients and physicians, of the most com- mon signs and symptoms of ITP reported at diagnosis or at any stage of treatment, fatigue was substantially underreported by physicians compared with the percent- age of patients who reported fatigue as a symptom of their disease. I-WISh was a cross-sectional survey of 1,491 patients from 12 countries and 472 physicians from 13 countries that studied the burden of ITP and impact on patient quality of life. Participants completed a 30-minute online survey that included demographics, signs and symptoms, impact of symptoms, and patient–doctor relationships.

The researchers, led by Caroline Kruse of the Platelet Disorder Support Association in Cleveland, found that the most frequent patient-reported signs and symptoms mirrored those reported by physicians. For example, the most frequent symp- tom reported by patients and doctors at diagnosis was petechiae (65% and 83%, respectively). However, fatigue was underreported as a symptom by physicians when compared with patients (30% at diagnosis for phy- sicians compared with 58% for patients). When rating the severity of symptoms (on a 7-point Likert scale, with 7 = ‘the worst imaginable severity’), fatigue was one of the most severe patient-reported symp- toms, scoring ≥5 both at diagnosis (74%) and survey completion (65%). Heavy menstrual bleeding (reported by 84% at diagnosis and 63% at study completion) and anxiety around a sta- ble platelet count (78%; 65%) were also reported as severe, as was thrombosis, which while not common was considered severe (62%; 74%).

Patients considered heavy menstrual bleeding (75%, n=118/158), thrombosis (74%, n=25/34) and fatigue (73%, n=544/743) to be the symptoms they would most like to resolve. Physicians, on the other hand, perceived a number of signs and symptoms as hav- ing a higher impact on quality of life than fatigue (based on a 7-point Likert scale, with 7 = ‘a great deal’). For example, phy- sicians most often identified symptoms such as blood in urine/stool (81%), profuse bleeding during surgery (79%) and men- orrhagia (78%) as having the most impact on a patient’s quality of life, while just 59% believed fatigue has a high impact. And while 66% of physicians reported that ITP-related fatigue reduces quality of life, just 46% identified fatigue as severe (scored ≥5 on a 7-point Likert scale; 7 = ‘completely fatigued’). “The Platelets Disorder and Support Association has conducted numerous focus groups, and we have been told by the tens of thousands of ITP patients and caregivers we serve that debilitating fatigue is one of the most common and most severe patient-reported symptoms of ITP, and many patients say their fatigue is worse when their platelet count is low,” said Ms. Kruse in an interview with Elsevier’s PracticeUpdate . “We often hear from patients that doc- tors dismiss symptoms of fatigue as

" People with ITP regularly cite the stress and anxiety associated with watching their numbers. This all has a huge impact on quality of life, ability to work, go to school, travel, and just enjoy life. " PRACTICEUPDATE CONFERENCE SERIES • ASH 2018 12