® ASH NEWS AND REPORTS JULY/AUGUST 2017 VOLUME 14 ISSUE 4

DIFFUSION FEATURE

More Than an Aspirin a Day to Keep Disparities of Adolescent and Young Adult Patients in Recurrent Venous Thromboembolism Away the Treatment of Malignant Hematologic Diseases Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or aspirin for LEIDY L. ISENALUMHE, MD, MS extended treatment of venous thromboembolism. N Engl J Med. 2017;376:1211-1222. Adult Clinical Hematology-Oncology Fellow, H. Lee Moffitt Cancer Center and Research Institute; Pediatric Hematologist/ Oncologist; Chair, ASH Trainee Council; Tampa, FL

hether to extend anticoagulant therapy for a deep The Adolescent and Young Adult (AYA) Progress Review Group (PRG) defines the vein thrombosis or pulmonary embolism beyond the AYA cancer population as patients ranging from 15 to 39 years of age. An estimated acute treatment period can be a problematic decision. 69,000 AYA individuals are diagnosed with cancer each year — six times more than Anticoagulant therapy reduces the risk of recurrent venous children younger than 14 years.1 The AYA age demarcation was established as a Wthromboembolic events (VTE), but at the cost of an increased risk of high-risk population after data from the Surveillance, Epidemiology, and End Results 1-3 bleeding. Reducing the intensity of anticoagulant therapy or switching (SEER) study showed a lack in improvement in survival for patients with many forms 3 to aspirin have both been proposed as options in patients who wish of cancer.2,3 The most common malignancies are leukemia, lymphoma, germ cell tumors, and central to continue protection, but the efficacy and safety of these strategies is nervous system tumors among 15 to 24 year olds, with the incidence of breast cancer, colorectal still uncertain. cancer, and melanoma increasing among older AYA patients1 (Figure). Dr. Jeffrey I. Weitz and colleagues reported the results of a double- blind, randomized controlled trial, “EINSTEIN CHOICE,” which Figure Common Types of Cancer Affecting AYAs compared rivaroxaban 10 mg daily (low intensity) with rivaroxaban 20 mg daily (standard intensity) and aspirin 100 mg daily for prevention of recurrent VTE. All 3,365 randomly assigned patients received six to 12 months of anticoagulant therapy prior to enrollment. Patients with provoked or unprovoked VTE were eligible as long as their clinician believed there was uncertainty about the value of long-term treatment. Study duration was up to 12 months. The primary efficacy outcome measure was symptomatic fatal or nonfatal recurrent VTE, and the primary safety outcome was major bleeding.

The results showed that the rivaroxaban 20-mg and 10-mg doses were both superior to aspirin for the prevention of recurrent VTE (rivaroxaban 20 mg, 1.5%; rivaroxaban 10 mg, 1.2%; aspirin, 4.4%; HR [rivaroxaban 20 mg vs. aspirin], 0.34; 95% CI, 0.20-0.59; p<0.001; HR [rivaroxaban 10 mg vs. aspirin], 0.26; 95% CI, 0.14-0.47; p<0.001). Between the two doses of rivaroxaban, there was no difference in the risk of recurrence (HR, 1.34; 95% CI, 0.65-2.75; p=0.42) or the risk of major bleeding (0.5% and 0.4%, respectively). Furthermore, the risk of major bleeding in both rivaroxaban arms was similar to aspirin (0.3%). The risk of clinically relevant nonmajor bleeding was not significantly different across the three groups (rivaroxaban 10 mg, 2.0%; rivaroxaban 20 mg, 2.7%; aspirin, 1.8%).

There are important limitations to this study that should be considered. First, the total number of events (80) was small. This is likely due to

the substantial proportion of patients with provoked VTE enrolled in *includes testicular cancer. **includes breats, cervical, colon and other less prevalent cancers. ***includes malignant bone tumors and other less prevalent cancers. the study (60%). This group is known to have a low risk of recurrence Adapted from1 A Snapshot of Adolescent and Young Adult Cancers: National Cancer Institute. [cited 2015 Nov 28]; NCI Surveillance, Epidemiology, and End without anticoagulant therapy; therefore their inclusion in the study is Results (SEER) Program. Data is from SEER 18, 2007-2011, ages 15-39. Available from: www.cancer.gov/research/progress/snapshots/adolescent-young-adult. controversial.5 Additionally, the duration of treatment was limited to one year. Patients facing this choice are deciding if they should continue In 2007, the AYA PRG released a comprehensive guide explaining the disparities experienced by AYA anticoagulation indefinitely, which can mean decades of treatment. cancer patients that have led to their poor outcomes and lack of progress throughout the years.2 Lastly, the study was not powered to determine if 10 mg of rivaroxaban These disparities include lack of health insurance, differences in is noninferior to 20 mg with respect to efficacy. Table 1: List of the disease biology, delay of diagnosis and treatment, increased toxicities, Disparities Experienced lower socioeconomic status,4 and overall lack of awareness in the Overall, the results of the EINSTEIN CHOICE study show that even by AYA Hematology- medical field as to the special needs of this population (Table 1). low-dose anticoagulation is superior to aspirin, and without a higher oncology Patients price to pay with respect to bleeding. Consequently, the key message The goal of the AYA PRG was not only to introduce and educate of this trial is that patients who wish to continue protection from Access to health care the medical field about this high-risk population, but also to start recurrent VTE have little to gain by switching to aspirin. However, what Psychosocial stressors this study cannot do is confirm that rivaroxaban 10 mg once daily is a systematic mitigation of the disparities. Since the release of sufficient for patients with a high risk of recurrence. Delay in diagnosis the PRG guide, progress has been made, including an increase in AYA-specific scientific peer review publications, formation of AYA Delay in treatment 1. Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison of low-intensity warfarin therapy oncology programs, development of AYA-specific national workshops with conventional-intensity warfarin therapy for long-term prevention of recurrent venous Treatment site and committees, development of clinical trials targeting AYAs, and thromboembolism. N Engl J Med. 2003;349:631-639. expansion of inclusion criteria to include AYAs.4,5 Additionally, the 2. Ridker PM, Goldhaber SZ, Glynn RJ. Low-intensity versus conventional-intensity Reduced rates of clinical warfarin for prevention of recurrent venous thromboembolism. N Engl J Med. European Cancer Registry (EUROCARE) and NCI SEER data have trial enrollment and 2003;349:2164-2167. reported improvement in survival rates for the AYA population.5,6 3. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous treatment standardization thromboembolism. N Engl J Med. 2013;368:699-708. Despite some improvement in survival, AYAs still have lower five- 4. Simes J, Becattini C, Agnelli G, et al. Aspirin for the prevention of recurrent venous Increased toxicity year relative survival rates for acute lymphoblastic leukemia (ALL), thromboembolism: the INSPIRE collaboration. Circulation. 2014;130:1062-1071. acute myeloid leukemia (AML), rhabdomyosarcoma, Ewing sarcoma, 5. Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode of and breast cancer compared with children and older adults.6 Notably, the incidence of all invasive symptomatic venous thromboembolism provoked by a transient risk factor: a systematic 7 review. Arch Intern Med. 2010;170:1710-1716. cancers continues to increase in AYAs compared with any other age group.

Although many common malignancies overlap in younger and older patients, research advances LORI-ANN LINKINS, MD, MSC (CLIN EPI), FRCPC in ALL, breast cancer, colorectal cancer, sarcoma, and melanoma have identified age-dependent Dr. Linkins indicated no relevant conflicts of interest. (Cont. on page 2)

PRESIDENT’S COLUMN – ASK THE HEMATOLOGIST – MINI REVIEW – Contributing Editor PROFILES – Dr. Jack Hirsh reflects on a 2 Dr. Ken Anderson outlines six strategic 4 Dr. John Hausdorff gives his take on the 5 Dr. Omar Abdel-Wahab summarizes key 6 life devoted to hematology; mentee Dr. John priorities for the Society. SPIKES protocol for conveying bad news. findings related to histiocytoses. Kelton pays tribute. President’s Column HTHE ematologist ASH NEWS AND REPORTS® ISSN 1551-8779 PUBLISHED BIMONTHLY

Editor-in-Chief: Beyond Business As Usual Jason Gotlib, MD, MS n May of this year, ASH held its yearly Executive Committee Spring Retreat, in Quebec City, Canada, where Executive Committee Stanford Cancer Institute members and senior staff have an opportunity to collaborate, bond, and be inspired by our diverse points of view. This year, there Stanford, CA I emerged the beginnings of some major strategic initiatives and goals for ASH to develop further in the coming months and years. These Contributing Editors: initiatives demonstrate ASH’s constant growth and commitment to improvement in the field of hematology. Omar Abdel-Wahab, MD Memorial Sloan-Kettering Cancer Center ASH realizes that there is a need to facilitate the sharing of high-quality clinical data for ASH members and the hematology community, New York, NY and to provide direct data management support for disease-specific research activities. Thus, ASH has committed to developing its own data registry focusing initially on sickle cell disease (SCD) and multiple myeloma. And given our ongoing efforts to conquer SCD, ASH Michael DeBaun, MD continues to take on new ways to equip hematologists with the tools and knowledge they need to best serve SCD patients. For example, Vanderbilt University ASH is exploring the development of a clinical trials network for SCD to help clinical research sites develop and test interventional Nashville, TN therapeutics that may improve SCD patient outcomes. Tracy I. George, MD University of New Mexico Another takeaway is the impressive work of ASH’s standing committees. For one, ASH’s Committee on Quality continues to work on Albuquerque, NM improving quality of care, mainly through clinical practice guideline development. ASH is currently developing guidelines related to venous thromboembolism, SCD, von Willebrand disease, and other topics, while partnering with other professional societies to bring the Jonathan Hoggatt, PhD guidelines to life. (Learn more at www.hematology.org/quality.) MGH/Harvard University Cambridge, MA ASH leadership has long been concerned with recruiting and retaining an adequate pipeline of hematologists, and the Committee on Caron Jacobson, MD Training is in the early stages of conducting a long-term workforce study to help inform these efforts. In the meantime, the Committee Dana-Farber Cancer Institute on Educational Affairs has been hard at work on a plan to grow and evolve the Society’s education initiatives to meet the challenges Boston, MA of the workforce today and in the future. Exemplifying this growth is the Society’s forthcoming effort to offer readily accessible digital learning opportunities; to collaborate across disciplines to introduce treatment approaches that are more comprehensive; and to develop Sioban Keel, MD workshops that are more hands-on and interactive, to name just a few examples of the educational programs ASH will begin rolling out. University of Washington Seattle, WA Finally I’d like to share an update relevant to ASH’s work in the areas of precision medicine and immune therapies. Most recently, the Task Lori-Ann Linkins, MD, MSc, FRCPC Force on Precision Medicine has taken steps toward developing partnerships with key entities. In the coming months, ASH will join forces McMaster University with the National Institutes of Health Clinical Genomics Resource to collect and annotate germline variants relevant to malignant and Hamilton, Canada nonmalignant hematology disorders, and with the National Cancer Institute Genomic Data Commons to improve on existing genomic data storage, among other goals. Meanwhile the Task Force on Immunotherapies will sponsor a workshop in 2018 to foster advances in novel Stephan Moll, MD treatments for hematologic disorders and in metrics to assess both efficacy and toxicity. University of North Carolina Chapel Hill, NC I share these plans as a glimpse into ASH’s determination to do more than business as usual. These initiatives will assure that together, we Paul Moss, MBBS, PhD, FRCP translate exciting scientific advances to the bedside and toward improved patient care, while training the next generation of hematology University of Birmingham researchers and caregivers. As always, it is also a signal to members that there will be many new ways to help ASH grow by becoming Birmingham , United Kingdom involved. These programs further highlight the commitment at ASH to serve both clinicians and scientists around the world and to remain Elizabeth Raetz, MD the premier hematology society striving to further the understanding, diagnosis, treatment, and prevention of blood diseases worldwide. University of Utah Salt Lake City, UT Noopur Raje, MD Kenneth C. Anderson, MD Massachusetts General Hospital Boston, MA Andrew Roberts, MBBS, PhD University of Melbourne Melbourne, Australia AYA Treatment Disparities Managing Editor (Cont. from page 1) Juana Llorens, MS differences in disease biology within the same malignancy.8,9 ALL is In addition to biological differences in disease, socioeconomic factors Editorial Associate the most common malignancy in AYAs with a continued increase in such as lack of health insurance are associated with advanced stage at Laura M. Santini, MS incidence in the past 10 years, and still remains the leading cause of presentation, delay in diagnosis and definitive treatment, and increased 7-10 14-16 Graphic Designer AYA cancer deaths. The overall survival (OS) for AYAs with ALL is 52 mortality. Persons between the ages of 18 and 34 years are more grayHouse design percent, compared with 90 percent in children.6 Age-related genetic and likely to be uninsured compared to other age groups.16 In AYA patients biological variation in ALL are well established and likely contribute to with Hodgkin lymphoma, having public health insurance was associated American Society of Hematology the continued poor OS. AYA patients diagnosed with ALL have a higher with an increased risk of advanced disease at time of diagnosis.17 Having 2021 L Street, NW, Suite 900 frequency of genetic alterations that are associated with poor prognosis, no insurance or public health insurance, as well as low socioeconomic Washington, DC 20036 such as Ph+ ALL, Ph-like ALL, hypodiploidy, and iAMP21 (Table 2).7-9,11,12 status, act as barriers to treatment at National Cancer Institute (NCI) [email protected] Recent epidemiological data have indicated that AML patients between –designated comprehensive cancer centers (CCCs), where the the ages of 15 and 39 years had a much lower five-year OS compared with outcomes are superior to those of other institutions.18,19 Dr. Julie A. ©2017 by the American Society of Hematology. younger patients (50% and 66%, respectively), and age is an established Wolfson and colleagues reported on the inferior outcomes of AYA poor prognostic factor in adults with AML.6,7,13 The presence of specific patients with ALL and AML who were treated at non–NCI-designated All materials contained in this newsletter are protected by copyright laws and may not be used, genetic abnormalities also seems to differ between pediatric and AYA CCCs or Children’s Oncology Group (COG) centers. Age, lack of private reproduced, or otherwise exploited in any manner AML, but data are limited due to the low number of AYAs treated on AML health insurance, and nonwhite race/ethnicity were additional barriers without the express prior written permission of The clinical trials.13 Compared to children younger than 16 years, AYAs aged to treatment at CCC or COG centers. AYAs treated at CCC/COG centers Hematologist: ASH News and Reports. Any third- 16 to 21 years were more likely to have normal cytogenetics, favorable had similar outcomes compared with children treated at CCC/COG party materials communicated to The Hematologist become its copyrighted property and may be prognostic markers such as NPM1 and CEBPA, and a higher incidence of sites, suggesting that treatment at such centers may have attenuated used, reproduced, or otherwise exploited by The acute promyelocytic leukemia, but they were also more likely to carry the poor outcomes reported in AYAs with ALL (<30 years of age) and Hematologist. unfavorable markers such as FLT3-ITD (Table 2).13 AML (<22 years of age).20 There are many more factors that contribute Contributing authors have declared any financial to the lag in progress of AYAs that are beyond interest in a product or in potentially competing the scope of this article. products, regardless of the dollar amount. Any such Table 2: Differences in Disease Biology of Hematologic Neoplasms in AYAs financial interest is noted at the bottom of the article. The following quote from English philosopher Dr. Gotlib has no relevant conflicts of interest to Positive prognostic factors Negative prognostic factors John Locke summarizes what we have learned disclose. thus far and what we need to do to move B-ALL ETV6-RUNX1 Ph-like ALL The material published in The Hematologist is for • Higher incidence in younger • Age 1-9 years: 10% forward: “The improvement of understanding informational purposes only. The opinions of the patients • Age 16-20 years: 21% is for two ends: first, our own increase of authors and editors of The Hematologist are their Hyperdiploidy • Age 21-39 years: 27% knowledge; secondly, to enable us to deliver own and do not necessarily represent official policy that knowledge to others.” of the American Society of Hematology. ASH does • Higher incidence in younger KMT2A rearrangements not recommend or endorse any specific tests, patients RAS mutations physicians, products, procedures, or opinions, and iAMP21 Recently the NCI National Clinical Trials disclaims any representation, warranty, or guaranty GATA3 Network (NCTN) underwent major as to the same. Reliance on any information • Germline variants are associated restructuring, with the nine adult cooperative provided in this publication is solely at your own risk. with predisposition to AYA ALL groups merging into four (Alliance Oncology, Early T-Cell HOX+ Eastern Cooperative Oncology Group/ Precursor ALL • Higher incidence in AYA American College of Radiology Imaging Network [ECOG-ACRIN], NRG Oncology, and Acute Myeloid Normal cytogenetics, FLT3-ITD Southwest Oncology Group [SWOG]). Such Leukemia NPM1 and CEBPA • Incidence increases with age changes benefit the AYA oncology community • Higher incidence in AYAs by expanding access to clinical trials for this Abbreviations: ALL, acute lymphoblastic leukemia; AYA, adolescent and young adult. (Cont. on page 12)

2 The Hematologist: ASH NEWS AND REPORTS NEWS AND REPORTS

The ASH Global Research Award: Q&A ASH News Daily Call for Authors With the Program Chairs ASH is in search of the next team of Authors for this year’s ASH News Daily. If you are an ASH member (MD or PhD) who has a passion for writing as great as your love Taking a cue from more than 30 years of success with the ASH Scholar Award for hematology, you may be just the right fit. Ideal candidates are proficient, published program, the new ASH Global Research Award aims to support hematologists writers (please send at least two clips) who are curious about, and willing to cover, during the critical period between completion of training and the establishment areas outside their comfort zone. You must be able to attend the annual meeting in of their independent careers. However, this program was created specifically for December, as well as one in-person board meeting in early October. We are also trainees and early investigators practicing outside the United States and Canada. seeking those who: To better understand its purpose and goals for its first year, The Hematologist discussed the award program with committee Co-Chairs Drs. Ruben A. Mesa and • Have a flexible schedule at the annual meeting and are good at managing their time Andrew Roberts. • Enjoy science writing and can also apply a creative approach to it

This award supports hematologists transitioning to careers as • Are cognizant of timelines and are dependable with schedules and firm deadlines independent investigators. Why is this stage so crucial? How is the • Enjoy networking and doing author outreach program different from other ASH career and training award programs? • Are mid-career professionals interested in becoming more involved with ASH. Ruben Mesa, MD: The transition from one’s training program If this sounds like you, please email Managing Editor Juana Llorens (jllorens@ to becoming an independent investigator is truly one of the hematology.org) with the following: most challenging for individuals. The Global Research Award program’s goal is to expand the reach of academic hematology • A letter of interest and make specific contributions to the development of • Two writing samples meaningful scientific research. This award is distinct from other ASH programs in its breadth and scope, offering at a global level • Your CV some of the opportunities previously only available in the United States and Canada. Materials are due by July 31, 2017. For more information on ASH News Daily, visit www.hematology.org/Annual-Meeting/AND.aspx. Andrew Roberts, MD: ASH recognizes that careers in academic and research-focused hematology vary widely around the world, and that the type and scope of investigator- led research that makes a difference also differs between regions and countries. This means that programs appropriately designed for emerging investigators in North America may not be fit-for-purpose in Africa, Asia, Latin America, or Europe. The ASH Global Research Award has been designed with AML Matters July 28 in Minneapolis, MN this heterogeneity in mind. It aims to identify outstanding people early in their careers and support them to conduct programs that will advance hematology in AML Matters is an education program designed to improve the diagnosis and treatment their region. It is structured to enable as fair a competition as possible between of acute myeloid leukemia (AML). The program is being hosted by ASH, the American applicants from different regions by recognizing inherent differences in opportunity, Society for Clinical Pathology, National Marrow Donor Program, Oncology Nursing infrastructure, and regional need. Society, and The France Foundation. Upcoming dates include: • Minneapolis, MN — July 28, 2017 Why is global collaboration so important to hematology, and how does this program support that? • Durham, NC — October 20, 2017 • Philadelphia, PA — October 27, 2017 RM: Global collaboration is important in hematology. For example, decreasing morbidity and mortality rates of acute promyelocytic leukemia in Latin America Visit www.hematology.org/amlmatters for more information. was a collaborative effort made with the assistance of ASH. This award will further aid global collaboration by supporting promising investigators from a range of countries, including those with less-developed research infrastructures. Additionally, since these awards connect individuals with leaders in their areas of research, this will enhance collaboration.

AYA Treatment Disparities AR: Global collaboration is integral to many areas of hematology research (e.g., the ASH Member and Committee Chair genomics of acute myeloid leukemia, childhood bone marrow failure syndromes) Recognized by NCI and essential when it comes to addressing the needs of patients in areas of the world where resource limitations preclude use of therapies routinely available in Dr. Charles Mullighan, ASH member and chair of the ASH Committee North America. ASH is hopeful that the ASH Global Research Award will not just on Scientific Affairs, was named a recipient of the National Cancer advance the development of future leaders, but also create networks that enable Institute Outstanding Investigator Award. The award offers seven major blood disorders to be tackled in a global fashion. years of funding, giving cancer researchers time to make new breakthroughs or extend previous discoveries. Dr. Mullighan What are some of the goals for the program in its first year? Do you and his lab at St. Jude Children’s Research Hospital have used expect to face any challenges? If so, how will they be overcome? genomic profiling and experimental modeling to make advances in identification and understanding of high-risk and relapsed leukemia. RM: The goals of the award in its first year are to build awareness of the program Congratulations to Dr. Mullighan! and to have a broad range of applicants representing many different countries, particularly from the developing world. As with any new award, it will take time to get the word out and refine the functionality of the program. The steering committee has deliberated extensively on the parameters of the program in terms of eligibility and flexibility in using the award. We will refine these parameters further and learn how best to communicate the spectrum of opportunities available to investigators who participate. 2017 ASH Annual Meeting Upcoming AR: The fact that we will receive a diverse array of proposals from applicants who come from a variety of training systems, cultural backgrounds, and economic Deadlines environments means that assessing the applications against each other will not Save these date for the world’s most comprehensive hematology event of the year, be straightforward. We have established a review system that should be able to the 59th ASH Annual Meeting and Exposition, in vibrant Atlanta. The meeting will deal with this heterogeneity fairly, but this will be tested carefully as we go ahead. provide an invaluable educational experience and the opportunity to review thousands I expect that we will need to adjust the system as we learn more about what this of scientific abstracts highlighting updates in the hottest topics in hematology. award can achieve in different parts of the world. Network with top minds in the field as well as a global community of more than 25,000 hematology professionals from every subspecialty. Visit www.hematology.org/Annual- What is the long-term vision for the award program, and how do you hope Meeting for more information. to see it evolve? • ASH Foundation Run/Walk registration opening — July 6, 2017, 11:00 a.m. Eastern RM: The long-term vision of the award is to increase tools to foster a global time hematology community. This will include educational efforts like the Clinical • ASH Global Capacity-Building Showcase poster submission deadline — July 17, Research Training Institute in Latin America and Asia and Highlights of ASH in 2017, 11:59 p.m. Pacific time various regions. We hope to see this program grow through engagement with other national societies and organizations. • Members-only registration and housing opening — July 19, 2017, 11:00 a.m. Eastern time AR: Wouldn’t it be great if the ASH Global Research Award becomes as • Abstract submission deadline — August 2, 2017, 11:59 p.m. Pacific time empowering and enabling for early-career hematologists in Asia, Africa, Latin America, and Europe as the ASH Scholar Award has been for their peers in North • Advance registration and housing opens for non-members — August 9, 2017, America? That’s part of the long-term vision. Additionally, connecting the best from 11:00 a.m. Eastern time many parts of the world is a great way to drive collaboration and strengthen the global hematology community.

The Hematologist: ASH NEWS AND REPORTS 3 THE PRACTICING HEMATOLOGIST

ASH does not recommend or endorse any specific tests, physicians, products, procedures, or opinions, and disclaims any representation, warranty, or guaranty as to the same. Reliance on any information provided in this article is solely at your own risk.

Ask the Hematologist

JOHN HAUSDORFF, MD Medical Director, Palliative Medicine Service, Community Hospital of the Monterey Peninsula; Medical Director, Hospice of the Central Coast, Monterey; Medical Oncology and Hematology, Pacific Cancer Care; Monterey, CA

Knowledge Summary/Strategy

The Question When it is time to break the news, patients and families Summarize, and decide where to go next. It may be How do you approach giving bad news to patients and their benefit from a brief summary of what we knew (or thought treatment options, agreeing to meet next week, directly families? we knew), what we hoped for, and finally, what we have addressing prognosis, and/or discussing hospice care. now learned. Speak slowly, make eye contact, use simple terms, and if you must use medical jargon, translate as you For Doug, the nature of our talk was my acknowledging go. Beware of providing too many details, and gently but and preparing for the very real possibility that, despite our The Response resolutely cut to the chase. Most patients, especially during best efforts, this could rapidly lead to demise and death, Doug had essential thrombocythemia (ET) that eventually emotionally charged times, are best served with clear, even today. We would do our best, but it looked bad. He transformed into post-ET myelofibrosis. He required nonmedical language. Then explain what the bad news and his wife understood, and months earlier we all agreed splenectomy 13 years ago. His thrombotic diathesis, means. If you pause after relating what the findings are, the that heroics were not appropriate. In fact, he never got refractory to warfarin, was controlled with enoxaparin or patient and family may ask what the findings mean. In this to angiography; that afternoon he passed away, before I fondaparinux for the next decade. With time, he developed way you have allowed them to once again invite you to tell finished clinic and with family at his side. increasing circulating blasts. and year after year, we kept more. expecting transformation to acute leukemia. Now a frail Dr. Baile and colleagues have written extensively on this 76-year-old, Doug spoke with me several times about important communication skill. “SPIKES” was published as a this possibility. He became transfusion-dependent, but Empathic Response/Empathic Silence six-step protocol with attention to the oncology community 1 throughout the next six months, he continued to enjoy This is new territory for many of us. After hearing bad in 2000. Our hematology patients get sick, receive bad work in his yard. news, patients and families often feel traumatized and news, and die. Yet the evidence suggests that palliative 2,3 overcome with emotion. Rather than speaking up, changing care services are underutilized in our field. Importantly, When he bled spontaneously into his arm, fondaparinux the subject, or moving to therapeutic options, a little “palliative care” here refers to the days, months, or years was reduced. A week later, he bled into the silence is often best. Silence is powerful and valuable. When before hospice care, when symptom management, clarifying retroperitoneum. With the patient hospitalized and you do speak, an “empathic response” is your best move: goals, advance care planning, and clear communication is so hypotensive, we transfused while exploring angiography. Speak words that acknowledge that your patient is feeling essential. He looked like hell. And I was late for heme-onc clinic. something. The response may be a statement or question; Years ago, I would have encouraged him to “hang in there,” go with what feels right at the time. For example: There are obstacles, of course, to implementing the reassuring him that he was under excellent hospitalist “SPIKES” protocol. Hematologists often are in a rush, care, and pledging to return that evening. I now recognize, “This must be very hard news for you to hear.” whether in clinic or on rounds in the hospital. Portals that however, that this was inadequate. For this probable “I imagine this is very disappointing.” allow patients direct access to their results online seem to impending disaster, I had to “break the bad news” openly “Is this a big surprise, or did you kind of expect this?” enhance patient autonomy, but at the price of meaningful and prepare him and his wife. interpretation and context, and this can seriously And our own feelings count as well: undermine the doctor-patient relationship. The same is As hematologists-oncologists we break bad news frequently true of the electronic medical record if we’re trying to listen — diagnosis, recurrence, progression, incurability, “I’m so sorry, and I am really disappointed, too.” to and talk with patients. The most important elements, prognosis, impending death — but most of us have had “I was also hoping we’d have more time.” however, are our own levels of comfort with handling the little formal training in this area. Dr. Walter F. Baile and intense feelings of the sick and vulnerable, and the extent to 1 colleagues taught a wonderfully useful approach called Try not to immediately shift away from the uncomfortable which we truly believe that the nuanced, challenging, and “SPIKES,” which I have outlined and modified in this article. silence, the sadness, or the tears. This is how we process exceptionally important task of breaking bad news skillfully tragedy. and sensitively is our responsibility. Setting As hematologists, we need to enhance our own palliative care skill sets, since most of the work falls on our shoulders. If at all possible, never give bad news by phone or in the The “SPIKES” Protocol hallway. Sit, with TV and cell phones off. It may require We should also be aware of an ever-increasing workforce of having other family members present, as well as extra Figure highly trained palliative care professionals who can assist chairs. Pull your chair close to the patient’s bed or us when the going gets rough, and when hematologic care chair, nonverbally signaling your connection and your becomes something much bigger — care of the critically ill therapeutic alliance, perhaps holding a hand or touching human being, of the aggrieved family, and of the dying. an arm, making sure you face both patient and family, and 1. Baile WF, Buckman R, Lenzi R, et al. SPIKES - a six-step protocol using eye contact as you speak. At this point, we are setting for delivering bad news: application to the patient with cancer. the stage. Oncologist. 2000;5:302-311. 2. Manitta V, Zordan R, Cole-Sinclair M, et al. The symptom burden of patients with hematological malignancy: a cross-sectional Perception observational study. J Pain Symptom Manage. 2011;42:432-442. Ask the patient and family what they think is going on. 3. Manitta VJ, Phillip JA, Cole-Sinclair MF. Palliative care and the hemato-oncological patient: can we live together? A review of the engages This simple act them (a critical element in good literature. J Palliat Med. 2010;13:1021-1025. communication) and sends the message that what they think matters, such that we start with their perception of the situation. Furthermore, in this way we’re more likely Dr. Hausdorff indicated no relevant conflicts of interest. to reframe or educate successfully, especially if any misunderstandings are openly expressed first.

Invitation This simple step, however phrased (e.g.,“Shall I share the results of the scan with you now?” or “Is this a good time to tell you what I believe is happening?”), shows respect, focuses attention, and essentially asks for permission. We are about to announce something unpleasant. We may disappoint and occasionally devastate the recipients of the news we are about to deliver. Do it gently and with humility. Many patients and families feel violated when we tell them terrible things, so obtaining permission first signifies they’ve agreed to hear it and are ready to allow us into their world.

4 The Hematologist: ASH NEWS AND REPORTS MINI REVIEW

Histiocytoses: Clonal Disorders of Hematopoiesis Driven by MAP Kinase Signaling

OMAR ABDEL-WAHAB, MD Assistant Member, Human Oncology and Pathogenesis Program; Attending Physician, Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center; New York, NY

Histiocytic neoplasms (or histiocytoses) describe a group of diseases believed of these agents for adults with histiocytosis. A number of clinical studies have now to be derived from dendritic cell, monocyte, and/or macrophage lineages, demonstrated the efficacy of vemurafenib for BRAF V600E-mutant histiocytosis. In the one which result in an accumulation of lesional cells and ensuing damage in a clinical trial that has been published, a cohort of 22 ECD and four LCH patients experienced variety of tissues throughout the body. The protean clinical manifestations a response rate of 64 percent to vemurafenib (Figure 2A).11 Extended follow-up of this study of histiocytoses, which affect children as well as adults, combined with their has identified that these responses are durable, with a median treatment duration now of diverse histologic presentation and 14.9 months (range, 2-43 months).12 rarity, has made these diseases among the most Figure 1 challenging hematologic disorders to diagnose and Given that the use of vemurafenib requires categorize. In fact, for decades, histiocytoses such documentation of the BRAF V600E mutation as Langerhans cell histiocytosis (LCH), Erdheim- combined with the fact that nearly 50 percent of Chester disease (ECD), and juvenile xanthogranuloma histiocytosis patients lack this mutation, there (JXG) were considered to be inflammatory, non- has been an ongoing effort to identify targeted neoplastic conditions, with potentially similar origins therapies for BRAF-wild-type patients. Currently, it to hemophagocytic lymphohistiocytosis (HLH). appears that the use of single-agent MEK inhibitors, However, a series of discoveries regarding the including trametinib or cobimetinib, may have molecular genetic causes of histiocytoses over the great efficacy for adults with BRAF-wild-type LCH last seven years has reshaped our understanding of or ECD (Figure 2B). Despite promising initial data nearly all subtypes and has led to potent targeted on this approach, it is important to realize that it treatments for patients affected by these conditions. is not yet known if the variety of activating MEK1 We now understand that LCH, ECD, and JXG are clonal mutations all respond to MEK1/2 inhibition nor is disorders with a high frequency of somatic mutations it understood which MEK inhibitor is ideal for use resulting in activation of the MAP kinase signaling in histiocytosis. In order to determine the safety pathway. These advances have been described in a and efficacy of single-agent MEK inhibition based number of excellent recent reviews.1,2 In this article, on the diverse genetic alterations present in BRAF- we summarize some of the most important findings wild-type histiocytosis patients, our group has an regarding histiocytoses. ongoing phase II trial of single-agent cobimetinib for adults with histiocytic disorders (ClinicalTrials.gov Classification of Histiocytoses identifier NCT02649972). In the World Health Organization (WHO) classification of hematopoietic malignancies, histiocytic neoplasms Conclusions and Unanswered Questions are included under the rubric of “mature lymphoid, The discovery of recurrent clonal mutations histiocytic, and dendritic neoplasms.”3 There are activating the MAP kinase pathway in histiocytosis currently nine WHO-recognized entities including as well as the response of these patients to small histiocytic sarcoma, LCH, Langerhans cell sarcoma, molecules inhibiting this pathway has been Toward a molecular genetic understanding of histiocytic neoplasms. (A) Word indeterminate dendritic cell tumor, interdigitating remarkable. Despite these advances, there is a cloud of the various names and eponyms for systemic histiocytic neoplasms that have dendritic cell sarcoma, follicular dendritic cell been used since the initial descriptions of the diseases 150 years ago. (B) Pie charts need to continue genetic analysis of the variety sarcoma, fibroblastic reticular cell tumor, disseminated of somatic mutations affecting MAP kinase signaling that are now known to occur in of histologically defined forms of histiocytosis JXG, and ECD. These are currently differentiated Langherans cell histiocytosis and Erdheim-Chester disease. The majority of recurrent other than LCH, ECD, and ICH to determine if these from one another based on histologic and/or mutations that have been identified are mutually exclusive activating mutations affecting conditions also harbor high frequencies of somatic immunophenotypic characteristics with distinct MAP kinase signaling, with the most common being the BRAF V600E mutation. mutations, some of which may be important in Reprinted by permission from the American Association for Cancer Research. genetic alterations only defined for a few. Additionally, molecular diagnosis or treatment. Additionally, there it is also important to be aware of an alternate is a need to more conclusively define the cellular Figure 2 classification system for histiocytic and dendritic origin(s) of LCH and ECD. Although accumulating cell neoplasms recently proposed by the Histiocyte data suggest that these conditions are derived Society. 4 The different eponyms that have been used from hematopoietic progenitors and/or myeloid for systemic histiocytoses are shown in Figure 1A. progenitors, it also is possible that more than one cell of origin may characterize these disorders. Somatic Mutations Drive Histiocytoses Despite categorization of histiocytoses with lymphoid Dr. Abdel-Wahab indicated no relevant conflicts neoplasms in the WHO classification, it is important of interest. to note that 1) gene expression analyses of LCH and ECD indicate that these disorders bear greater 1. Haroche J, Cohen-Aubart F, Rollins BJ, et al. resemblance to myeloid lineage cells than dendritic Histiocytoses: emerging neoplasia behind inflammation. 5,6 cells ; 2) genetic analyses have identified that Lancet Oncol. 2017;18:e113-e125. mutations in histiocytosis lesional cells can be found 2. Egeler RM, Katewa S, Leenen PJ, et al. Langerhans in CD34+ and circulating myeloid cells in patients6,7; cell histiocytosis is a neoplasm and consequently and 3) functional analyses suggest that at least its recurrence is a relapse: In memory of Bob Arceci. some histiocytoses are derived from hematopoietic Pediatr Blood Cancer. 2016;63:1704-1712. precursors.8 These observations suggest that LCH, 3. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision ECD, and JXG may actually be more appropriately of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375-2390. considered clonal disorders of the myeloid lineage. 4. Emile JF, Abla O, Fraitag S, et al. Revised classification of histiocytoses and neoplasms of the macrophage- Interestingly, a series of studies performing mutational dendritic cell lineages. Blood. 2016;127:2672-2681. analysis of histiocytosis lesional biopsies has 5. Diamond EL, Durham BH, Haroche J, et al. Diverse identified that both LCH and ECD are characterized by and Targetable Kinase Alterations Drive Histiocytic approximately 50 percent of patients having a BRAF Neoplasms. Cancer Discov. 2016;6:154-165. V600E mutation (Figure 1B). The BRAF V600E mutation 6. Berres ML, Lim KP, Peters T, et al. BRAF-V600E is common to a variety of epithelial cancers, strongly expression in precursor versus differentiated dendritic promotes activation of the MAP kinase pathway, and Examples of responses of BRAF V600E and MAP2K1 mutant adults with cells defines clinically distinct LCH risk groups. J Exp Med. 2014;211:669-683. sensitizes cells to inhibitors of this pathway. Further Erdheim-Chester disease (ECD) to molecularly targeted therapies. (A) Positron studies to define mutations present in BRAF-wild-type emission tomography (PET) scan and brain MRI of a BRAF V600E-mutant ECD patient 7. Milne P, Bigley V, Bacon CM, et al. Hematopoietic origin of Langerhans cell histiocytosis and Erdheim Chester patients have since identified that nearly all LCH and with skeletal and parenchymal brain lesions pre- and eight-weeks post-treatment with the BRAF inhibitor vemurafenib. (B) PET scan of a MAP2K1 Q56P-mutant ECD patient disease in adults. Blood. 2017;pii:blood-2016-12-757823. ECD patients have a mutation activating the same with disease infiltration in facial sinuses, heart, and kidneys pre- and four-weeks post- [Epub ahead of print]. pathway as BRAF V600E mutations. This includes treatment with the MEK1/2 inhibitor cobimetinib. 8. Durham B, Roos-Weil D, Baillou C, et al. Functional mutations in MAP2K1 (encoding the MEK1 kinase just Evidence for Derivation of Systemic Histiocytic downstream of BRAF), NRAS, KRAS, and ARAF as well Neoplasms from Hematopoietic Stem/Progenitor Cells. as activating translocations in BRAF, ALK, and NTRK1 (reviewed recently9). The high frequency Blood. 2017. [In press]. of mutations in MAP2K1 and ARAF make LCH and ECD quite unusual in that these kinases are 9. Durham BH, Diamond EL, Abdel-Wahab O. Histiocytic neoplasms in the era of personalized genomic medicine. Curr Opin Hematol. 2016;23:416-425. much less frequently mutated in any other form of cancer. In addition to the above, genetic analysis of indeterminate dendritic cell histiocytosis identified that a high frequency of these 10. Brown RA, Kwong BY, McCalmont TH, et al. ETV3-NCOA2 in indeterminate cell histiocytosis: clonal translocation supports sui generis. Blood. 2015;126:2344-2345. tumors have a specific translocation (ETV3-NCOA2) that appears to define this histologic entity.10 11. Hyman DM, Puzanov I, Subbiah V, et al. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N Engl J Med. 2015;373:726-736. Therapeutic Targeting of BRAF and MEK in Histiocytosis 12. Diamond EL, Subbiah V, Lockhart C, et al. Vemurafenib in patients with Erdheim-Chester disease Based on the success of targeting BRAF V600E mutant melanoma with RAF and MEK inhibitors, (ECD) and Langerhans cell histiocytosis (LCH) harboring BRAF-V600 mutations: a cohort of the the discovery of BRAF V600E-mutant LCH and ECD led to efforts to determine the efficacy Histology-Independent VE-Basket study. Blood. 2016;128:480.

The Hematologist: ASH NEWS AND REPORTS 5 PROFILES I N HEMATOLOGY

Shifting the Focus of Medical Research From the Bench to the Bedside

JACK HIRSH, CM, MD, FRCP(C), FRACP, FRSC, DSC Professor Emeritus, McMaster University, Hamilton, Ontario, Canada

Unlike other commentators who have been featured in these columns, I had no role models to guide members in a variety of specialties, but my group and I concentrated on clinical research in thrombosis. me in my career path because clinical research, as we know it today, was not being performed in the mid-1960s. Instead, clinician researchers focused their efforts on understanding the pathophysiology The McMaster environment was enormously supportive of our research, as was the Canadian funding scene. of disease and not on solving the problems that they encountered in clinical practice; their research Throughout a 45-year period I mentored, advised, in the laboratory was disassociated from their activities in the clinic. and collaborated with numerous outstanding clinical investigators, some of whom stayed and joined the McMaster faculty and others who moved to Faculties in Canada, After I graduated from medical school at Melbourne patients were unaware of the flimsy evidence on which they Australia, Europe, Asia, and the United States. Some of my University in Australia, in 1959, I completed four years of made many of their clinical decisions. Venous thrombosis earlier fellows and recruits such as Drs. John Kelton, Jeffrey residency training in internal medicine and an additional and pulmonary embolism (PE) were diagnosed on clinical Weitz, and Mark Levine branched out into their own fields year in laboratory hematology. It was then that I developed grounds, and anticoagulant management was haphazard and became international leaders in their respective areas. an interest in research, but I had no idea how to go and not standardized. It was then that I decided that I Others such as Drs. Russell Hull, Graham Turpie, Jeffrey about obtaining the necessary training. I sought advice would focus my research on problems that I encountered Ginsberg, Harry Buller, Giancarlo Agnelli, Phillip Wells, from Professor Carl de Gruchy, a prominent Australian in my clinical practice and that I would use my laboratory Gary Raskob, Agnes Lee, Mark Crowther, David Anderson, hematologist, who suggested that I specialize in thrombosis. to complement patient management. This shift in research Clive Kearon, and John Eikelboom remained in clinical He said that thrombosis bridged hematology and cardiology philosophy, in which the research question is driven by thrombosis research and became famous in their own right. and would become an important field in medicine. He patient-important problems and in which the laboratory is Working with collaborators and trainees during a span of encouraged me to locate suitable training positions, used to help explain unexpected findings in clinical trials almost 50 years, I performed research that changed clinical so I applied for, and obtained, research fellowships at was novel at the time and provided the basis for evidence- practice. I established clinical standards for the laboratory Washington University in St. Louis, Missouri, where I worked based medicine. monitoring of warfarin and heparin and introduced the with Drs. Sol Sherry and Tony Fletcher; the London Post international normalized ratio in North America. We Graduate School in London, U.K., where I was fortunate to be I performed clinical studies which convinced physicians demonstrated the benefit of aspirin in stroke prevention, Professor John Dacie’s sole trainee; and in Toronto, Canada, that they should use standardized diagnostic testing to established standards for the short- and long-term treatment where I worked for Dr. Fraser Mustard. These researchers confirm a clinical suspicion of VTE. I introduced (and of VTE, the diagnosis of venous thrombosis and PE, and personally performed) venograms to confirm a the out-of-hospital treatment of venous thrombosis. We diagnosis of deep vein thrombosis. I standardized performed pivotal studies on the prevention of venous heparin monitoring, switching from the whole thrombosis with anticoagulants and mechanical devices, and blood clotting time to the activated partial my group was one of three that demonstrated the clinical thromboplastin time, and I standardized advantages of low-molecular-weight heparin. More recently, prothrombin time monitoring for warfarin. I we were involved in some of the pivotal studies with direct obtained local funding for a nonrandomized acting anticoagulants in the prevention of stroke in atrial trial that showed that streptokinase was much fibrillation, and in the prevention and treatment of VTE. more effective than heparin in lysing PEs. I also performed an experimental study in pregnant I remain involved in clinical practice and retain my passion rabbits to determine the optimal time to switch for discovery and for teaching new fellows. My students have from warfarin to heparin in pregnant mothers become my teachers. Drs. Sackett and Gent (who were never (with prosthetic heart valves) to limit bleeding in my students) taught me methodology and the rudiments both mothers and their fetuses. of biostatistics. Dr. Weitz taught me biochemistry, and Dr.

This shift in research philosophy, in which the research question is driven by patient-important problems and in which the laboratory is used to help explain unexpected findings in clinical trials was novel at the time and provided the basis for evidence-based medicine.

My clinical colleagues were very cooperative, Gordon Guyatt refined my knowledge of grading evidence supportive, and collegial. I was hailed as a and convinced me of the importance of including patients’ success in Melbourne, but I sensed that my values and preferences in clinical decision-making. Now at clinical research lacked rigor. Then, in 1969, the age of 82, I am fortunate to belong to an outstanding my life changed! I was invited to pay a visit to research group led by one of my former students, Dr. the newly formed Faculty of Health Sciences Eikelboom, and I continue to mentor and learn from fellows at McMaster University in Hamilton, Ontario. and new faculty who are members of our group. When I visited, I was impressed with the energy, enthusiasm, creativity, and other outstanding Of course, I have other passions. I love spending time with qualities of the founding members. I was offered my wife of 54 years and family made up of three children, were giants in their fields, and of the many lessons that an appointment but was torn by obligations to my family and four grandchildren, and two great-grandchildren, whose ages I learned, two stand out and continue to serve me well: colleagues in Melbourne. Two factors swayed me. My wife span nine to 55 years. I have always loved participating in First, to succeed in research, a person requires passion, told me that we should “go for it.” Additionally, I had several sporting activities and have graduated from playing tennis “stick-with-it-ness,” and stamina. Second, don’t give up on a long discussions with Dr. David Sackett when I visited and squash to the more sedate (but fiendishly difficult) game problem because you lack the expertise to solve it. McMaster. David, who at my age (mid-30s) was founding of golf, to which I am moderately addicted. I enjoy reading Chairman of the Department of Clinical Epidemiology and history, science, and good mysteries. In 1968, I returned to a faculty appointment at Melbourne Biostatistics, was the missing link that I was seeking in order University in the Department of Medicine headed by to perform worthwhile clinical research. He taught me how Finally, I showed this piece to two of my colleagues, each Professor de Gruchy. I chose venous thromboembolism to focus my research on patient-important questions and whom told me that it was too light on showcasing myself and (VTE) as my clinical field and used the training received outcomes and to design rigorous clinical studies required too strong on highlighting my colleagues. But, they missed overseas to set up a platelet/coagulation/fibrinolysis to change clinical practice. Soon after I moved to McMaster the point. I was not being overly generous. My success in laboratory. My laboratory research was opportunistic and (in December 1969), I met Dr. Michael Gent, a mathematician research has been strongly dependent on three factors: mainly phenomenological, though I did use the laboratory who morphed into an outstanding biostatistician. The three my passion for learning; my ability to attract smart young to support clinical studies with anticoagulants and with of us became firm friends and colleagues, each with our researchers and provide an environment that entices them streptokinase. I was shocked to realize that almost all own growing research groups, but sharing a common aim to stay; and the wonderfully supportive environment at patient management decisions lacked a firm scientific basis. to perform clinical research that improves clinical practice. McMaster University, which was unparalleled. Even more shocking to me was that physicians caring for Dave and Mike collaborated with and advised many faculty

6 The Hematologist: ASH NEWS AND REPORTS THE HEMATOLOGIST ADVOCATE

HEADLINES FROM Washington

Thoughts From a Protégé JOHN G. KELTON, CM, FRSC, MD Congress Begins FY 2018 Budget Process

Executive Director, Michael G. DeGroote Initiative for Innovation President Trump Seeks Massive Public Health Program Cuts; ASH Members Go to Capitol Hill to Protect in Healthcare; Dean Emeritus, Michael G. DeGroote School of Medicine; Dean & Vice President Emeritus, Faculty of Health Federal Research Funding Sciences; McMaster University, Hamilton, Ontario, Canada In late May, the president released the full version of his proposed fiscal year (FY) 2018 budget, which seeks to cut more than $54 billion from nondefense discretionary (NDD) programs, including more than $7 billion I was completing fellowship training in the in cuts from current funding for the National Institutes of Health (NIH). The proposal would amount to nearly United States when I became aware of the a 21 percent cut to the medical institute, wiping out recent funding increases and negating a major boost innovative research studies coming from from last year’s 21st Century Cures Act for targeted initiatives such as the Cancer Moonshot, as well as the $2 McMaster University. When I visited the billion increase Congress provided NIH in the final FY 2017 funding bill signed into law in early May. campus and spoke with potential supervisors, I met Dr. Jack Hirsh and immediately fell under his spell. Jack was made for the role of “mentor,” The president’s proposed budget seeks to also cut other important public health programs, including nearly even long before the actual concept of mentorship became $1 billion from the Centers for Disease Control and Prevention (CDC), which has a role in preventing and popular. It seemed impossible to me that such a modest understanding blood diseases and disorders, including sickle cell disease (SCD) as well as bleeding and blood person could simultaneously have a crackling intellect, clotting disorders. The proposal also looks to cut Medicaid by $610 billion throughout the course of a decade. an intense curiosity, and an energy level well beyond the Medicaid is critical for patients with SCD and bleeding disorders such as hemophilia and von Willebrand disease. Tasmanian devil of his home country. Jack was also nice — terribly nice. It is important to remember that the president’s nonbinding budget proposal merely sets forth the new Administration’s priorities and is just one step in a lengthy federal budget process. The proposed budget was When I first met Jack, I had a foundation in basic science, received less than enthusiastically by members of Congress, who will spend the summer holding hearings and but I had not acquired the ability to align bench research with patient care. In the area of translational research, Jack Hirsh drafting legislation to establish spending levels for federal programs for FY 2018, which begins on October 1 of was a master without peer. He did not invent the concept of this year. evidence-based medicine, but he was certainly one of the first clinician-scientists to harness its remarkable power to ASH remains committed to protecting federal research funding and promoting strong, sustained, and answer important clinical questions. Each week, the clinical predictable funding for NIH. ASH members have been advocating with members of Congress, and the and research fellows would update their research at our Society has been partnering with other advocacy groups to amplify our impact. In June, ASH members and meetings. The educational experience was remarkable. Jack researchers, physicians, and patients from the Thrombosis & Hemostasis Societies of North America (THSNA) taught us that a failed experiment was often as informative met with more than 30 congressional offices to discuss the value of biomedical research with members of as a successful one. Above all, he showed us the power Congress and to seek to protect public health funding from the drastic cuts proposed for FY 2018. of unbridled optimism in a field where most experiments fail and some patients are beyond our help. We made our pilgrimages to Jack’s office where he would assume his These face-to-face meetings are an essential component of ASH’s advocacy efforts, providing an opportunity characteristic posture: leaning forward, listening intently, for members of Congress and their staff members to gain insight into issues of concern to hematologists and one hand under each thigh, legs swinging below the chair. their patients. However, the Society needs the help of all of its members in continuing to focus attention on Like bloodied fighters, the research fellows would explain the importance of federal research funding and the need for predictable and sustained funding for NIH. Please our (often) failed experiments, while Jack asked questions. visit the ASH website (www.hematology.org/Advocacy) for updates on the FY 2018 budget process and for Throughout this process, our initial pessimism (often a information about how you can contact your senators and representative to protect NIH funding in FY 2018. sense of pending doom) turned into faint hope, and then miraculously into outright optimism. We came to believe that we were on the threshold of success, and only a few more experiments in a slightly different direction could lead to victory. A key principle of research that Jack taught me is, “What is the question?” Those four plain words represent ACA Update not just the question of that particular experiment, but the value of the research itself. Our ability to ask and answer As this issue of The Hematologist went to press, the U.S. Senate was still debating how to proceed with Jack’s trademark question is what separates workmanlike consideration of the American Health Care Act (AHCA) that passed out of the House of Representatives experimentation from truly important research. in early May by a narrow party line vote. The Congressional Budget Office (CBO), which is responsible for reporting nonpartisan cost estimates for proposed legislation, released the score for the AHCA almost three I have learned through a nearly four-decade-long career in weeks after the legislation passed the House. The CBO estimates for the AHCA indicate that by 2026, 23 medicine that this is not a solo sport. Everything depends million more people will be without health insurance. The majority of the new uninsured will be low-income on the people around you. They set the circumstances, individuals and families, as the AHCA will lower federal Medicaid spending by $834 billion over 10 years. The the examples, and occasionally the limits that define our CBO also reported that the AHCA will reduce the cumulative federal deficit by $119 billion by 2026. professional progress. At McMaster, Jack was building a team. He was the force that built a team of achievers, consecutive clusters of McMaster health scientists who ASH is also concerned about the bill’s proposed elimination of the Public Health and Prevention Fund which went into the worlds of academia and medicine and became has supported many critical projects at the CDC, including investments in immunization and healthcare leaders. He made research a team sport by the sheer force associated infections. Currently the fund comprises approximately 12 percent of the CDC’s budget and should of his example and leadership. I can count at least fifty be preserved. scientists, half a dozen departmental chairs, and at least three medical school deans scattered across Canada and The Society is committed to ensuring that all individuals who need the services of a hematologist have access the United States who owe big parts of their careers to Jack. to one, and that patients have affordable and reliable coverage options so that the most appropriate and I am one of them. effective treatment options are available to them. ASH will continue to monitor this process with respect to the impact on hematology practice. Jack’s intensity in research also extended to sports. With each passing decade, Jack picked up and invariably conquered a new sport, taking them on with a ferocity that exhausted everyone, except of course himself. I watched him cycle through one sport per decade, including tennis, squash, and jogging. All the same. All predictable. Seldom Sickle Cell Disease Congressional Briefing did Jack’s energy wane. Instead, it would take about a decade for accumulated injuries to impose a switch. Jack’s A congressional briefing on SCD and gene editing took place on June 7, 2017, at the Rayburn House Office current sport is golf. I recall playing with Jack in the first Building on Capitol Hill. The briefing was hosted by the House Research & Development Caucus and the few years he took up the sport. He was extoling (with Congressional Sickle Cell Disease Caucus, and co-sponsored by ASH, the Sickle Cell Disease Association of some authority) the value of a natural swing. To the casual America, the National Marrow Donor Program/Be The Match, the American Society of Gene & Cell Therapy, observer, the swing could only be called natural if shoulder and the Pediatric Hospital Sickle Cell Collaborative, with the goal of educating members of Congress and their entrapment prohibits raising the club face higher than waist- staff on scientific advances that could potentially cure this devastating disease. level. That day, I defeated Jack, and vowed never to play him again since I knew I could never replicate the outcome. His swing has improved, his game has improved (he often scores Speakers included ASH members Drs. Linda Burns and Dan Bauer, who discussed the progress in SCD his age), and his former students receive the frequent news research as well as curative options such as bone marrow transplantation and gene editing. Constance that he has added to his collection of holes-in-one. He’s up Benson, a former SCD patient and a transplant recipient concluded the briefing with an inspiring talk about to four. From the white tees. her personal experiences living with the disease and choosing transplantation as a cure. To learn more about ASH’s multifaceted SCD initiative, visit www.hematology.org/Advocacy/4329.aspx. To read the State of Sickle Cell Disease: 2016 Report, visit www.hematology.org/SCDReport. (Cont. on next page)

The Hematologist: ASH NEWS AND REPORTS 7 Bone Marrow Fecundity: Turning Over New Expanding Host Tumor Immunity, One Neoantigen Stem Cells in Aplastic Anemia at a Time

Townsley DM, Scheinberg P, Winkler T, et al. Eltrombopag added to standard Khodadoust MS, Olsson N, Wagar LE, et al. Antigen presentation profiling reveals immunosuppression of aplastic anemia. N Engl J Med. 2017;376:1540-1550. recognition of lymphoma immunoglobulin neoantigens. Nature. 2017;543:723-727.

n insurmountable limitation in treating bone marrow failure has always r. Michael Khodadoust and colleagues use liquid chromatography and tandem mass been the number of residual stem cells. That is, until now. Dr. Danielle M. spectrometry to perform direct proteomic analysis of 17 primary mantle cell lymphoma Townsley and colleagues from the National Institutes of Health have (MCL) samples and two MCL cell lines to identify major histocompatibility complex– demonstrated in a nonrandomized historically controlled trial that the ad- (MHC-) presented tumor neoantigens (Figure). Through immunoprecipitation, they isolatedD 24,000 unique MHC-I–associated peptides and 12,500 unique MHC-II-associated Adition of eltrombopag, an oral thrombopoetin-receptor agonist, to standard therapy, improves rates of hematologic response in patients with severe aplastic anemia. peptides. Combining this with whole-exome sequencing and direct sequencing of immunoglobulin (Ig) heavy- and light-chain–variable regions, the researchers found that of the approximately 13 to The empty bone marrow seen on trephine core biopsy in aplastic anemia is a stark 175 nonsynonymous somatic mutations per patient, only mutated peptides derived from Ig genes and accurate indication of depleted hematopoietic precursors; the cells are simply were presented by MHC. For all others, only unmutated parts of the protein were presented. not there. Sensitive flow cytometry designed to enumerate the immature precursor Interestingly, MHC presentation was polarized such that nearly all Ig-variable neoantigens were cells corroborates this morphologic impression. Multiple lines of evidence have presented by MHC-II, whereas the majority of Ig-constant neoantigens were presented by MHC-I. established immune-mediated destruction of stem cells as the cause of bone Of the Ig-variable neoantigens, just about half of them were the result of somatic hypermutation or marrow failure. Cytotoxic lymphocytes, cytokines, and a relative paucity of V-D-J recombination. T-regulatory cells leads to loss of stem-cell progenitors. The exact cause of immune dysregulation is unknown, but it may be associated with acquired mutations in Using synthetic neoantigen peptide tetramers with affinity for HLA-DR*0401, they screened the cytotoxic T cells, leading to constitutive activation, in combination with the loss of blood of three patients with an HLA-DR*0401 allele for neoantigen-specific CD4+ T cells and the immune modulating effect of T-regulatory cells. As such, immunosuppression, found them in one of the three patients. These CD4+ T cells appeared to be memory T cells and in the form of horse antithymocyte globulin and cyclosporine, have been lacked PD-1 expression, and were skewed towards a Th2/Th17 phenotype. T-cell receptor (TCR) the cornerstone of therapy. The historical overall response rate to standard sequencing identified two dominant T-cell clones, both of which were induced upon neoantigen immunosuppressive therapy in aplastic anemia is 66 percent. With the addition of peptide autologous vaccination. Ex vivo expanded neoantigen specific CD4+ T cells stimulated by eltrombopag to standard immunosuppressive therapy, Dr. Townsley and colleagues autologous neoepitopes resulted in the production of IL-4 and granzyme and could mediate the have improved the overall response rate to 94 percent at six months. killing of autologous lymphoma cells in an antigen-specific manner.

The researchers divided patients two years and older with previously untreated Non-Hodgkin lymphomas (NHLs) are susceptible to immune attack, as evidenced by the efficacy severe aplastic anemia into three cohorts. All cohorts were treated with a of allogeneic stem cell transplantation, but can evade host-immune recognition. Attempts to standard immunosuppression regimen of ATGAM (Pfizer Inc.) and cyclosporine. harness the host’s own immune system against the lymphoma with immune checkpoint blockade Eltrombopag was added to the standard regimen in three dosing schedules have been less successful varying in the timing and duration of eltrombopag therapy. The primary efficacy Figure than in Hodgkin lymphoma endpoint was complete hematologic response at six months, defined as an or certain solid tumors. Dr. absolute neutrophil count of at least 1,000/mm3, a hemoglobin level of at least Label each Khodadoust and colleagues 10 g/dL, and a platelet count of at least 100,000/mm3. The primary safety sample with examined a panel of primary TMT10plex endpoint included overall safety profile in the six months after initiation of therapy. Elute MCH-II MCL samples and cell Secondary endpoints included survival and clonal evolution, defined as a new peptides Isobaric Mass lines by direct proteomic clonal cytogenetic abnormality or characteristic changes in the bone marrow Tagging antigen profiling to identify consistent with the myelodysplastic syndrome or acute myeloid leukemia. Reagents tumor neoantigens and their potential to elicit The overall complete response rate in all three cohorts was 36 percent — a Pool the an antitumor immune MCH-I individual attack. They demonstrate significant improvement over the historical control cohort (p<0.0001). The Peptide-MHC IP cohort with the longest duration of eltrombopag therapy had the highest plexes the feasibility of such an complete response rate (p<0.0001). Significant adverse events attributed to the } approach and identify genes drug included grade 2 cutaneous eruptions in two patients. The overall survival in the Ig-variable region rate at two years was 97 percent. Results of bone marrow cellularity and CD34+ LC-MS/MS to be the major source of cell counts are shown in the Figure (available in the online version of this article analysis MHC-presented lymphoma at www.hematology.org/thehematologist). neoantigens. Strikingly, these Whole neoantigens are presented A significant secondary endpoint in this study was clonal cytogenetic evolution. exome and lg almost exclusively in the The potential for clonal cytogenetic evolution was of particular interest because sequencing Neoantigen context of MHC class II, and of the well-known predisposition of patients with aplastic anemia to experience peptide the cognate neoantigen- clonal hematopoiesis. In the milieu of bone marrow failure, the small number identification specific CD4+ host T of residual stem cells attempt to maintain peripheral counts, which leads to cells are skewed to a Th2 telomere attrition resulting in chromosome instability and increasing the odds of phenotype. Why or how is harmful mutations. This eventuality was of particular concern in a trial in which unclear at this point, but it both diminished immunosurveillance and growth promotion were stimulated in Schematic of proteomic and sequencing platform may lead to tumor immune tandem. Clonal cytogenetic evolution occurred in seven patients at two years. It is used to identify tumor neoantigens. Tumor samples evasion, or even tumor cell important to note that the rates of clonal evolution in all three cohorts were within from 17 patients with mantle cell lymphoma were used progression via support the range of what would be anticipated with immunosuppression alone. to 1) isolate major histocompatibility complex (MHC) and activation by cognate ligands through immunoprecipitation (IP) followed by helper T cells. Despite this, The mechanism by which eltrombopag improves recovery of peripheral counts liquid chromatography-tandem mass spectroscopy (LC- these CD4+ T cells are in aplastic anemia is unknown. The results are particularly surprising because MS/MS) and 2) perform whole exome sequencing and able to mediate tumor cell endogenous levels of erythropoietin and other hematopoietic growth factors immunoglobulin gene sequencing in order to identify killing in an antigen specific are markedly elevated in patients with aplastic anemia but are clearly unable to neoantigen peptides. manner and autologous promote effective hematopoiesis. Furthermore, therapy with granulocyte colony- tumor vaccination results in stimulating factor in aplastic anemia is usually ineffective. Dr. Townsley and induction of anti-tumor CD4+ colleagues speculate that improved bioavailability of the synthetic agonist may T cell clones. This has therapeutic potential, especially in a group of diseases with relatively low play a role in its efficacy. mutation burden, which may be predicted to be less responsive to immune checkpoint blockade. Identification and ex vivo expansion of autologous neoantigen specific CD4+ T cells has the In summary, the potential addition of growth agonist into the immunosuppressive potential to be a new form of cell therapy for these patients. armamentarium is a promising and exciting development. A large randomized placebo-controlled trial of eltrombopag (RACE: ClinicalTrials.gov number, NCT02099747) is underway and will hopefully replicate the results of Dr. Townsley and colleagues and shed more light on potential risks of relapse and clonal evolution.

SIMONE DAVION, MD, AND TRACY I. GEORGE, MD CARON A. JACOBSON, MD Dr. Davion and Dr. George indicated no relevant conflicts of interest. Dr. Jacobson indicated no relevant conflicts of interest.

8 The Hematologist: ASH NEWS AND REPORTS HERDOO2 Score: How Long to Treat With Anticoagulation?

Rodger MA, Le Gal G, Anderson DR, et al. Validating the HERDOO2 rule to guide treatment duration for women with unprovoked venous thrombosis: multinational prospective cohort management study. BMJ. 2017;356:j1065.

atients with unprovoked venous thromboembolism (VTE) — deep vein thrombosis is a risk factor for recurrence,5-7 others have not confirmed this.8 Discrepant data also exist on (DVT) and/or pulmonary embolism (PE) — have a 30 percent risk of recurrent VTE over whether older age is a risk factor for recurrence; while some studies have found older age to be five years if anticoagulation is stopped after the initial three to 12 months of acute VTE a recurrence risk factor,8 others have not confirmed this9,10 and even found the opposite (e.g., treatment.1 While men have a higher risk of recurrence than women (over 5 years, younger age < 50 years increases risk of recurrence).11 2) The unprovoked VTE group was a P36% vs. 24%, respectively), the risk in both is considered to be high enough that evidence- mixture of true unprovoked VTE and VTE associated with minor or weak transient risk factors based guidelines recommend long-term anticoagulation for patients with unprovoked VTE, and was treated and analyzed as one homogenous group. However, previous data suggest that independent of sex, if they tolerate anticoagulation well and are not at high risk for bleeding.2,3 risk of recurrence in the unprovoked versus minor risk factor–associated groups is different.12 3) Patients with strong thrombophilias were excluded from the present study. It is not clear how In 2008, Dr. Marc A. Rodger and colleagues published the “HERDOO2 rule,” created from the inclusion of such patients would have influenced the results. Given that strong thrombophilias results of a prospective multicenter cohort study of 646 participants with a first, unprovoked are not very prevalent, inclusion would likely not have changed the results. Nevertheless, VTE treated with short-term anticoagulation.4 No predictors for a low risk of recurrence were applying this score to a more general, untested population and using it for clinical decision found in men, but in women, a low-risk group was identified (Table). They concluded that women making has some imponderability factor. 4) Only 25.4 percent of study patients were on a with unprovoked VTE with a HERDOO2 score of 0 to 1 could discontinue anticoagulation, non-warfarin anticoagulant at baseline, but many with VTE are now being treated with a direct while women with a score of at least 2, and all men, should continue. oral anticoagulant (DOAC). It is not clear whether the HERDOO2 score would also be valid if applied to patients on DOACs, as it is not known whether a D-dimer obtained while on a DOAC The work of Dr. Rodger and colleagues is a validation study of this HERDOO2 rule. 2,785 predicts recurrent VTE in a similar manner as it does while on warfarin. 5) In this study, the subjects (44.3% female) with first unprovoked VTE (proximal DVT or PE) who had completed HERDOO2 score was applied after five to 12 months of initial anticoagulation, but it is unclear five to 12 months of anticoagulation were enrolled at 44 medical centers in seven countries. if the score remains valid if applied earlier after initial VTE (i.e., after 3 months of anticoagulation, Index VTE events associated with minor or weak risk factors, such as travel, exogenous a time when many physicians are making the decision to continue or discontinue estrogens, minor immobilization or minor surgery were considered unprovoked and eligible for anticoagulation). enrollment; patients with strong thrombophilias were excluded. Women with a HERDOO2 Table: HERDOO2 Scoring Edema often decreases score of at least two and all men were advised to continue long-term anticoagulation; women after the initial DVT, with a score of zero to one were advised to discontinue anticoagulants. Patients were followed Predictor Scoring but postthrombotic for one year and assessed for the primary outcome, recurrent major VTE (proximal DVT and pigmentation increases, H Hyperpigmentation 1 point total, segmental or greater PE). Not all patients followed the recommendation to discontinue or and these changes if any one of continue anticoagulation based on the decision rule’s risk assessment, allowing a risk of E Edema these criteria may influence the recurrence assessment in the various groups listed below. R Redness of either leg is present HERDOO2 score if obtained at an earlier In low-risk women who discontinued anticoagulation (n = 591), VTE recurrence per patient- D D-dimer ≥ 250 μg/L while anticoagulated 1 point time. year was 3.0 percent (95% CI, 1.8-4.8%). In high-risk women and men who discontinued O Obesity with BMI 30 kg/m2 1 point anticoagulation (n = 323), it was 8.1 percent (95% CI, 5.2-11.9%). In high-risk women and men ≥ To discuss and decide who continued anticoagulation (n = 1,802), it was 1.6 percent (95% CI, 1.1-2.3%), and in high- O Older age, i.e. ≥ 65 years 1 point with the patient who has risk women who discontinued anticoagulation (n = 101), VTE recurrence per patient-year was a VTE how long to treat Decision Making: 7.4 percent (95% CI, 3.0-15.2%). with anticoagulation, Women: 0-1, discontinue anticoagulation; 2, continue anticoagulation. ≥ we use the recurrence All men: continue long-term anticoagulation. This study validated the original HERDOO2 rule: Women with a first unprovoked VTE event triangle depicted in the and a HERDOO2 score of 0 to 1 have a low risk of recurrent VTE and can safely discontinue Figure. In patients at anticoagulants, whereas women with a score of at least 2, and all men, have a high risk of intermediate risk of recurrence (patient “B”), situations where we or the patient is ambivalent recurrence and should continue long-term anticoagulation. Noteworthy is that 51.3 percent as to whether to stop anticoagulation, or in women with true unprovoked VTE with a strong of women with unprovoked VTE were classified as low risk, appropriate for discontinuation of preference to come off anticoagulation, we use the D-dimer as an aid in decision making. anticoagulation. Thus, long-term anticoagulation, as recommended by existing guidelines, could It is also this group of patients in which we contemplate obtaining a thrombophilia work- be avoided in a substantial number of women if following HERDOO2. up, as finding a strong thrombophilia predicts a higher risk of recurrent VTE (i.e., moves the patient down in the recurrence triangle). However, caveats are that strong thrombophilias are We do not routinely use the HERDOO2 score for decision-making on length of anticoagulation uncommon and a large number of patients would need to be tested to find one case of a strong in women with a history of unprovoked VTE, for five reasons. 1) There is equivocal evidence thrombophilia, and some discrepant data exist on what truly constitutes a “strong thrombophilia.” in the literature that the predictors identified in the HERDOO2 cohort are universal predictors of recurrence in women. Discrepant data exist on whether obesity is truly a risk factor for Finally, we do apply the HERDOO2 score to women in the intermediate risk of recurrence recurrence; while some studies have, similar to Dr. Rodger and colleagues, found that obesity group in the triangle to see whether it matches the decision making that we arrive at with the D-dimer result (± strong thrombophilia) alone. However, none of the predictors of VTE Figure recurrence should be used dogmatically or with too much confidence in the predictor’s validity, given the number of limitations discussed above.

1. Kearon C, Akl EA. Duration of anticoagulant therapy for deep vein thrombosis and pulmonary embolism. Blood. 2014;123:1794-1801. 2. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149:315-352. 3. Streiff MB, Agnelli G, Connors JM, et al. Guidance for the treatment of deep vein thrombosis and pulmonary embolism. J Thromb Thrombolysis. 2016;41:32-67. 4. Rodger MA, Kahn SR, Wells PS, et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ. 2008;179:417-426. 5. Eichinger S, Hron G, Bialonczyk C, et al. Overweight, obesity, and the risk of recurrent venous thromboembolism. Arch Intern Med. 2008;168:1678-1683. 6. Heit JA, Mohr DN, Silverstein MD, et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med. 2000;160:761-768. 7. Olié V, Zhu T, Martinez I, et al. Sex-specific risk factors for recurrent venous thromboembolism. Thromb Res. 2012;130:16-20. 8. Vučković BA, Cannegieter SC, van Hylckama Vlieg A, et al. Recurrent venous thrombosis related to overweight and obesity: results from the MEGA follow-up study. J Thromb Haemost. 2017;doi:10.1111/jth.13710. [Epub ahead of print]. 9. Eischer L, Eichinger S, Kyrle PA. Age at first venous thromboembolism and risk of recurrence: a prospective cohort Recurrence triangle. Patient A: major transient risk factor associated VTE; patient B: minor/ study. Medicine (Baltimore). 2009;88:366-370. weak risk factor associated VTE, such as travel, estrogens, minor immobility, minor surgery; patient 10. Christiansen SC, Lijfering WM, Helmerhorst FM, et al. Sex difference in risk of recurrent venous thrombosis an the risk C, woman with true unprovoked VTE; patient D, man with unprovoked VTE. Abbreviations: DD, profile for a second event. J Thromb Haemost. 2010;8:2159-2168. D-dimer; VTE, venous thromboembolism. 11. Tosetto A, Iorio A, Marcucci M, et al. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J Thromb Haemost. 2012;10:1019-1025. ºVTE is a proximal deep vein thrombosis or pulmonary embolism. 12. Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism *HERDOO2 score is only to be used in women. provoked by a transient risk factor: a systematic review. Arch Intern Med. 2010;170:1710-1716.

DAMON E. HOUGHTON, MD, MSc, AND STEPHAN MOLL, MD Dr. Houghton and Dr. Moll indicated no relevant conflicts of interest.

The Hematologist: ASH NEWS AND REPORTS 9 Redefining Induction Failure Is Upfront Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma the Standard?

O’Connor D, Moorman AV, Wade R, et al. Use of minimal residual disease assessment to redefine Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, induction failure in pediatric acute lymphoblastic leukemia. J Clin Oncol. 2017;35:660-667. bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376:1311-1320.

raditionally, remission status has been determined by bone marrow morphology at the end of the igh-dose melphalan with autologous stem cell transplantation induction phase of treatment in acute lymphoblastic leukemia (ALL). Minimal residual disease (MRD) is an important consolidative strategy for treating multiple testing is now routinely performed in conjunction with morphologic assessment to determine the myeloma. However, a core question is the timing of intensive depth of remission, and MRD response is the most powerful prognostic determinant. Although the treatment when combination regimens such as lenalidomide, vastT majority of children achieve a remission (<5% blasts by morphology) with frontline induction therapy, bortezomib,H and dexamethasone (RVD) can achieve deep responses a small percentage fail induction. While in the majority of cases MRD assessments are concordant with with minimal toxicity. Recently, the Intergroupe Francophone du Myélome morphology, discordance can be observed. This raises the question of how to determine induction response (IFM) reported the results of a large phase III trial, IFM 2009, that was most reliably, as patients with persistence of a high tumor burden at the end induction fare poorly with designed to answer the question of when to undergo autologous stem conventional treatment and may be candidates for alternative therapies. cell transplantation: upfront as part of the initial treatment, versus at time of relapse. To address the question of the role and accuracy of conventional morphology and MRD in defining induction failure, Dr. David O’Connor and colleagues analyzed 3,113 pediatric patients with newly diagnosed ALL who In this trial, all patients (N=700) received standard induction with RVD were treated on the Medical Research Council UKALL 2003 trial. All patients underwent routine morphologic for three cycles followed by stem cell collection. The patients were assessment of marrow response at individual treating centers at the end of induction (EOI), and response then randomized to upfront transplant with high-dose melphalan and was categorized as M1 (<5% blasts), M2 (5-25% blasts), or M3 (>25% blasts). Induction failure was autologous stem cell transplantation, followed by consolidation with defined as failure to achieve morphologic complete remission (<5% bone marrow blasts). In parallel, bone two additional cycles of RVD. The other half went on to five additional marrow MRD was measured at one of five laboratories in the United Kingdom using standardized real-time cycles of RVD for a total of eight cycles. Following completion of initial quantitative polymerase chain reaction for immunoglobulin and T-cell receptor gene rearrangements, with treatment, both groups received maintenance lenalidomide for one year. a cutoff of 0.01 percent used to define MRD positivity. All patients underwent routine cytogenetic testing The median progression free survival (PFS) was significantly longer for chromosomal abnormalities of known prognostic significance. Patients lacking established cytogenetic in the upfront arm than in the deferred arm, 50 versus 36 months alternations were designated “B-other,” and a representative cohort of these patients underwent additional (p<0.001). Depth of response was also higher in patients who received testing for ABL1, ABL2, PDGFRB, CSF1R, CRLF2, and JAK2 rearrangements. intensive therapy initially, based on achieving complete response (59% vs. 48%; p=0.03) and absence of minimal residual disease (MRD; 79% Fifty-nine patients (1.9%) had morphologic induction failure at the EOI, with 44 M2 and 15 M3 marrow vs. 65%; p<0.001). (Of note, MRD was measured by a flow cytometry responses. Patients with M2 marrow responses received intensified chemotherapy on protocol, whereas assay with a sensitivity of 1×10-4, which is less sensitive than current those with M3 marrow responses were taken off protocol to receive salvage therapy. Patients with assays such as by next- generation sequencing.) Overall, patients morphologic induction failure had poor outcomes, with a five-year event-free survival (EFS) of 50.7 percent who were MRD-negative had improved PFS and overall survival (OS) and a five-year overall survival (OS) of 57.7 percent, and outcomes did not differ significantly among those compared with MRD-positive patients (HR, 0.3 and 0.34, respectively). who underwent hematopoietic stem cell transplantation. Not unexpectedly, induction failure was associated However, at four years, OS was similar, at 81 percent versus 82 percent with high-risk clinical and cytogenetic features. between the MRD-negative and MRD-positive arms, respectively. As expected, there were more adverse events related to myelosuppression The authors analyzed the relationship between morphologic response and molecular MRD at the EOI. While and gastrointestinal adverse effects in the upfront transplant arm. Also of there was concordance between MRD and morphologic responses in the vast majority of cases, 61 patients interest were four cases of acute myelogenous leukemia in the upfront (2.3%) were identified with M1 marrow morphologic responses but with discordantly high MRD levels of arm versus one case in the deferred arm. at least 5 percent. These patients had a five-year EFS of 47 percent that was comparable to morphologic induction failure (5-year EFS, 50.7%). Discordantly high MRD in patients in morphologic remission was more The results from this study are key for helping to frame the discussion common in children with T-cell ALL (8%) than B-lineage ALL (1.5%), p<0.001. Conversely, another very with patients about the timing of transplant. The induction regimen of small group of six discordantly low MRD patients was identified with morphologic induction failures (M2) but RVD used in the study reflects current practice, especially given the with MRD less than 0.01 percent and this group had a five-year EFS of 100 percent. recent SWOG trial showing superiority of the triplet compared with lenalidomide and dexamethasone.1 The trial illustrates the importance of Approximately one third of the induction failure patients defined by both morphology and MRD levels of 5 depth of response correlating with improved outcomes, and an upfront percent or greater fell into the “B-other” cytogenetic group, where expanded testing for genetic fusions was approach provides a means for achieving this. Despite the significant performed. Notably, EBF1-PDGFRB fusions, which have been successfully targeted with imatinib, were improvement in PFS, there was no OS advantage. This is likely a detected in approximately 10 reflection of the evolving maturity of the data. Importantly, in the deferred Figure percent of induction failure arm, 21 percent of patients were not able to receive a salvage transplant patients overall. Based on the due to refractory disease, and there were also an increased number of findings in this report, the UK myeloma-related deaths. group has revised their definition of induction failure to include at The DETERMINATION trial (NCT01208662) is an ongoing investigation least 5 percent residual disease in the United States that parallels the IFM study with the same trial by either MRD or morphology. design. The DETERMINATION trial is actively accruing patients, and Thus the new definition doubles the findings from this study will be an important complement to the IFM the number of induction study. The main difference in the U.S. arm of the trial is the duration failures (Figure). Given the high of maintenance lenalidomide. In the U.S. arm, patients are maintained proportion of adverse cytogenetic until relapse, whereas in the IFM study, maintenance was for one year alterations in this group, patients only. Maintenance lenalidomide is increasingly becoming adopted with induction failure now also as standard practice in the United States based on trials showing undergo expanded cytogenetic improvement in PFS, and in a meta-analysis, improvement in OS.2 testing for targetable fusions. Results from DETERMINATION will provide greater clarity on how long to use maintenance lenalidomide and whether longer maintenance This report provides important will narrow the gap in PFS between upfront and deferred transplant new insight into improving the approaches. Additionally, the larger number of patients, when combined accuracy of induction response with the IFM study, may help identify subgroups who benefit more from assessment by incorporating upfront transplant. In the IFM study, there was no statistically significant MRD. While this report suggests improvement in PFS for patients with high-risk disease, based on that treatment response may be International Staging System (ISS) III staging or by cytogenetics, though more accurately determined by this may reflect the smaller number of patients in these groupings. MRD alone, given the relatively Finally, there will be more robust data from MRD assessments using small number of discordant a more sensitive sequencing assay, which is relevant since achieving cases, confirmatory studies using MRD negative status resulted in improved disease control irrespective different MRD methodologies of treatment arm. This may help clarify if patients who are MRD negative and therapeutic backbones are may consider a deferred transplant approach. Overall, the results from presently underway. Additionally, the U.S. arm, combined with the IFM 2009 results, will provide valuable the MRD threshold that optimally guidance on the place of autologous stem cell transplantation and help Event-free survival (EFS) in 120 patients with induction failure on the defines a poor risk group remains individualize treatment for newly diagnosed patients. basis of new criteria (M2 and M3 marrow and/or end of induction to be defined. This work is anticipated to lead to a revised 1. Durie BG, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone minimal residual disease ≥5%) compared with those patients who versus lenalidomide and dexamethasone alone in patients with newly diagnosed achieved complete remission at the end of induction. Data indicate universal definition of induction myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a eight-year EFS estimates. Numbers within each group are indicated in failure in the future, identifying randomised, open-label, phase 3 trial. Lancet. 2017;389:519-527. the at-risk table beneath the graph. O/E, observed/expected. Reprinted an expanded group of patients 2. Attal M, Palumbo A, Holstein SA, et al. Lenalidomide (LEN) maintenance (MNTC) after with permission. © 2017 American Society of Clinical Oncology. All with poor outcomes, who may high-dose melphalan and autologous stem cell transplant (ASCT) in multiple myeloma (MM): a meta-analysis (MA) of overall survival (OS). J Clin Oncol. 2016;34:8001. rights reserved. benefit from alternative treatment approaches.

ELIZABETH RAETZ, MD ANDREW J. YEE, MD, AND NOOPUR RAJE, MD Dr. Raetz indicted no relevant conflicts of interest. Dr. Yee and Dr. Raje indicated no relevant conflicts of interest.

10 The Hematologist: ASH NEWS AND REPORTS Cellular Heterogeneity Based on Microniches Cautiously Optimistic About Gene Therapy in Sickle Cell Disease: A New Arrow in the Quiver for Cure

Oyler-Yaniv A, Oyler-Yaniv J, Whitlock BM, et al. A tunable diffusion- Ribeil JA, Hacein-Bey-Abina S, Payen E, et al. Gene therapy in a patient with sickle cell consumption mechanism of cytokine propogation enables plasticity in cell- disease. N Engl J Med. 2017;376:848-855. to-cell communication in the immune system. Immunity. 2017;46:609-620.

ematologists and immunologists are often focused on cellular heterogeneity. ntil recently, two major barriers limited cure for individuals with sickle cell disease New markers or transcriptome profiles are ever increasing, breaking down (SCD). First, for both children and adults, there has been a paucity of donors blood and tissue resident cells into smaller and more discrete “cell types.” — estimated at only 18 percent of those considering hematopoietic stem cell With the emergence of single-cell RNA sequence profiling, heterogeneity is transplantation (HSCT).1 Second, myeloablative conditioning regimens had typically Ubeen too toxic for adults. Over the past 10 years, however, two strategies have emerged to beingH discovered in what were thought to be more or less homogenous cell populations. address these intrinsic challenges, making cure a realistic outcome in an increasing number of Recent work from Dr. Alon Oyler-Yaniv and colleagues outlines research strategies children and adults with SCD. The first strategy is nonmyeloablative HSCT; it recently has been for the future, and may help to explain some of this heterogeneity. The premise of successfully applied in adults with SCD, with HLA-matched sibling donors. To increase the pool their work is that cell-to-cell communication via cytokines in tissues is dependent of donors, the most promising experimental strategy is the use of haploidentical transplantation on the ability of that cytokine to diffuse from the source, and on the number of cells with posttransplant cyclophosphamide — a nonmyeloablative strategy2 with greater than 90 consuming the cytokine. Therefore, in a tissue with a high number of cells that have a percent donor availability. Gene therapy is now a second strategy to increase the donor pool, at receptor for the cytokine (consumers), the relative distribution of a cytokine produced least in children with SCD. by a cell will be low, creating a small “cytokine niche” (Figure). In contrast, a tissue with a low number of consumers will have more distribution, creating a larger niche. Dr. Jean-Antoine Ribeil and colleagues should be congratulated on performing the first ever successful gene therapy trial in SCD. The technical, scientific, and research governance barriers To test the effect of diffusion-consumption on cytokine responses, the authors chose were significant, and the authors clearly addressed each one successfully. Equally laudable to use a model of regulatory T cells (Treg) as the consumers, as they have high levels is the bravery of the participant and the of the high-affinity IL-2 receptor a chain (IL-2Ra). Because normal tissue culture Figure participant’s family. The family’s altruism and plates have cells at too low of a density to be representative of solid tissue density trust in both their clinical and research teams and to allow the medium to uniformly mix, the authors fabricated their own 96-well HSPC should not be taken lightly. The gene therapy Transplant plate that they named “the clusterwell plate.” This allowed cell suspensions to be was designed using the LentiGlobin BB305 loaded into the plate and then centrifuged to created densely packed cell cultures. (Bluebird Bio) vector, which encodes for the Using this clusterwell plate, the authors created cell suspensions with various ratios human hemoglobin B genetic variant. Briefly, of Tregs and of CD4 depleted splenocytes, which do not respond to IL-2 and are Modified HSPCs bone marrow harvest was obtained twice, and thus “inert cells” in their model system. This created scenarios where the total number CD34+ (stem) cells were transduced with the of cells was the same, but the number of consumers was altered. To measure the LentiGlobin BB305 vector (Figure). Next, a myeloablative dose of busulfan with area under effects of diffusion-consumption, the authors intracellularly stained for pSTAT5, which Gene Therapy is immediately downstream of the IL-2 receptor. The authors demonstrate that as the (e.g., globin gene insertion, the curve 19,363 μmol/min was administered, density of consumers decreased, a larger fraction of the CD4+ IL-2Ra+cells were gene editing, etc.) and after a two-day washout period, the + 6 + exposed to IL-2 and were positively stained for pSTAT5. In contrast, as the consumer Patient transduced CD34 cells (5.6 × 10 CD34 density increased, pSTAT5 staining decreased. In fact, labeled cells at the bottom cells/kg) were infused. Fifteen months after of the well were unable to respond to IL-2 when consumer density was higher, Bone completion of the procedure, the participant demonstrating a restricted cytokine distribution in these cultures. marrow did not report any vaso-occlusive pain harvest episodes, and the level of donor beta globin To visualize these microniches created by diffusion-consumption of IL-2, the authors production was approximately 50 percent. developed an imaging assay they called PlaneView imaging. The authors mixed either HSPCs consuming T cells or a combination of 10 percent consumers and 90 percent inert Why the optimism? As a proof of principle, splenocytes with 0.1 percent IL-2–producing T cells. This mixture was then deposited gene therapy for SCD is a therapeutic in a monolayer on a glass slide, and 10 more layers of cells without producers were Typical process of gene therapy for paradigm shift. Theoretically, donor availability added, creating a three-dimensional system with a small number of producers on the hematopoietic disorders. Hematopoietic is no longer an obstacle for children and adults bottom. When pSTAT5 was then imaged, spherical microdomains of IL-2 response stem and progenitor cells (HSPCs) can be with SCD. With the rapid pace of transplant were seen. In settings where 100 percent of the cells were consumers, the length modified directly, as is the case for currently biology research, conditioning regimens are scale of the cytokine niche was approximately 3.5 cell diameters, while the 10 used therapies. The genetically modified expected to evolve from myeloablative to percent consumer setting (with the same total number of cells) was approximately HSPCs are then transplanted back into nonmyeloablative approaches. Until such 13.5 cell diameters. the patient. When HSPCs are modified advances, gene therapy will most likely be directly, modification may not occur in every restricted to children rather than adults with This study demonstrates that spatial heterogeneity, created by diffusion-consumption cell. Goodman MA et al, Ther Adv Hematol. SCD who may not tolerate the current high 15(5):302-315, copyright © 2016 by SAGE cytokine gradients, can result in downstream heterogeneity of a cell population that dose of busulfan. Publications. Reprinted by Permission of otherwise would be SAGE Publications, Ltd. Figure considered homogenous. Why the caution? Children with SCD living In in vivo studies, these in high-income countries no longer have a microniches were also life-threatening disease, but rather a chronic disease with disease-associated, life-threatening demonstrated by the events. Two large observational studies in children with SCD indicated 15-year–3 and 16-year4 authors in immune Kaplan-Meier survival estimates of approximately 99 percent with and without hydroxyurea tissues and could therapy, respectively. A third cohort study of children with SCD from a region in Paris, France, dynamically change indicated that after introduction of the online guidelines, there was also an increase in the overall depending on stimuli. five-year survival from 98.3 percent to 99.2 percent.5 In terms of morbidity, the rate of stroke in a Given the abundance population of children with SCD can drop a log-fold at SCD centers screening with transcranial of single-cell RNAseq Doppler and subsequently treating those with abnormal values with regular blood transfusions profiling being performed for at least a year, then switching to therapy with hydroxyurea indefinitely. For children with SCD in tissues, tumors, etc., living in low- and middle-income countries, where approximately 90 percent of all children with spatial organization of SCD are born, gene therapy is not an option. In summary, gene therapy to treat children with the cells within a tissue SCD is currently restricted to those who: 1) have severe disease; 2) have failed blood transfusion needs to be considered or hydroxyurea therapy; 3) require treatment for comorbidities; 5) live in a high-income country; and may account and 6) are not likely to die from the disease in childhood. Given the known short-and long-term for transcriptomic toxicities of myeloablative doses of busulfan, the calculated trade-off of gene therapy is that the differences that are benefits will outweigh the unknown late potential adverse effects of busulfan in this population. completely independent of underlying genetic The bottom line is that gene therapy provides a new option for curing SCD, a disease that differences amongst still remains with only one Food and Drug Administration–approved disease-modifying agent, hydroxyurea. The SCD community remains cautiously optimistic that some of the intrinsic Diagram of simple diffusion-consumption kinetics. cells. As the bone challenges with gene therapy for SCD will be overcome with the rapid advancement of transplant Cytokines are secreted by a producing cell and freely marrow hematopoietic diffuse between cells. Upon binding to a receptor, the niche is densely packed immunobiology. and contains a high cytokine is endocytosed, or consumed. This creates a 1. Mentzer WC, Heller S, Pearle PR, et al. Availability of related donors for bone marrow transplantation in sickle cell anemia. gradient of localized cytokine niche with a typical length variability of cells, it Am J Pediatr Hematol Oncol. 1994;16:27-29. scale of lniche. Increasing consumers will lead to a is possible that these 2. Bolaños-Meade J, Fuchs EJ, Luznik L, et al. HLA-haploidentical bone marrow transplantation with posttransplant decrease in the lniche, and vice versa. When lniche is small same cytokine or growth cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood. 2012;120:4285-4291. relative to the total organ size, increases in cell-to-cell factor microniches exist, 3. Lê PQ, Gulbis B, Dedeken L, et al. Survival among children and adults with sickle cell disease in Belgium: benefit from variability are likely. (Reprinted from Immunity, Vol 46, Oyler- perhaps governing hydroxyurea treatment. Pediatr Blood Cancer. 2015;62:1956-1961. Yaniv A et al, A Tunable Diffusion-Consumption Mechanism hematopoiesis at very 4. Telfer P, Coen P, Chakravorty S, et al. Clinical outcomes in children with sickle cell disease living in England: a neonatal of Cytokine Propagation Enables Plasticity in Cell-to-Cell defined locales within the cohort in East London. Haematologica. 2007;92:905-912. Communication in the Immune System, pp 609-620, bone marrow space. 5. Couque N, Girard D, Ducrocq R, et al. Improvement of medical care in a cohort of newborns with sickle-cell disease in North Copyright 2017, with permission from Elsevier.) Paris: impact of national guidelines. Br J Haematol. 2016;173:927-937.

JONATHAN HOGGATT, PhD MICHAEL R. DEBAUN, MD Dr. Hoggatt indicated no relevant conflicts of interest. Dr. DeBaun indicated no relevant conflicts of interest.

The Hematologist: ASH NEWS AND REPORTS 11 AYA Treatment Disparities (Cont. from page 2) “And Then There Were 10”: Dendritic Cells and Monocytes group, and broadening the potential to form intergroup trials Undergo a Reclassification with the expertise of both pediatric and adult hematologist/ oncologists. In November 2013, the COG AYA committee and Villani AC, Satija R, Reynolds G, et al. Single-cell RNA-seq reveals new types of human blood dendritic the SWOG AYA committee formed the NCTN AYA Working cells, monocytes, and progenitors. Science. 2017. doi:10.1126/science.aah4573. [Epub ahead of print.] Group with the primary objectives of increasing enrollment of AYA patients onto NCTN trials and developing AYA- focused clinical trials.21 To further spread the knowledge we axonomy is a science that struggles to be fashionable. The great evolutionary biologist Steven Jay Gould have obtained in the past 10 years, hematology/oncology commented that “Taxonomy is often regarded as the dullest of subjects, fit only for mindless ordering and professionals must also structure targeted educational sometimes denigrated as mere ‘stamp collecting.’” Yet, medicine needs order, and who could deny that opportunities for physicians. the classic chart of “blood cell differentiation,” beloved of scuffed laboratory walls, is imprinted onto the hippocampalT map of all hematologists? Greater than 25 percent of AYA patients are treated at community centers.22 The NCI community oncology research Classification systems reflect current technology, and it is no surprise to witness the inexorable dominance of program (NCORP) was established to expand access of NCTN molecular biology. In this remarkable article, Dr. Alexandra-Chloé Villani and colleagues at the Broad Institute deliver a trials to patients treated in the community and patients radical revision of the classification of dendritic cells and monocytes. afflicted by health disparities.21 Additionally, as the increase in AYA oncology programs continues,5 we must also lead the The breathtaking capabilities of contemporary molecular biology lie at the heart of the analysis. In particular, the work charge for recruiting and retaining AYA-focused hematology/ focuses on the use of RNA-Seq, a procedure in which all of the mRNA sequences inside a cell are sequenced such oncology professionals. This can be in accomplished in that a complete map of the transcriptional activity can be generated. This technology is the mRNA equivalent of “next various ways, such as dual training in internal medicine generation DNA sequencing” and is rapidly replacing microarray analysis. Perhaps even more remarkable is that this or pediatrics followed by a combined pediatrics and adult work was done on single cells. This combination of detailed transcriptional assessment and single-cell analysis offers hematology/oncology fellowship, or additional AYA-focused remarkable possibilities for future biological insights. Of the 30,000 genes available within our DNA, around 5,000 fellowship training after initial certification in adult or are expressed at any time in a single cell, and RNA-Seq normally sequences around 1 million reads such that the pediatric hematology/oncology. technology can discover not only which genes are being expressed but also how many mRNA transcripts are present in the cell. The AYA population is a unique, high-risk group of patients Dendritic cells (DCs) are relative youngsters within hematopoiesis, characterized by Dr. Ralph Steinman in 1973, and facing malignant diseases at an age where they are transitioning broadly classified into conventional DCs (cDCs), which express CD11c, and CD123+ plasmacytoid DCs (pDCs). to independence. It is a time at which they can emotionally cDCs are highly efficient at priming T cell immune responses whereas pDCs are potent producers of interferon-α in comprehend the burden of their disease, yet may not be as response to viral infection. Monocytes are a more familiar feature on our blood smears and have also undergone a established socially, financially, and emotionally as their adult binary subdivision through immunophenotyping into classical CD14++ and nonclassical CD14+CD16++ subsets. counterparts, and may not have the comparable support structure as younger patients. Although we should be proud of In this data-rich but wonderfully accessible article, the authors undertook RNA-Seq on 2,400 single DCs (defined as the progress that has taken place in the past decade, we cannot HLA-DR+ lineage–) and monocytes (CD14+ lineage–) from a single individual. Sequence data were analyzed through lose momentum — we need to build the strong and sustainable a statistical approach called principal component analysis (PCA), which categorized dendritic cells into six major foundation for treatment that our AYA patients deserve. subgroups, while monocytes fell into four subtypes. Surface markers were then used to isolate these subsets, confirm that the cells retained the original RNA profile, and show that the pattern was common in 10 different subjects. Dr. Isenalumhe indicated no relevant conflicts of interest.

Several novel findings emerge from the reclassification of dendritic cells into six subtypes, termed DC1 to DC6. 1. National Cancer Institute. A snapshot of adolescent and young adult CD11c+ conventional DCs can be subdivided into those that are CD141+ or CD1C+, or indeed lack both of these cancers. [Cited 2015, Nov 28]; Access via: www.cancer.gov/research/ molecules. In the new classification, the CD141+ subset becomes DC1 and is renamed CLEC9A+ DC on the basis progress/snapshots/adolescent-young-adult. + 2. Albritton K, Caligiuri M, Anderson B, et al. Closing the gap: research and that CLEC9A is a perfect discriminative marker. The CD1C subset is split into two groups, with differential MHC care imperatives for adolescents and young adults with cancer. Natl Cancer class II or monocytic gene expression (termed DC2 and DC3), while the DC4 group represents the CD1C and Inst. 2006;06-6067. CD141 “double negative” group. DC5 is a completely new subset, representing 2 to 3 percent of DCs, and has 3. Bleyer WA. Cancer in older adolescents and young adults: epidemiology, been termed “AS DC” on the basis of expression of AXL and SIGLEC genes. Finally, DC6 represents the original diagnosis, treatment, survival, and importance of clinical trials. Med pDC subset. Pediatr Oncol. 2002;38:1-10. 4. Isenalumhe L, Fridgen O, Beaupin LK, et al. Disparities in adolescents and young adults with cancer. Cancer Control. 2016;23:424-433. Also of note was the finding of a small population of cDC progenitor cells, representing one in 5,000 of the DC + intermediate 5. Ferrari A, Barr RD. International evolution in AYA oncology: current status population, with a CD100 CD34 phenotype. Morphology plays a role here and shows these cells to possess and future expectations. Pediatr Blood Cancer. 2017;e26528. [Epub ahead a high nuclear-to-cytoplasmic ratio with circular or indented nuclei. of print]. 6. Keegan THM, Ries LAG, Barr RD, et al. Comparison of cancer survival The team went on to study monocytes, defined as CD14+lineage–, and delineated four subtypes — two major subsets trends in the United States of adolescents and young adults with those in defined by CD14+ and CD16 expression, and a further two, one with cytotoxic genes and the other with an unknown children and older adults. Cancer. 2016;122:1009-1016. 7. Barr RD, Ries LAG, Lewis DR, et al. Incidence and incidence trends of the function. most frequent cancers in adolescent and young adult Americans, including “nonmalignant/noninvasive” tumors. Cancer. 2016;122:1000-1008. Several practical lessons are readily apparent from this classification. Functionally, the DC1 through DC5 subsets 8. Tricoli JV, Blair DG, Anders CK, et al. Biologic and clinical characteristics are capable of stimulating strong T cell responses, whereas DC6 operates primarily for interferon production. The of adolescent and young adult cancers: acute lymphoblastic leukemia, description of a progenitor pool colorectal cancer, breast cancer, melanoma, and sarcoma. Cancer. will allow potential expansion of 2016;122:1017-1028. 9. Tricoli JV, Seibel NL, Blair DG, et al. Unique characteristics of adolescent DC cells in vitro with considerable and young adult acute lymphoblastic leukemia, breast cancer, and colon opportunities for genetic cancer. J Natl Cancer Inst. 2011;103:628-635. manipulation. Additionally, it will 10. Mullighan CG, Willman CL. Advances in the biology of acute lymphoblastic prove possible to understand more leukemia-from genomics to the clinic. J Adolesc Young Adult Oncol. closely how DC tumors arise during 2011;1:77-86. differentiation, and Dr. Villani and 11. Bleyer WA, Barr RD. Cancer in adolescents and young adults. Springer- Verlag Berlin Heidelberg. 2007. doi:10.1007/978-3-540-68152-6. colleagues begin this process by 12. Heerema NA, Carroll AJ, Devidas M, et al. Intrachromosomal amplification showing that the rare condition of of chromosome 21 is associated with inferior outcomes in children with blastic plasmacytoid DC neoplasia acute lymphoblastic leukemia treated in contemporary standard-risk is most closely related to the pDC children’s oncology group studies: a report from the children’s oncology (DC6) subset. group. J Clin Oncol. 2013;31:3397-3402. 13. Creutzig U, Kutny MA, Schlenk RF. Acute myelogenous leukemia. In: Cancer in Adolescents and Young Adults. Springer-Verlag Berlin Heidelberg. It should be remembered that this 2007;10.1007/978-3-540-68152-6. classification will itself ultimately be 14. Grassley CE. Living Without Health Insurance: Hearing Before the Committee refined and replaced. It is based on Finance, US Senate. DIANE Publishing; 2001 [Cited 2015, Dec 1]. Access solely on transcriptional activity, via: https://www.congress.gov/108/crpt/srpt31/CRPT-108srpt31.pdf. without regard for features such 15. Martin S, Ulrich C, Munsell M, et al. Delays in cancer diagnosis in underinsured young adults and older adolescents. Oncologist. as phenotype and function, and 2007;12:816-824. assesses cells in their resting state, 16. Smith JC, Medalia C. Health Insurance Coverage in the United States: 2013. without considering factors such US Department of Commerce, Economics and Statistics Administration, as inflammation. Nevertheless, this Bureau of the Census. 2014 [Cited 2015, Dec 17]. Access via: www.nber.org/ report represents a considerable cps/hi/2014redesign/p60-250.pdf. advance in our understanding of 17. Smith EC, Ziogas A, Anton-Culver H. Association between insurance and socioeconomic status and risk of advanced stage Hodgkin lymphoma in Establishing a human blood monocyte and dendritic cell atlas. these important innate immune adolescents and young adults. Cancer. 2012;118:6179-6187. Researchers isolated approximately 2,400 cells enriched from the healthy human subsets. We can now expect 18. Rosenberg AR, Kroon L, Chen L, et al. Insurance status and risk of cancer blood HLA-DR+ lineage− compartment and subjected them to single-cell RNA this approach to be used for all mortality among adolescents and young adults. Cancer. 2015;121:1279-1286. sequencing. This strategy, together with follow-up profiling and functional and subsets within the hematologic 19. Wolfson JA, Sun CL, Wyatt LP, et al. Impact of care at comprehensive phenotypic characterization, led them to update the original cell classification to lineage. That hippocampal map of cancer centers on outcome: Results from a population-based study. include six dendritic cells (DCs), four monocyte subtypes, and one conventional hematopoiesis is going to get a lot Cancer. 2015;121:3885-3893. DC progenitor. From Villani AC et al. Single-cell RNA-seq reveals new types 20. Wolfson J, Sun CL, Wyatt L, et al. Adolescents and young adults with more complicated. acute lymphoblastic leukemia and acute myeloid leukemia: impact of of human blood dendritic cells, monocytes, and progenitors. Science. 2017. care at specialized cancer centers on survival outcome. Cancer Epidemiol doi:10.1126/science.aah4573. Reprinted with permission from AAAS. Biomarkers Prev. 2017;26:312-320. 21. Weiss AR, Nichols CR, Freyer DR. Enhancing adolescent and young adult oncology research within the national clinical trials network: rationale, progress, and emerging strategies. Semin Oncol. 2015;42:740-747. PAUL MOSS, PhD 22. Yeager ND, Hoshaw-Woodard S, Ruymann FB, et al. Patterns of care Dr. Moss indicated no relevant conflicts of interest. among adolescents with malignancy in Ohio. J Pediatr Hematol Oncol. 2006;28:17-22.

12 The Hematologist: ASH NEWS AND REPORTS NIDDK Announcement: Resources and Funding Available for Research in Nonmalignant Hematology

TERRY ROGERS BISHOP, PhD, ON BEHALF OF THE NIDDK CCEH CONSORTIUM Program Director, Division of Kidney, Urologic, and Hematologic Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health; Bethesda, MD

The Division of Kidney, Urologic, and to contact the core director of the facility prior to • Assistance with hematopoiesis assays (e.g., murine bone Hematologic Diseases (KUH) of the National submission of the application. marrow collection, fluorescence-activated cell sorting, Institute of Diabetes and Digestive and colony-forming units) Kidney Diseases (NIDDK) supports a The consortium consists of 17 core facilities that provide: • CRISPR libraries consortium of Cooperative Centers of Excellence in Hematology (CCEH). Each • CD34 purified primary human hematopoietic stem/ • Zebrafish and other model organisms for the study of center is composed of three to four biomedical research progenitor cells, granulocyte colony-stimulating factor human hematologic diseases core facilities providing state-of-the-art cellular and mobilized and nonmobilized apheresis collections • Metabolomic profiles on large and small numbers of cells molecular biology tools or reagents and expertise. They • Xenotransplantation studies (including highly engineered each award pilot and feasibility projects as well as • Heme and iron quantitative assays humanized mice and large animal models) providing structured enrichment programs with visiting • Angiogenic assays, especially during hematopoietic scholars and instructional presentations. • High-resolution microscopy (with cytoskeleton and development in the fetal liver hematopathology expertise) • Flow cytometry assays. The NIDDK-supported consortium seeks to build and • Time-lapse microscopy provide research infrastructure in the field of nonmalignant The table below provides contact information for the hematology. This activity helps to achieve the NIDDK • Human induced pluripotent stem cells generation currently funded NIDDK CCEHs. director’s vision of maintaining a vigorous investigator- • Multiple genome editing procedures, predominantly, initiated research portfolio; preserving a stable pool CRISPR/Cas-9 For more information, access each center’s website. of talented new investigators; fostering exceptional • Assistance with retroviral/lentiviral design and The charge for each service is available by contacting research training and mentoring opportunities; and production the center directly. Additionally, each center is seeking ensuring knowledge dissemination through outreach and collaborations for new pilot and feasibility projects that communications. The consortium accomplishes its mission will grow into successful NIDDK R01 awards. primarily by sharing resources of the CCEH consortium and fertilizing collaborations across disciplines. More information is available via www.niddk. CENTER DIRECTOR PHONE EMAIL WEBSITE nih.gov/about-niddk/meet-the-director/mission- vision/Pages/mission-vision.aspx. Boston Children’s Stuart Orkin 617-919-2042 [email protected] http://zfrhmaps.tch.harvard.edu/cemh/ Hospital Leonard Zon 617-919-2068 [email protected] This year (fiscal year 2017) the consortium piloted a Partner Pilot and Feasibility (PPF) Fred Hutchinson Cancer Beverly Torok-Storb 206-667-4549 [email protected] http://sharedresources.fredhutch.org/ program to initiate collaborations by funding Research Center Shelly Heimfeld 604-874-4004 [email protected] core-facilities/cceh-administration projects that use cores located at two different Hal Broxmeyer 317-274-7510 [email protected] Centers. In the fall of 2017, the PPF program will Indiana University www.ccehindy.org/ begin to accept applications from investigators Edward F Srour 317-274-3589 [email protected] in U.S.-based institutions to partner with one of John Phillips 801-581-6650 [email protected] the center’s core facilities. These PPF projects University of Utah http://cihd.cores.utah.edu/ need to include plans for collaboration and James Cox 801-587-7779 [email protected] not simply describe use of the core facilities. Diane Krause 203-737-1678 [email protected] Interested applicants are strongly encouraged Yale University http://medicine.yale.edu/labmed/ycceh/ Patrick Gallagher 203-688-2896 [email protected]

CONVERSATION STARTER

Featured content from Blood Advances, Volume 1, Issue 14

Gene Correction of HAX1 Reversed Kostmann Disease Phenotype in Patient-Specific Induced Pluripotent Stem Cells

Severe congenital neutropenia (SCN; Kostmann disease) is a heritable disorder characterized by a granulocytic maturation arrest. Biallelic mutations in HCLS1 associated protein X-1 (HAX1) are frequently detected in affected individuals, including those of the original pedigree described by Dr. Rolf Kostmann in 1956. In this article, Dr. Erik Pittermann and colleagues demonstrate defective neutrophilic differentiation and compensatory monocyte overproduction from patient-derived induced pluripotent stem cells (iPSCs) carrying the homozygous HAX1W44X nonsense mutation. Findings made in isogenic iPSC-derived myeloid cells highlight the complex transcriptional changes underlying Kostmann disease. Thus, the authors show that patient-derived HAX1W44X-iPSCs recapitulate the Kostmann disease phenotype in vitro and confirm HAX1 mutations as the disease-causing monogenic lesion. This study paves the way for non–virus-based gene therapy approaches in SCN.

Pittermann E, Lachmann N, MacLean G, et al. Blood Advances. 2017;1:903-914. More available at www. bloodadvances.org.

The Hematologist: ASH NEWS AND REPORTS 13 Clinical Trials Corner

than 300 mg/month with hemoglobin levels measured STUDY DESIGN: This is a multi-arm phase III, Are We Recruiting an Army for 10 g/dL or greater.8 In light of these uncertainties and randomized, open-label clinical trial that compares associations, well-designed clinical trials are needed to chemoimmunotherapy with three combinations of Magneto? Optimizing Iron Utilization in evaluate the safety of different IV iron dosing strategies in non-DNA damaging drugs as first-line therapy for fit Hemodialysis hemodialysis patients. patients. Standard chemoimmunotherapy is fludarabine, cyclophosphamide, and rituximab (FCR) for patients 65 STUDY TITLE: Proactive IV Iron Therapy for Hemodialysis COMMENT: IV iron utilization in hemodialysis patients years or younger, and bendumustine-rituximab (BR) for Patients (PIVOTAL) has increased over time, and higher iron utilization is patients older than 65 years. Two of the experimental associated with higher iron stores. The mean serum ferritin arms contain a combination of the BCL2 inhibitor, CLINICALTRIALS.GOV IDENTIFIER: None (this is a European of U.S. patients on hemodialysis increased from 300 to venetoclax, with an anti-CD20 antibody (either rituximab trial) 600 ng/mL from 1993 to 2010 and to 799 ng/mL in 2014.9 or obinutuzumab); the third also includes the BTK One large study of hemodialysis patients receiving ESAs inhibitor ibrutinib with venetoclax and obinutuzumab. EU CLINICAL TRIALS REGISTER: 2013-002267-25. and intravenous iron dosed in keeping within current The co-primary endpoints are peripheral blood (PB) www.clinicaltrialsregister.eu/ctr-search/trial/2013-002267-25/GB. guidelines, demonstrated hepatic iron overload on MRI in minimal residual disease (MRD) negativity at 15 months the majority of patients.10 Despite this pattern of increased and progression-free survival (PFS); each will be tested SPONSOR: King’s College Hospital NHS Foundation Trust iron utilization, neither the risks nor the benefits of IV iron independently, enabling superiority to be established treatment in hemodialysis patients receiving ESAs are for an experimental arm if either endpoint is significantly STUDY DESIGN: Multicenter, prospective, open-label, understood sufficiently. The PIVOTAL study will begin to different in a favorable direction. The primary comparison randomized controlled trial address this fundamental gap in knowledge and should for MRD negativity is between the chemoimmunotherapy help inform practice not only in the United Kingdom, but and the obinutuzumab-venetoclax (GVe) arms. The primary TARGET ENROLLMENT: 2,080 also in the United States and elsewhere. comparison for PFS is between the chemoimmunotherapy and obinutuzumab-ibrutinib-venetoclax (GIVe) arms. The 1. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as PARTICIPATING CENTERS: 50 clinics in the United Kingdom secondary outcomes are multiple and include complete compared with low hematocrit values in patients with cardiac response rates, duration of response, overall survival, disease who are receiving hemodialysis and epoetin. N Engl J ACCRUAL GOAL: 2,080 Med. 1998;339:584-590. safety, and quality-of-life. Efficacy outcomes may be compared among other arms in a predefined hierarchical 2. Pfeffer MA, Burdmann EA, Chen CY, et al. Baseline characteristics sequence. STUDY DESIGN: PIVOTAL is a multicenter, prospective, in the Trial to Reduce Cardiovascular Events With Aranesp open-label, randomized controlled trial investigating the Therapy (TREAT). Am J Kidney Dis. 2009;54:59-69. effects of two different doses of intravenous (IV) iron in 3. Singh AK, Szczech L, Tang KL, et al. Correction of anemia RATIONALE: The chemoimmunotherapy combination 1 patients with chronic kidney disease on hemodialysis. with epoetin alfa in chronic kidney disease. N Engl J Med. FCR was first reported as initial therapy in 2005 and was 2006;355:2085-2098. The primary study endpoint is to compare the effect of confirmed as the gold-standard front-line therapy for 4. Drüeke TB, Locatelli F, Clyne N, et al. Normalization of fit patients in 2010.2 The alternative BR regimen is less a proactive high-dose IV iron regimen with a reactive hemoglobin level in patients with chronic kidney disease and low-dose IV iron regimen on all-cause mortality and the effective but is better tolerated and is a standard for older anemia. N Engl J Med. 2006;355:2071-2084. 3 incidence of nonfatal cardiovascular events (myocardial fit patients. Both produce significant acute toxicity and 5. Coyne DW, Kapoian T, Suki W, et al. Ferric gluconate is highly carry risks of late complications such as myelodysplastic infarction, stroke, and hospitalization for heart failure) in efficacious in anemic hemodialysis patients with high serum patients on hemodialysis. Secondary endpoints include ferritin and low transferrin saturation: results of the Dialysis syndromes or acute myeloid leukemia, and yet, for most the comparison of the two regimens on erythropoiesis- Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) patients, the treatment is not curative. Therefore, more study. J Am Soc Nephrol. 2007;18:975-984. stimulating agent (ESA) dose requirements, red blood cell effective therapies with less toxicity are needed. New transfusion requirements, complications of hemodialysis 6. Avni T, Bieber A, Grossman A, et al. The safety of intravenous iron targeted agents avoid some of the toxicities associated preparations: systematic review and meta-analysis. Mayo Clin treatment, and patient quality of life. Safety concerns of with DNA damage, show efficacy as single agents, and Proc. 2015;90:12-23. preliminary efficacy and tolerability in combination. IV iron will be analyzed by incidence of vascular access 7. Miskulin DC, Tangri N, Bandeen-Roche K, et al. Intravenous iron thrombosis, hospitalization for infection, and infectious exposure and mortality in patients on hemodialysis. Clin J Am Soc episodes. Researchers will recruit and randomly assign Nephrol. 2014;9:1930-1939. Prolonged survival without toxicity is the goal of therapy, but the prognosis of patients with CLL lacking either 2,080 hemodialysis patients from 50 clinics to one of two 8. Bailie GR, Larkina M, Goodkin DA, et al. Data from the Dialysis treatment arms. Patients assigned to the proactive arm Outcomes and Practice Patterns Study validate an association del(17p) or TP53 mutation is sufficiently favorable to will receive 400 mg/month IV iron sucrose, unless their between high intravenous iron doses and mortality. Kidney Int. require surrogate measures as primary endpoints in 2015;87:162-168. ferritin is greater than 700 µg/L and transferrin saturation trials. PFS is an established surrogate for overall survival (TSAT) is greater than 40 percent. Patients assigned to the 9. Fishbane S, Matthew AT, Wanchoo R. Intravenous iron exposure (OS) in this disease setting, and PB MRD–negativity and outcomes in patients on hemodialysis. Clin J Am Soc Nephrol. reactive arm will receive low-dose IV iron sucrose only if is an independent predictor of PFS and OS with 2014;9:1837-1839. chemoimmunotherapy.4 Venetoclax in combination with an the ferritin is less than 200 μg/L and TSAT is less than 20 10. Rostoker G, Griuncelli M, Loridon C, et al. Hemodialysis- percent. Eligible patients are at least 18 years old and newly anti-CD20 antibody induces MRD negativity in the majority associated hemosiderosis in the era of erythropoiesis-stimulating 5 established (<12 months duration) on hemodialysis for end- agents: a MRI study. Am J Med. 2012;125:991-999.e1. of patients with CLL in either the relapsed/refractory or 6 stage renal failure receiving an ESA for anemia, and with front-line setting. The study therefore tests whether GVe induces a greater rate of PB MRD-negativity than standard a ferritin level less than 400 μg/L and TSAT lower than 30 – Siobán Keel, MD percent. Patients with limited life expectancy or awaiting therapy, as an early indicator of comparative efficacy. a renal transplant within the next 12 months are excluded Ibrutinib induces a high rate of durable responses when from the study. Dr. Keel indicated no relevant conflicts of interest. given continuously and synergizes with venetoclax to kill CLL cells in vitro;7,8 its use for three years as an addition to GVe in the GIVe arm is anticipated to reduce the risk RATIONALE: IV iron utilization has increased and ESA utilization has decreased in the United States’ hemodialysis of relapse. Consequently, PFS is the primary endpoint for patient population in recent years. A number of factors comparison between GIVe and chemoimmunotherapy. are associated with these trends. Several trials raised Can Chemoimmunotherapy Be concerns about the safety of ESA dosing in those with Bettered As Front-Line Therapy for COMMENT: Patients with CLL and their doctors are wanting renal failure .1-4 These studies led to labeling revisions; CLL in Fit Patients? more from first-line therapy. Treatment decisions are concurrently, the U.S. Centers for Medicare and Medicaid becoming increasingly complex and require consideration of disease genetics, age, fitness, comorbidities, and goals Services introduced a bundled payment methodology for STUDY TITLE: A Phase III Multicenter, Randomized, dialysis services, including ESA and IV iron, which were of treatment. Add to this the handful of new agents and Prospective, Open-Label Trial of Standard combinations, and patients and their doctors could well previously separately billable (providing incentives to Chemoimmunotherapy (FCR/BR) Versus Rituximab Plus reduce utilization of high-cost items such as ESAs). IV be facing decision matrices akin to a Rubik’s cube as they Venetoclax (RVe) Versus Obinutuzumab (GA101) Plus iron treatment, even with high levels of serum ferritin, strive toward personalized medicine. Patients who are fit Venetoclax (GVe) Versus Obinutuzumab Plus Ibrutinib results in increased hemoglobin levels and reduced ESA for chemoimmunotherapy usually are looking to achieve Plus Venetoclax (GIVe) in Fit Patients With Previously dose requirements and cost of care.5 Prior observational long-term leukemia-free survival (or at least PFS) without Untreated Chronic Lymphocytic studies confirming the safety of IV iron in this setting have the early and late toxicities induced by FCR. produced conflicting results, and moreover, have largely Leukemia (CLL) Without del(17p) or TP53 Mutation studied outcomes in patients treated at a time when lower (CLL13/GAIA) The CLL13/GAIA study led by Dr. Barbara Eichhorst cumulative iron doses were used.6,7 Large randomized focuses on this large group of patients. While the long- clinical trials of various doses of IV iron confirming the CLINICALTRIALS.GOV IDENTIFIER: NCT02950051 term efficacy of chemoimmunotherapy is well understood, safety of this more aggressive IV iron repletion and rituximab plus venetoclax (RVe), GVe and GIVe are new improvement in patient-centered outcomes such as SPONSOR: German CLL Study Group regimens, with only RVe having follow-up beyond two 5 mortality, hospitalization, infectious risk, and quality of years. Consequently, the optimal duration of venetoclax life, are lacking. Additionally, IV iron has been implicated COLLABORATING STUDY GROUPS: Nordic CLL Group, in RVe and GVe, or ibrutinib and venetoclax in GIVe, is not in potentially causing oxidative stress and inflammation, HOVON and SAKK known, but investigators are working on the premise that as well as endothelial and immune dysfunction. The first line therapy for fit patients should be time-limited Dialysis Outcomes and Practice Patterns Study, a recent ACCRUAL GOAL: 920 eligible patients rather than indefinite until progression. So, the non-DNA observational study using data obtained as part of the damaging combinations chosen are based on preliminary international prospective cohort study of hemodialysis PARTICIPATING CENTERS: 160 centers across Germany, data, including from those tested in ongoing German CLL patients 18 years or older, found all-cause mortality Austria, Switzerland, The Netherlands, Belgium, Denmark, Study Group trials. elevated among patients receiving IV iron doses higher Sweden, Norway, and Finland

14 The Hematologist: ASH NEWS AND REPORTS The major complication of thrombolysis with tissue plasminogen activator (tPA) in the setting of stroke is hemorrhagic conversion. Using a mouse model, Dr. Fabrício Simão and colleagues demonstrate that The trial’s complex design combines pragmatism with Editors’ Choice hemorrhagic complications are mediated by tPA-induced sophistication, reflecting the tension between the large upregulation of plasma kallikrein, inhibition of which sample sizes needed to compare multiple regimens increases the effectiveness of tPA and reduces hemorrhagic for multiple endpoints and the imperative to accrue complications. rapidly and deliver answers in the shortest timeframes. It complements the first randomized study of a non- DNA-damaging regimen (ibrutinib-rituximab) versus chemoimmunotherapy (FCR) in fit patients 70 years of APRIL 27, 2017 age or younger. The National Cancer Institute-sponsored Yoshizato T, Nannya Y, Atsuta Y, et al. Genetic abnormalities U.S. intergroup study (NCT02048813) led by Dr. Tait in myelodysplasia and secondary acute myeloid leukemia: Shanafelt and highlighted in the May/June 2015 issue of impact on outcome of stem cell transplantation. Blood. The Hematologist, completed accrual in June 2016, and the 2017;129:2347-2358. first interim analysis for its primary endpoint of PFS will be In this plenary paper, Dr. Tetsuichi Yoshizato and next year, two years after the last accrual. colleagues offer a detailed genomic analysis of a substantial cohort of 797 patients with myelodysplastic syndrome and Once we have the results of the primary analyses for both secondary acute myeloid leukemia who received unrelated these trials, physicians and patients will know whether stem cell transplants, and identify unique predictors of chemoimmunotherapy can be bettered as front-line Dr. Bob Löwenberg (Editor-in-Chief) and Dr. Nancy Berliner outcome. therapy for CLL without TP53 dysfunction in fit patients. (Deputy Editor-in-Chief) have combined efforts to identify some Of course, even if the trials are positive, important of the most outstanding Blood articles that have appeared either Cox TM, Drelichman G, Cravo R, et al. Eliglustat maintains questions are likely to remain incompletely answered. For in print or online during the two-month interval between issues long-term clinical stability in patients with Gaucher example, which non-DNA damaging regimen is best? What of The Hematologist. The goal is to underscore the remarkable disease type 1 stabilized on enzyme therapy. Blood. are the optimal durations of use for individual targeted research that is published in Blood and to highlight the exciting 2017;129:2375-2383. therapy elements (time-limited, until MRD negativity is progress that is being made in the field. Dr. Timothy M. Cox and colleagues report on a cohort of achieved, or indefinite)? Do the trial outcomes equally more than 150 adults with type 1 (non-neuronopathic) apply to specific genetic subgroups, which can be cured Gaucher disease who remained clinically stable after with FCR, such as IGHV-mutated CLL? In any case, the switching from recombinant glucocerebrosidase APRIL 6, 2017 CLL13/GAIA trial is likely to shape the future of front-line replacement therapy to eliglustat tartrate, an oral inhibitor therapy for fit patients with CLL for many years to come, Landier W, Chen Y, Hageman L, et al. Comparison of of glucocerebroside synthase (a substrate reduction and accrual should be strongly supported. self-report and electronic monitoring of 6MP intake in therapy). childhood ALL: a Children’s Oncology Group study. Blood. 1. Keating MJ, O’Brien S, Albitar M, et al. Early results 2017;129:1919-1926. of a chemoimmunotherapy regiment of fludarabine, Compliance with 6-mercaptopurine (6MP) during acute cyclophosphamide, and rituximab as initial therapy for chronic MAY 4, 2017 lymphocytic leukemia. J Clin Oncol. 2005;23:4079-4088. lymphoblastic leukemia maintenance therapy is critical for sustained remission. Dr. Wendy Landier and colleagues Walton BL, Lehmann M, Skorczewski T, et al. Elevated 2. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of hematocrit enhances platelet accumulation following rituximab to fludarabine and cyclophosphamide in patients with show that self-reporting markedly overestimates chronic lymphocytic leukaemia: a randomised, open-label, phase compliance, highlighting a need for better monitoring vascular injury. Blood. 2017;129:2537-2546. 3 trial. Lancet. 2010;376:1164-1174. methods to improve compliance and outcomes. Dr. Bethany L. Walton and colleagues infused red cells 3. Eichhorst B, Fink AM, Bahlo J, et al. First-line into normal mice to demonstrate that elevated hematocrit chemoimmunotherapy with bendamustine and rituximab versus Riesner K, Shi Y, Jacobi A, et al. Initiation of acute is an independent contributor to arterial thrombosis, fludarabine, cyclophosphamide, and rituximab in patients graft-versus-host disease by angiogenesis. Blood. as it increases the frequency and duration of platelet with advanced chronic lymphocytic leukaemia (CLL10): an 2017;129:2021-2032. international, open-label, randomised, phase 3, non-inferiority interactions with the growing thrombus. trial. Lancet Oncol. 2016;17:928-942. Dr. Katarina Riesner and colleagues investigate the role 4. Böttcher S, Ritgen M, Fischer K, et al. Minimal residual disease of angiogenesis in graft-versus-host disease (GVHD) quantification is an independent predictor of progression- and show that, rather than occurring as a response to free and overall survival in chronic lymphocytic leukemia: a infiltrating leukocytes, angiogenesis occurs very early after MAY 11, 2017 multivariate analysis from the randomized GCLLSG CLL8 trial. J transplantation and is involved in the initiation of GVHD. Fischer K, Al-Sawaf O, Fink AM, et al. Venetoclax and Clin Oncol. 2012;30:980-988. obinutuzumab in chronic lymphocytic leukemia. Blood. 5. Seymour JF, Ma S, Brander DM, et al. Venetoclax plus rituximab Hiwarkar P, Amrolia P, Sivaprakasam P, et al. Brincidofovir 2017;129:2702-2705. in relapsed or refractory chronic lymphocytic leukaemia: a is highly efficacious in controlling adenoviremia in phase 1b study. Lancet Oncol. 2017;18:230-240. pediatric recipients of hematopoietic cell transplant. Blood. Dr. Kirsten Fischer and colleagues present efficacy and 6. Fischer K, Al-Sawaf O, Fink AM, et al. Venetoclax and 2017;129:2033-2037. safety data from a preliminary study of first-line venetoclax obinutuzumab in chronic lymphocytic leukemia. Blood. and obinutuzumab in older chronic lymphocytic leukemia 2017;129:2702-2705. Dr. Prashant Hiwarkar and colleagues present encouraging patients with comorbidities. 7. Cervantes-Gomez F, Lamothe B, Woyach JA, et al. data suggesting that brincidofovir provides excellent Pharmacological and Protein Profiling Suggests Venetoclax (ABT- activity and safety in controlling adenoviremia during the 199) as Optimal Partner with Ibrutinib in Chronic Lymphocytic early lymphopenic phase after hematopoietic stem cell Leukemia. Clin Cancer Res. 2015;21:3705-3715. transplantation. MAY 18, 2017 8. Deng J, Isik E, Fernandes SM, et al. Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity Hovorkova L, Zaliova M, Venn NC, et al. Monitoring of to venetoclax in chronic lymphocytic leukemia. Leukemia. childhood ALL using BCR-ABL1 genomic breakpoints 2017;doi:10.1038/leu.2017.32. [Epub ahead of print]. APRIL 13, 2017 identifies a subgroup with CML-like biology. Blood. 2017;129:2771-2781. Muchtar E, Gertz MA, Kumar SK, et al. Improved outcomes – Andrew Roberts, MBBS, PhD, FRACP, FRCPA for newly diagnosed AL amyloidosis between 2000 and Dr. Lenka Hovorkova and colleagues report that discordant 2014: cracking the glass ceiling of early death. Blood. results of DNA-based minimal residual disease monitoring 2017;129:2111-2119. of BCR-ABL1 and immunoglobulin/T-cell receptor gene rear- rangements suggest that an unexpectedly high percentage Dr. Roberts has received research funding from and of childhood acute lymphoblastic leukemias may in fact be AbbVie and Genentech (venetoclax), and Janssen Palladini G, Milani P, Foli A, et al. A phase 2 trial of chronic myeloid leukemias in lymphoid blast crisis. (sponsor for ibrutinib outside the United States). pomalidomide and dexamethasone rescue treatment in He is employed part-time by the Walter and Eliza patients with AL amyloidosis. Blood. 2017;129:2120-2123. Hall Institute, which receives milestone and royalty The papers by Dr. Eli Muchtar and colleagues, and payments for venetoclax but receives no financial Dr. Giovanni Palladini and colleagues each reflect the benefits personally. significant progress and challenges associated with Blood Strengthens Its Position As the Top treatment of systemic light chain (AL) amyloidosis, based Journal in Hematology on evolving myeloma-derived cytotoxic therapy. The newly released 2016 Journal Citation Reports (Clarivate Analytics, 2017) contains excellent news news for Blood: APRIL 20, 2017 • Impact Factor increased from 11.847 to 13.164! Noy A, de Vos S, Thieblemont C, et al. Targeting Bruton • With 161,962 total citations generated in 2016, tyrosine kinase with ibrutinib in relapsed/refractory marginal Blood is the most-cited journal in hematology, #19 zone lymphoma. Blood. 2017;129:2224-2232. out of the 12,085 journals Dr. Ariela Noy and colleagues present results of a phase • 0.31360 Eigenfactor Score ranks Blood #1 in 2 trial of ibrutinib for patients with relapsed/refractory Hematology, #23 out of all journals marginal zone lymphoma, demonstrating durable “The newly released publication metrics in terms of responses in approximately half of the patients. impact factor, number of citations, and Eigenfactor mark the significance of the Blood journal for Simão F, Ustunkaya T, Chermont AC, et al. Plasma kallikrein hematology and beyond.” – Editor-in-Chief Bob mediates brain hemorrhage and edema caused by tissue Löwenberg, MD, PhD plasminogen activator therapy in mice after stroke. Blood. 2017;129:2280-2290.

The Hematologist: ASH NEWS AND REPORTS 15 IMAGE CHALLENGE MARK YOUR CALENDAR Not All Neutrophils Are Created Equal

NABEEL R. YASEEN, MD, PhD Professor, Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL July A peripheral blood smear review was requested on a 58-year-old man with a history of plasma cell myeloma. Representative images from the blood smear are shown 6 TRTH Letter of Intent Due below. www.hematology.org/awards Based on the neutrophil morphology, this patient was likely treated with: 15 2017-2018 ASH Mentor Award nomination packages due A. Bortezomib, lenalidomide, dexamethasone www.hematology.org/awards B. Carfilzomib, lenalidomide, dexamethasone C. Autologous stem cell transplantation 15 2017-2018 Honorific Awards nominations due www.hematology.org/awards D. Allogeneic stem cell transplantation 17 ASH Global Capacity-Building Showcase poster For the solution to the quiz, visit The Hematologist online, www.hematology.org/Thehematologist/ submission deadline Images. www.hematology.org/Annual-Meeting

19 2017 ASH Annual Meeting registration and housing Dr. Yaseen indicated no relevant conflicts of interest. opens (members only) www.hematology.org/Annual-Meeting

28 AML Matters Program Minneapolis, MN www.hematology.org/meetings

August

2 2017 ASH Annual Meeting abstract submission deadline www.hematology.org/Annual-Meeting

5-11 ASH Clinical Research Training Institute Washington, DC www.hematology.org/awards

9 2017 ASH Annual Meeting advance registration and housing opens (non-members) Put your fellow readers to the test, and send us your Image Challenge submissions! Email case www.hematology.org/Annual-Meeting descriptions and image files to the Managing Editor at [email protected]. 31 ASH Global Research Award letters of intent due www.hematology.org/awards

September

7 ASH Consultative Hematology Course Chicago, IL www.hematology.org/meetings

8-9 2017 ASH Meeting on Hematologic Malignancies Chicago, IL www.hematology.org/malignancies

October

17-20 2017 ASH Medical Educators Institute www.hematology.org/educators

20 AML Matters Program Durham, NC www.hematology.org/meetings

27 AML Matters Program Philadelphia, PA www.hematology.org/meetings Read The Hematologist online at www.hematology.org/thehematologist, and catch up on the latest news in the field of hematology right on your desktop, mobile phone, or tablet.