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

ASK THE HEMATOLOGIST – Dr. John Hausdorff gives his take on the SPIKES protocol for conveying bad news.

MINI REVIEW – Contributing Editor Dr. Omar Abdel-Wahab summarizes key findings related to histiocytoses.

PRESIDENT’S COLUMN – Dr. Ken Anderson outlines six strategic priorities for the Society.

PROFILES – Dr. Jack Hirsh reflects on a life devoted to hematology; mentee Dr. John Kelton pays tribute.

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Disparities of Adolescent and Young Adult Patients in the Treatment of Malignant Hematologic DiseasesLEIDY L. ISENALUMHE, MD, MS

Adult Clinical Hematology-Oncology Fellow, H. Lee Moffitt Cancer Center and Research Institute; Pediatric Hematologist/Oncologist; Chair, ASH Trainee Council; Tampa, FL

The Adolescent and Young Adult (AYA) Progress Review Group (PRG) defines the AYA cancer population as patients ranging from 15 to 39 years of age. An estimated 69,000 AYA individuals are diagnosed with cancer each year — six times more than children younger than 14 years.1 The AYA age demarcation was established as a high-risk population after data from the Surveillance, Epidemiology, and End Results (SEER) study showed a lack in improvement in survival for patients with many forms

of cancer.2,3 The most common malignancies are leukemia, lymphoma, germ cell tumors, and central nervous system tumors among 15 to 24 year olds, with the incidence of breast cancer, colorectal cancer, and melanoma increasing among older AYA patients1 (Figure).

In 2007, the AYA PRG released a comprehensive guide explaining the disparities experienced by AYA cancer patients that have led to their poor outcomes and lack of progress throughout the years.2

These disparities include lack of health insurance, differences in disease biology, delay of diagnosis and treatment, increased toxicities, lower socioeconomic status,4 and overall lack of awareness in the medical field as to the special needs of this population (Table 1).

The goal of the AYA PRG was not only to introduce and educate the medical field about this high-risk population, but also to start a systematic mitigation of the disparities. Since the release of the PRG guide, progress has been made, including an increase in AYA-specific scientific peer review publications, formation of AYA oncology programs, development of AYA-specific national workshops and committees, development of clinical trials targeting AYAs, and expansion of inclusion criteria to include AYAs.4,5 Additionally, the European Cancer Registry (EUROCARE) and NCI SEER data have reported improvement in survival rates for the AYA population.5,6 Despite some improvement in survival, AYAs still have lower five-year relative survival rates for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), rhabdomyosarcoma, Ewing sarcoma,

and breast cancer compared with children and older adults.6 Notably, the incidence of all invasive cancers continues to increase in AYAs compared with any other age group.7

Although many common malignancies overlap in younger and older patients, research advances in ALL, breast cancer, colorectal cancer, sarcoma, and melanoma have identified age-dependent

F E A T U R ED I F F U S I O N

LORI-ANN LINKINS, MD, MSC (CLIN EPI), FRCPC

Dr. Linkins indicated no relevant conflicts of interest. (Cont. on page 2)

More Than an Aspirin a Day to Keep Recurrent Venous Thromboembolism AwayWeitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017;376:1211-1222.

Whether to extend anticoagulant therapy for a deep vein thrombosis or pulmonary embolism beyond the acute treatment period can be a problematic decision. Anticoagulant therapy reduces the risk of recurrent venous

thromboembolic events (VTE), but at the cost of an increased risk of bleeding. Reducing the intensity of anticoagulant therapy1-3 or switching to aspirin3 have both been proposed as options in patients who wish to continue protection, but the efficacy and safety of these strategies is still uncertain.

Dr. Jeffrey I. Weitz and colleagues reported the results of a double-blind, randomized controlled trial, “EINSTEIN CHOICE,” which 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 the study (60%). This group is known to have a low risk of recurrence without anticoagulant therapy; therefore their inclusion in the study is controversial.5 Additionally, the duration of treatment was limited to one year. Patients facing this choice are deciding if they should continue anticoagulation indefinitely, which can mean decades of treatment. Lastly, the study was not powered to determine if 10 mg of rivaroxaban is noninferior to 20 mg with respect to efficacy.

Overall, the results of the EINSTEIN CHOICE study show that even low-dose anticoagulation is superior to aspirin, and without a higher price to pay with respect to bleeding. Consequently, the key message of this trial is that patients who wish to continue protection from recurrent VTE have little to gain by switching to aspirin. However, what this study cannot do is confirm that rivaroxaban 10 mg once daily is sufficient for patients with a high risk of recurrence.

1. Kearon C, Ginsberg JS, Kovacs MJ, et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med. 2003;349:631-639.

2. Ridker PM, Goldhaber SZ, Glynn RJ. Low-intensity versus conventional-intensity warfarin for prevention of recurrent venous thromboembolism. N Engl J Med. 2003;349:2164-2167.

3. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368:699-708.

4. Simes J, Becattini C, Agnelli G, et al. Aspirin for the prevention of recurrent venous thromboembolism: the INSPIRE collaboration. Circulation. 2014;130:1062-1071.

5. Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med. 2010;170:1710-1716.

Table 1: List of the Disparities Experienced by AYA Hematology-oncology Patients

Access to health care

Psychosocial stressors

Delay in diagnosis

Delay in treatment

Treatment site

Reduced rates of clinical trial enrollment and treatment standardization

Increased toxicity

Figure Common Types of Cancer Affecting AYAs

*includes testicular cancer. **includes breats, cervical, colon and other less prevalent cancers. ***includes malignant bone tumors and other less prevalent cancers.

Adapted from1 A Snapshot of Adolescent and Young Adult Cancers: National Cancer Institute. [cited 2015 Nov 28]; NCI Surveillance, Epidemiology, and End Results (SEER) Program. Data is from SEER 18, 2007-2011, ages 15-39. Available from: www.cancer.gov/research/progress/snapshots/adolescent-young-adult.

2 The Hematologist: ASH NEWS AND REPORTS

ASH NEWS AND REPORTS ®

ISSN 1551-8779PUBLISHED BIMONTHLY

Editor-in-Chief:Jason Gotlib, MD, MSStanford Cancer InstituteStanford, CA

Contributing Editors:Omar Abdel-Wahab, MDMemorial Sloan-Kettering Cancer CenterNew York, NY

Michael DeBaun, MDVanderbilt UniversityNashville, TN

Tracy I. George, MDUniversity of New MexicoAlbuquerque, NM

Jonathan Hoggatt, PhDMGH/Harvard UniversityCambridge, MA

Caron Jacobson, MD Dana-Farber Cancer InstituteBoston, MA

Sioban Keel, MDUniversity of WashingtonSeattle, WA

Lori-Ann Linkins, MD, MSc, FRCPC McMaster UniversityHamilton, Canada

Stephan Moll, MD University of North Carolina Chapel Hill, NC

Paul Moss, MBBS, PhD, FRCPUniversity of BirminghamBirmingham , United Kingdom

Elizabeth Raetz, MDUniversity of UtahSalt Lake City, UT

Noopur Raje, MDMassachusetts General HospitalBoston, MA

Andrew Roberts, MBBS, PhD University of MelbourneMelbourne, Australia

Managing Editor

Juana Llorens, MS

Editorial Associate

Laura M. Santini, MS

Graphic Designer

grayHouse design

American Society of Hematology2021 L Street, NW, Suite 900Washington, DC 20036 jllorens@hematology.org

©2017 by the American Society of Hematology.

All materials contained in this newsletter are protected by copyright laws and may not be used, reproduced, or otherwise exploited in any manner without the express prior written permission of The Hematologist: ASH News and Reports. Any third-party materials communicated to The Hematologist become its copyrighted property and may be used, reproduced, or otherwise exploited by The Hematologist.

Contributing authors have declared any financial interest in a product or in potentially competing products, regardless of the dollar amount. Any such financial interest is noted at the bottom of the article.

Dr. Gotlib has no relevant conflicts of interest to disclose.

The material published in The Hematologist is for informational purposes only. The opinions of the authors and editors of The Hematologist are their own and do not necessarily represent official policy of the American Society of Hematology. 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 publication is solely at your own risk.

HematologistTHE

(Cont. on page 12)

President’s Column

Beyond Business As Usual

In May of this year, ASH held its yearly Executive Committee Spring Retreat, in Quebec City, Canada, where Executive Committee members and senior staff have an opportunity to collaborate, bond, and be inspired by our diverse points of view. This year, there

emerged the beginnings of some major strategic initiatives and goals for ASH to develop further in the coming months and years. These initiatives demonstrate ASH’s constant growth and commitment to improvement in the field of hematology.

ASH realizes that there is a need to facilitate the sharing of high-quality clinical data for ASH members and the hematology community, 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 continues to take on new ways to equip hematologists with the tools and knowledge they need to best serve SCD patients. For example, ASH is exploring the development of a clinical trials network for SCD to help clinical research sites develop and test interventional therapeutics that may improve SCD patient outcomes.

Another takeaway is the impressive work of ASH’s standing committees. For one, ASH’s Committee on Quality continues to work on 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 guidelines to life. (Learn more at www.hematology.org/quality.)

ASH leadership has long been concerned with recruiting and retaining an adequate pipeline of hematologists, and the Committee on Training is in the early stages of conducting a long-term workforce study to help inform these efforts. In the meantime, the Committee on Educational Affairs has been hard at work on a plan to grow and evolve the Society’s education initiatives to meet the challenges 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 workshops that are more hands-on and interactive, to name just a few examples of the educational programs ASH will begin rolling out.

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 Force on Precision Medicine has taken steps toward developing partnerships with key entities. In the coming months, ASH will join forces with the National Institutes of Health Clinical Genomics Resource to collect and annotate germline variants relevant to malignant and 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 treatments for hematologic disorders and in metrics to assess both efficacy and toxicity.

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 translate exciting scientific advances to the bedside and toward improved patient care, while training the next generation of hematology 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 involved. These programs further highlight the commitment at ASH to serve both clinicians and scientists around the world and to remain the premier hematology society striving to further the understanding, diagnosis, treatment, and prevention of blood diseases worldwide.

Kenneth C. Anderson, MD

In addition to biological differences in disease, socioeconomic factors such as lack of health insurance are associated with advanced stage at presentation, delay in diagnosis and definitive treatment, and increased mortality.14-16 Persons between the ages of 18 and 34 years are more likely to be uninsured compared to other age groups.16 In AYA patients with Hodgkin lymphoma, having public health insurance was associated with an increased risk of advanced disease at time of diagnosis.17 Having no insurance or public health insurance, as well as low socioeconomic status, act as barriers to treatment at National Cancer Institute (NCI) –designated comprehensive cancer centers (CCCs), where the outcomes are superior to those of other institutions.18,19 Dr. Julie A. Wolfson and colleagues reported on the inferior outcomes of AYA patients with ALL and AML who were treated at non–NCI-designated CCCs or Children’s Oncology Group (COG) centers. Age, lack of private health insurance, and nonwhite race/ethnicity were additional barriers to treatment at CCC or COG centers. AYAs treated at CCC/COG centers had similar outcomes compared with children treated at CCC/COG sites, suggesting that treatment at such centers may have attenuated the poor outcomes reported in AYAs with ALL (<30 years of age) and AML (<22 years of age).20 There are many more factors that contribute

to the lag in progress of AYAs that are beyond the scope of this article.

The following quote from English philosopher John Locke summarizes what we have learned thus far and what we need to do to move forward: “The improvement of understanding is for two ends: first, our own increase of knowledge; secondly, to enable us to deliver that knowledge to others.”

Recently the NCI National Clinical Trials Network (NCTN) underwent major restructuring, with the nine adult cooperative groups merging into four (Alliance Oncology, Eastern Cooperative Oncology Group/American College of Radiology Imaging Network [ECOG-ACRIN], NRG Oncology, and Southwest Oncology Group [SWOG]). Such changes benefit the AYA oncology community by expanding access to clinical trials for this

Table 2: Differences in Disease Biology of Hematologic Neoplasms in AYAs

Positive prognostic factors Negative prognostic factors

B-ALL ETV6-RUNX1• Higher incidence in younger

patients Hyperdiploidy

• Higher incidence in younger patients

Ph-like ALL • Age 1-9 years: 10%• Age 16-20 years: 21%• Age 21-39 years: 27%

KMT2A rearrangementsRAS mutationsiAMP21GATA3

• Germline variants are associated with predisposition to AYA ALL

Early T-Cell Precursor ALL

HOX+• Higher incidence in AYA

Acute Myeloid Leukemia

Normal cytogenetics,NPM1 and CEBPA

• Higher incidence in AYAs

FLT3-ITD• Incidence increases with age

Abbreviations: ALL, acute lymphoblastic leukemia; AYA, adolescent and young adult.

AYA Treatment Disparities

differences in disease biology within the same malignancy.8,9 ALL is the most common malignancy in AYAs with a continued increase in incidence in the past 10 years, and still remains the leading cause of AYA cancer deaths.7-10 The overall survival (OS) for AYAs with ALL is 52 percent, compared with 90 percent in children.6 Age-related genetic and biological variation in ALL are well established and likely contribute to the continued poor OS. AYA patients diagnosed with ALL have a higher frequency of genetic alterations that are associated with poor prognosis, such as Ph+ ALL, Ph-like ALL, hypodiploidy, and iAMP21 (Table 2).7-9,11,12 Recent epidemiological data have indicated that AML patients between the ages of 15 and 39 years had a much lower five-year OS compared with younger patients (50% and 66%, respectively), and age is an established poor prognostic factor in adults with AML.6,7,13 The presence of specific genetic abnormalities also seems to differ between pediatric and AYA AML, but data are limited due to the low number of AYAs treated on AML clinical trials.13 Compared to children younger than 16 years, AYAs aged 16 to 21 years were more likely to have normal cytogenetics, favorable prognostic markers such as NPM1 and CEBPA, and a higher incidence of acute promyelocytic leukemia, but they were also more likely to carry unfavorable markers such as FLT3-ITD (Table 2).13

(Cont. from page 1)

The Hematologist: ASH NEWS AND REPORTS 3

N E W S A N D R E P O R T S

The ASH Global Research Award: Q&A With the Program ChairsTaking a cue from more than 30 years of success with the ASH Scholar Award program, the new ASH Global Research Award aims to support hematologists during the critical period between completion of training and the establishment of their independent careers. However, this program was created specifically for trainees and early investigators practicing outside the United States and Canada. 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 Andrew Roberts.

This award supports hematologists transitioning to careers as independent investigators. Why is this stage so crucial? How is the program different from other ASH career and training award programs?

Ruben Mesa, MD: The transition from one’s training program to becoming an independent investigator is truly one of the most challenging for individuals. The Global Research Award program’s goal is to expand the reach of academic hematology and make specific contributions to the development of meaningful scientific research. This award is distinct from other ASH programs in its breadth and scope, offering at a global level some of the opportunities previously only available in the United

States and Canada.

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

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 their region. It is structured to enable as fair a competition as possible between applicants from different regions by recognizing inherent differences in opportunity, infrastructure, and regional need.

Why is global collaboration so important to hematology, and how does this program support that?

RM: Global collaboration is important in hematology. For example, decreasing morbidity and mortality rates of acute promyelocytic leukemia in Latin America 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.

AR: Global collaboration is integral to many areas of hematology research (e.g., the genomics of acute myeloid leukemia, childhood bone marrow failure syndromes) 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 North America. ASH is hopeful that the ASH Global Research Award will not just advance the development of future leaders, but also create networks that enable major blood disorders to be tackled in a global fashion.

What are some of the goals for the program in its first year? Do you expect to face any challenges? If so, how will they be overcome?

RM: The goals of the award in its first year are to build awareness of the program 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.

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 environments means that assessing the applications against each other will not be straightforward. We have established a review system that should be able to deal with this heterogeneity fairly, but this will be tested carefully as we go ahead. I expect that we will need to adjust the system as we learn more about what this award can achieve in different parts of the world.

What is the long-term vision for the award program, and how do you hope to see it evolve?

RM: The long-term vision of the award is to increase tools to foster a global hematology community. This will include educational efforts like the Clinical Research Training Institute in Latin America and Asia and Highlights of ASH in various regions. We hope to see this program grow through engagement with other national societies and organizations.

AR: Wouldn’t it be great if the ASH Global Research Award becomes as 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 America? That’s part of the long-term vision. Additionally, connecting the best from many parts of the world is a great way to drive collaboration and strengthen the global hematology community.

ASH News Daily Call for AuthorsASH 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 for hematology, you may be just the right fit. Ideal candidates are proficient, published writers (please send at least two clips) who are curious about, and willing to cover, areas outside their comfort zone. You must be able to attend the annual meeting in December, as well as one in-person board meeting in early October. We are also seeking those who:

• Have a flexible schedule at the annual meeting and are good at managing their time

• Enjoy science writing and can also apply a creative approach to it

• Are cognizant of timelines and are dependable with schedules and firm deadlines

• Enjoy networking and doing author outreach

• Are mid-career professionals interested in becoming more involved with ASH.

If this sounds like you, please email Managing Editor Juana Llorens (jllorens@hematology.org) with the following:

• A letter of interest

• Two writing samples

• Your CV

Materials are due by July 31, 2017. For more information on ASH News Daily, visit www.hematology.org/Annual-Meeting/AND.aspx.

AML Matters July 28 in Minneapolis, MNAML Matters is an education program designed to improve the diagnosis and treatment of acute myeloid leukemia (AML). The program is being hosted by ASH, the American Society for Clinical Pathology, National Marrow Donor Program, Oncology Nursing Society, and The France Foundation. Upcoming dates include:

• Minneapolis, MN — July 28, 2017

• Durham, NC — October 20, 2017

• Philadelphia, PA — October 27, 2017

Visit www.hematology.org/amlmatters for more information.

2017 ASH Annual Meeting Upcoming DeadlinesSave these date for the world’s most comprehensive hematology event of the year, the 59th ASH Annual Meeting and Exposition, in vibrant Atlanta. The meeting will provide an invaluable educational experience and the opportunity to review thousands of scientific abstracts highlighting updates in the hottest topics in hematology. 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-Meeting for more information.

• ASH Foundation Run/Walk registration opening — July 6, 2017, 11:00 a.m. Eastern time

• ASH Global Capacity-Building Showcase poster submission deadline — July 17, 2017, 11:59 p.m. Pacific time

• Members-only registration and housing opening — July 19, 2017, 11:00 a.m. Eastern time

• Abstract submission deadline — August 2, 2017, 11:59 p.m. Pacific time

• Advance registration and housing opens for non-members — August 9, 2017, 11:00 a.m. Eastern time

AYA Treatment Disparities ASH Member and Committee Chair Recognized by NCI

Dr. Charles Mullighan, ASH member and chair of the ASH Committee on Scientific Affairs, was named a recipient of the National Cancer Institute Outstanding Investigator Award. The award offers seven years of funding, giving cancer researchers time to make new breakthroughs or extend previous discoveries. Dr. Mullighan and his lab at St. Jude Children’s Research Hospital have used genomic profiling and experimental modeling to make advances in identification and understanding of high-risk and relapsed leukemia.

Congratulations to Dr. Mullighan!

4 The Hematologist: ASH NEWS AND REPORTS

T H E P R A C T I C I N G H E M A T O L O G I S T

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

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.

The Question

How do you approach giving bad news to patients and their families?

The Response Doug had essential thrombocythemia (ET) that eventually transformed into post-ET myelofibrosis. He required splenectomy 13 years ago. His thrombotic diathesis, refractory to warfarin, was controlled with enoxaparin or fondaparinux for the next decade. With time, he developed increasing circulating blasts. and year after year, we kept expecting transformation to acute leukemia. Now a frail 76-year-old, Doug spoke with me several times about this possibility. He became transfusion-dependent, but throughout the next six months, he continued to enjoy work in his yard.

When he bled spontaneously into his arm, fondaparinux was reduced. A week later, he bled into the retroperitoneum. With the patient hospitalized and hypotensive, we transfused while exploring angiography. He looked like hell. And I was late for heme-onc clinic. Years ago, I would have encouraged him to “hang in there,” reassuring him that he was under excellent hospitalist care, and pledging to return that evening. I now recognize, however, that this was inadequate. For this probable impending disaster, I had to “break the bad news” openly and prepare him and his wife.

As hematologists-oncologists we break bad news frequently — diagnosis, recurrence, progression, incurability, prognosis, impending death — but most of us have had little formal training in this area. Dr. Walter F. Baile and colleagues1 taught a wonderfully useful approach called “SPIKES,” which I have outlined and modified in this article.

SettingIf at all possible, never give bad news by phone or in the hallway. Sit, with TV and cell phones off. It may require having other family members present, as well as extra chairs. Pull your chair close to the patient’s bed or chair, nonverbally signaling your connection and your therapeutic alliance, perhaps holding a hand or touching an arm, making sure you face both patient and family, and using eye contact as you speak. At this point, we are setting the stage.

PerceptionAsk the patient and family what they think is going on. This simple act engages them (a critical element in good 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 to reframe or educate successfully, especially if any misunderstandings are openly expressed first.

InvitationThis 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.

KnowledgeWhen it is time to break the news, patients and families benefit from a brief summary of what we knew (or thought we knew), what we hoped for, and finally, what we have now learned. Speak slowly, make eye contact, use simple terms, and if you must use medical jargon, translate as you go. Beware of providing too many details, and gently but resolutely cut to the chase. Most patients, especially during emotionally charged times, are best served with clear, nonmedical language. Then explain what the bad news means. If you pause after relating what the findings are, the patient and family may ask what the findings mean. In this way you have allowed them to once again invite you to tell more.

Empathic Response/Empathic SilenceThis is new territory for many of us. After hearing bad news, patients and families often feel traumatized and overcome with emotion. Rather than speaking up, changing the subject, or moving to therapeutic options, a little silence is often best. Silence is powerful and valuable. When you do speak, an “empathic response” is your best move: Speak words that acknowledge that your patient is feeling something. The response may be a statement or question; go with what feels right at the time. For example:

“This must be very hard news for you to hear.” “I imagine this is very disappointing.” “Is this a big surprise, or did you kind of expect this?”

And our own feelings count as well:

“I’m so sorry, and I am really disappointed, too.” “I was also hoping we’d have more time.”

Try not to immediately shift away from the uncomfortable silence, the sadness, or the tears. This is how we process tragedy.

Summary/StrategySummarize, and decide where to go next. It may be treatment options, agreeing to meet next week, directly addressing prognosis, and/or discussing hospice care.

For Doug, the nature of our talk was my acknowledging and preparing for the very real possibility that, despite our best efforts, this could rapidly lead to demise and death, even today. We would do our best, but it looked bad. He and his wife understood, and months earlier we all agreed that heroics were not appropriate. In fact, he never got to angiography; that afternoon he passed away, before I finished clinic and with family at his side.

Dr. Baile and colleagues have written extensively on this important communication skill. “SPIKES” was published as a six-step protocol with attention to the oncology community in 2000.1 Our hematology patients get sick, receive bad news, and die. Yet the evidence suggests that palliative care services are underutilized in our field.2,3 Importantly, “palliative care” here refers to the days, months, or years before hospice care, when symptom management, clarifying goals, advance care planning, and clear communication is so essential.

There are obstacles, of course, to implementing the “SPIKES” protocol. Hematologists often are in a rush, whether in clinic or on rounds in the hospital. Portals that allow patients direct access to their results online seem to enhance patient autonomy, but at the price of meaningful interpretation and context, and this can seriously undermine the doctor-patient relationship. The same is true of the electronic medical record if we’re trying to listen to and talk with patients. The most important elements, however, are our own levels of comfort with handling the intense feelings of the sick and vulnerable, and the extent to which we truly believe that the nuanced, challenging, and exceptionally important task of breaking bad news skillfully and sensitively is our responsibility.

As hematologists, we need to enhance our own palliative care skill sets, since most of the work falls on our shoulders. We should also be aware of an ever-increasing workforce of highly trained palliative care professionals who can assist us when the going gets rough, and when hematologic care becomes something much bigger — care of the critically ill human being, of the aggrieved family, and of the dying.

1. Baile WF, Buckman R, Lenzi R, et al. SPIKES - a six-step protocol for delivering bad news: application to the patient with cancer. 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 observational study. J Pain Symptom Manage. 2011;42:432-442.

3. Manitta VJ, Phillip JA, Cole-Sinclair MF. Palliative care and the hemato-oncological patient: can we live together? A review of the literature. J Palliat Med. 2010;13:1021-1025.

Dr. Hausdorff indicated no relevant conflicts of interest.

The “SPIKES” Protocol

Figure

M I N I R E V I E W

Histiocytic neoplasms (or histiocytoses) describe a group of diseases believed to be derived from dendritic cell, monocyte, and/or macrophage lineages, which result in an accumulation of lesional cells and ensuing damage in a variety of tissues throughout the body. The protean clinical manifestations of histiocytoses, which affect children as well as adults, combined with their diverse histologic presentation and

rarity, has made these diseases among the most challenging hematologic disorders to diagnose and categorize. In fact, for decades, histiocytoses such as Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), and juvenile xanthogranuloma (JXG) were considered to be inflammatory, non-neoplastic conditions, with potentially similar origins to hemophagocytic lymphohistiocytosis (HLH). However, a series of discoveries regarding the molecular genetic causes of histiocytoses over the last seven years has reshaped our understanding of nearly all subtypes and has led to potent targeted treatments for patients affected by these conditions. We now understand that LCH, ECD, and JXG are clonal disorders with a high frequency of somatic mutations resulting in activation of the MAP kinase signaling pathway. These advances have been described in a number of excellent recent reviews.1,2 In this article, we summarize some of the most important findings regarding histiocytoses.

Classification of HistiocytosesIn the World Health Organization (WHO) classification of hematopoietic malignancies, histiocytic neoplasms are included under the rubric of “mature lymphoid, histiocytic, and dendritic neoplasms.”3 There are currently nine WHO-recognized entities including histiocytic sarcoma, LCH, Langerhans cell sarcoma, indeterminate dendritic cell tumor, interdigitating dendritic cell sarcoma, follicular dendritic cell sarcoma, fibroblastic reticular cell tumor, disseminated JXG, and ECD. These are currently differentiated from one another based on histologic and/or immunophenotypic characteristics with distinct genetic alterations only defined for a few. Additionally, it is also important to be aware of an alternate classification system for histiocytic and dendritic cell neoplasms recently proposed by the Histiocyte Society. 4 The different eponyms that have been used for systemic histiocytoses are shown in Figure 1A.

Somatic Mutations Drive HistiocytosesDespite categorization of histiocytoses with lymphoid neoplasms in the WHO classification, it is important to note that 1) gene expression analyses of LCH and ECD indicate that these disorders bear greater resemblance to myeloid lineage cells than dendritic cells5,6; 2) genetic analyses have identified that mutations in histiocytosis lesional cells can be found in CD34+ and circulating myeloid cells in patients6,7; and 3) functional analyses suggest that at least some histiocytoses are derived from hematopoietic precursors.8 These observations suggest that LCH, ECD, and JXG may actually be more appropriately considered clonal disorders of the myeloid lineage.

Interestingly, a series of studies performing mutational analysis of histiocytosis lesional biopsies has identified that both LCH and ECD are characterized by approximately 50 percent of patients having a BRAF V600E mutation (Figure 1B). The BRAF V600E mutation is common to a variety of epithelial cancers, strongly promotes activation of the MAP kinase pathway, and sensitizes cells to inhibitors of this pathway. Further studies to define mutations present in BRAF-wild-type patients have since identified that nearly all LCH and ECD patients have a mutation activating the same pathway as BRAF V600E mutations. This includes mutations in MAP2K1 (encoding the MEK1 kinase just downstream of BRAF), NRAS, KRAS, and ARAF as well as activating translocations in BRAF, ALK, and NTRK1 (reviewed recently9). The high frequency of mutations in MAP2K1 and ARAF make LCH and ECD quite unusual in that these kinases are 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 tumors have a specific translocation (ETV3-NCOA2) that appears to define this histologic entity.10

Therapeutic Targeting of BRAF and MEK in HistiocytosisBased on the success of targeting BRAF V600E mutant melanoma with RAF and MEK inhibitors, the discovery of BRAF V600E-mutant LCH and ECD led to efforts to determine the efficacy

Histiocytoses: Clonal Disorders of Hematopoiesis Driven by MAP Kinase SignalingOMAR 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

The Hematologist: ASH NEWS AND REPORTS 5

of these agents for adults with histiocytosis. A number of clinical studies have now demonstrated the efficacy of vemurafenib for BRAF V600E-mutant histiocytosis. In the one clinical trial that has been published, a cohort of 22 ECD and four LCH patients experienced a response rate of 64 percent to vemurafenib (Figure 2A).11 Extended follow-up of this study has identified that these responses are durable, with a median treatment duration now of

14.9 months (range, 2-43 months).12

Given that the use of vemurafenib requires documentation of the BRAF V600E mutation combined with the fact that nearly 50 percent of histiocytosis patients lack this mutation, there has been an ongoing effort to identify targeted therapies for BRAF-wild-type patients. Currently, it appears that the use of single-agent MEK inhibitors, including trametinib or cobimetinib, may have great efficacy for adults with BRAF-wild-type LCH or ECD (Figure 2B). Despite promising initial data on this approach, it is important to realize that it is not yet known if the variety of activating MEK1 mutations all respond to MEK1/2 inhibition nor is it understood which MEK inhibitor is ideal for use in histiocytosis. In order to determine the safety and efficacy of single-agent MEK inhibition based on the diverse genetic alterations present in BRAF-wild-type histiocytosis patients, our group has an ongoing phase II trial of single-agent cobimetinib for adults with histiocytic disorders (ClinicalTrials.gov identifier NCT02649972).

Conclusions and Unanswered QuestionsThe discovery of recurrent clonal mutations activating the MAP kinase pathway in histiocytosis as well as the response of these patients to small molecules inhibiting this pathway has been remarkable. Despite these advances, there is a need to continue genetic analysis of the variety of histologically defined forms of histiocytosis other than LCH, ECD, and ICH to determine if these conditions also harbor high frequencies of somatic mutations, some of which may be important in molecular diagnosis or treatment. Additionally, there is a need to more conclusively define the cellular origin(s) of LCH and ECD. Although accumulating data suggest that these conditions are derived from hematopoietic progenitors and/or myeloid progenitors, it also is possible that more than one cell of origin may characterize these disorders.

Dr. Abdel-Wahab indicated no relevant conflicts of interest.

1. Haroche J, Cohen-Aubart F, Rollins BJ, et al. Histiocytoses: emerging neoplasia behind inflammation. Lancet Oncol. 2017;18:e113-e125.

2. Egeler RM, Katewa S, Leenen PJ, et al. Langerhans cell histiocytosis is a neoplasm and consequently its recurrence is a relapse: In memory of Bob Arceci. Pediatr Blood Cancer. 2016;63:1704-1712.

3. Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375-2390.

4. Emile JF, Abla O, Fraitag S, et al. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016;127:2672-2681.

5. Diamond EL, Durham BH, Haroche J, et al. Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms. Cancer Discov. 2016;6:154-165.

6. Berres ML, Lim KP, Peters T, et al. BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med. 2014;211:669-683.

7. Milne P, Bigley V, Bacon CM, et al. Hematopoietic origin of Langerhans cell histiocytosis and Erdheim Chester disease in adults. Blood. 2017;pii:blood-2016-12-757823. [Epub ahead of print].

8. Durham B, Roos-Weil D, Baillou C, et al. Functional Evidence for Derivation of Systemic Histiocytic Neoplasms from Hematopoietic Stem/Progenitor Cells. Blood. 2017. [In press].

9. Durham BH, Diamond EL, Abdel-Wahab O. Histiocytic neoplasms in the era of personalized genomic medicine. Curr Opin Hematol. 2016;23:416-425.

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.

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.

12. Diamond EL, Subbiah V, Lockhart C, et al. Vemurafenib in patients with Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) harboring BRAF-V600 mutations: a cohort of the Histology-Independent VE-Basket study. Blood. 2016;128:480.

Examples of responses of BRAF V600E and MAP2K1 mutant adults with Erdheim-Chester disease (ECD) to molecularly targeted therapies. (A) Positron emission tomography (PET) scan and brain MRI of a BRAF V600E-mutant ECD patient 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 with disease infiltration in facial sinuses, heart, and kidneys pre- and four-weeks post-treatment with the MEK1/2 inhibitor cobimetinib.

Figure 2

Toward a molecular genetic understanding of histiocytic neoplasms. (A) Word cloud of the various names and eponyms for systemic histiocytic neoplasms that have been used since the initial descriptions of the diseases 150 years ago. (B) Pie charts of somatic mutations affecting MAP kinase signaling that are now known to occur in Langherans cell histiocytosis and Erdheim-Chester disease. The majority of recurrent mutations that have been identified are mutually exclusive activating mutations affecting MAP kinase signaling, with the most common being the BRAF V600E mutation. Reprinted by permission from the American Association for Cancer Research.

Figure 1

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

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

of disease and not on solving the problems that they encountered in clinical practice; their research

in the laboratory was disassociated from their activities in the clinic.

P R O F I L E S I N H E M A T O L O G Y

6 The Hematologist: ASH NEWS AND REPORTS

After I graduated from medical school at Melbourne University in Australia, in 1959, I completed four years of residency training in internal medicine and an additional year in laboratory hematology. It was then that I developed an interest in research, but I had no idea how to go about obtaining the necessary training. I sought advice from Professor Carl de Gruchy, a prominent Australian hematologist, who suggested that I specialize in thrombosis. He said that thrombosis bridged hematology and cardiology and would become an important field in medicine. He encouraged me to locate suitable training positions, so I applied for, and obtained, research fellowships at Washington University in St. Louis, Missouri, where I worked with Drs. Sol Sherry and Tony Fletcher; the London Post Graduate School in London, U.K., where I was fortunate to be Professor John Dacie’s sole trainee; and in Toronto, Canada, where I worked for Dr. Fraser Mustard. These researchers

were giants in their fields, and of the many lessons that I learned, two stand out and continue to serve me well: First, to succeed in research, a person requires passion, “stick-with-it-ness,” and stamina. Second, don’t give up on a problem because you lack the expertise to solve it.

In 1968, I returned to a faculty appointment at Melbourne University in the Department of Medicine headed by Professor de Gruchy. I chose venous thromboembolism (VTE) as my clinical field and used the training received overseas to set up a platelet/coagulation/fibrinolysis laboratory. My laboratory research was opportunistic and mainly phenomenological, though I did use the laboratory to support clinical studies with anticoagulants and with streptokinase. I was shocked to realize that almost all patient management decisions lacked a firm scientific basis. Even more shocking to me was that physicians caring for

patients were unaware of the flimsy evidence on which they made many of their clinical decisions. Venous thrombosis and pulmonary embolism (PE) were diagnosed on clinical grounds, and anticoagulant management was haphazard and not standardized. It was then that I decided that I would focus my research on problems that I encountered in my clinical practice and that I would use my laboratory to complement patient management. 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.

I performed clinical studies which convinced physicians that they should use standardized diagnostic testing to confirm a clinical suspicion of VTE. I introduced (and

personally performed) venograms to confirm a diagnosis of deep vein thrombosis. I standardized heparin monitoring, switching from the whole blood clotting time to the activated partial thromboplastin time, and I standardized prothrombin time monitoring for warfarin. I obtained local funding for a nonrandomized trial that showed that streptokinase was much more effective than heparin in lysing PEs. I also performed an experimental study in pregnant rabbits to determine the optimal time to switch from warfarin to heparin in pregnant mothers (with prosthetic heart valves) to limit bleeding in both mothers and their fetuses.

My clinical colleagues were very cooperative, supportive, and collegial. I was hailed as a success in Melbourne, but I sensed that my clinical research lacked rigor. Then, in 1969, my life changed! I was invited to pay a visit to the newly formed Faculty of Health Sciences at McMaster University in Hamilton, Ontario. When I visited, I was impressed with the energy, enthusiasm, creativity, and other outstanding qualities of the founding members. I was offered

an appointment but was torn by obligations to my family and colleagues in Melbourne. Two factors swayed me. My wife told me that we should “go for it.” Additionally, I had several long discussions with Dr. David Sackett when I visited McMaster. David, who at my age (mid-30s) was founding Chairman of the Department of Clinical Epidemiology and Biostatistics, was the missing link that I was seeking in order to perform worthwhile clinical research. He taught me how to focus my research on patient-important questions and outcomes and to design rigorous clinical studies required to change clinical practice. Soon after I moved to McMaster (in December 1969), I met Dr. Michael Gent, a mathematician who morphed into an outstanding biostatistician. The three of us became firm friends and colleagues, each with our own growing research groups, but sharing a common aim to perform clinical research that improves clinical practice. Dave and Mike collaborated with and advised many faculty

members in a variety of specialties, but my group and I concentrated on clinical research in thrombosis.

The McMaster environment was enormously supportive of our research, as was the Canadian funding scene. Throughout a 45-year period I mentored, advised, and collaborated with numerous outstanding clinical investigators, some of whom stayed and joined the McMaster faculty and others who moved to Faculties in Canada, Australia, Europe, Asia, and the United States. Some of my earlier fellows and recruits such as Drs. John Kelton, Jeffrey Weitz, and Mark Levine branched out into their own fields and became international leaders in their respective areas. Others such as Drs. Russell Hull, Graham Turpie, Jeffrey Ginsberg, Harry Buller, Giancarlo Agnelli, Phillip Wells, Gary Raskob, Agnes Lee, Mark Crowther, David Anderson, Clive Kearon, and John Eikelboom remained in clinical thrombosis research and became famous in their own right. Working with collaborators and trainees during a span of almost 50 years, I performed research that changed clinical practice. I established clinical standards for the laboratory monitoring of warfarin and heparin and introduced the international normalized ratio in North America. We demonstrated the benefit of aspirin in stroke prevention, established standards for the short- and long-term treatment of VTE, the diagnosis of venous thrombosis and PE, and the out-of-hospital treatment of venous thrombosis. We performed pivotal studies on the prevention of venous thrombosis with anticoagulants and mechanical devices, and my group was one of three that demonstrated the clinical advantages of low-molecular-weight heparin. More recently, we were involved in some of the pivotal studies with direct acting anticoagulants in the prevention of stroke in atrial fibrillation, and in the prevention and treatment of VTE.

I remain involved in clinical practice and retain my passion for discovery and for teaching new fellows. My students have become my teachers. Drs. Sackett and Gent (who were never my students) taught me methodology and the rudiments of biostatistics. Dr. Weitz taught me biochemistry, and Dr.

Gordon Guyatt refined my knowledge of grading evidence and convinced me of the importance of including patients’ values and preferences in clinical decision-making. Now at the age of 82, I am fortunate to belong to an outstanding research group led by one of my former students, Dr. Eikelboom, and I continue to mentor and learn from fellows and new faculty who are members of our group.

Of course, I have other passions. I love spending time with my wife of 54 years and family made up of three children, four grandchildren, and two great-grandchildren, whose ages span nine to 55 years. I have always loved participating in sporting activities and have graduated from playing tennis and squash to the more sedate (but fiendishly difficult) game of golf, to which I am moderately addicted. I enjoy reading history, science, and good mysteries.

Finally, I showed this piece to two of my colleagues, each whom told me that it was too light on showcasing myself and too strong on highlighting my colleagues. But, they missed the point. I was not being overly generous. My success in research has been strongly dependent on three factors: my passion for learning; my ability to attract smart young researchers and provide an environment that entices them to stay; and the wonderfully supportive environment at McMaster University, which was unparalleled.

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.

(Cont. on next page)

T H E H E M A T O L O G I S T A D V O C A T E

H E A D L I N E S F R O M

WashingtonCongress Begins FY 2018 Budget ProcessPresident Trump Seeks Massive Public Health Program Cuts; ASH Members Go to Capitol Hill to Protect Federal Research Funding

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 in cuts from current funding for the National Institutes of Health (NIH). The proposal would amount to nearly a 21 percent cut to the medical institute, wiping out recent funding increases and negating a major boost from last year’s 21st Century Cures Act for targeted initiatives such as the Cancer Moonshot, as well as the $2 billion increase Congress provided NIH in the final FY 2017 funding bill signed into law in early May.

The president’s proposed budget seeks to also cut other important public health programs, including nearly $1 billion from the Centers for Disease Control and Prevention (CDC), which has a role in preventing and understanding blood diseases and disorders, including sickle cell disease (SCD) as well as bleeding and blood clotting disorders. The proposal also looks to cut Medicaid by $610 billion throughout the course of a decade. Medicaid is critical for patients with SCD and bleeding disorders such as hemophilia and von Willebrand disease.

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 received less than enthusiastically by members of Congress, who will spend the summer holding hearings and drafting legislation to establish spending levels for federal programs for FY 2018, which begins on October 1 of this year.

ASH remains committed to protecting federal research funding and promoting strong, sustained, and predictable funding for NIH. ASH members have been advocating with members of Congress, and the Society has been partnering with other advocacy groups to amplify our impact. In June, ASH members and researchers, physicians, and patients from the Thrombosis & Hemostasis Societies of North America (THSNA) met with more than 30 congressional offices to discuss the value of biomedical research with members of Congress and to seek to protect public health funding from the drastic cuts proposed for FY 2018.

These face-to-face meetings are an essential component of ASH’s advocacy efforts, providing an opportunity for members of Congress and their staff members to gain insight into issues of concern to hematologists and their patients. However, the Society needs the help of all of its members in continuing to focus attention on the importance of federal research funding and the need for predictable and sustained funding for NIH. Please visit the ASH website (www.hematology.org/Advocacy) for updates on the FY 2018 budget process and for information about how you can contact your senators and representative to protect NIH funding in FY 2018.

ACA UpdateAs this issue of The Hematologist went to press, the U.S. Senate was still debating how to proceed with consideration of the American Health Care Act (AHCA) that passed out of the House of Representatives 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 weeks after the legislation passed the House. The CBO estimates for the AHCA indicate that by 2026, 23 million more people will be without health insurance. The majority of the new uninsured will be low-income individuals and families, as the AHCA will lower federal Medicaid spending by $834 billion over 10 years. The CBO also reported that the AHCA will reduce the cumulative federal deficit by $119 billion by 2026.

ASH is also concerned about the bill’s proposed elimination of the Public Health and Prevention Fund which has supported many critical projects at the CDC, including investments in immunization and healthcare associated infections. Currently the fund comprises approximately 12 percent of the CDC’s budget and should be preserved.

The Society is committed to ensuring that all individuals who need the services of a hematologist have access to one, and that patients have affordable and reliable coverage options so that the most appropriate and effective treatment options are available to them. ASH will continue to monitor this process with respect to the impact on hematology practice.

Sickle Cell Disease Congressional BriefingA congressional briefing on SCD and gene editing took place on June 7, 2017, at the Rayburn House Office Building on Capitol Hill. The briefing was hosted by the House Research & Development Caucus and the Congressional Sickle Cell Disease Caucus, and co-sponsored by ASH, the Sickle Cell Disease Association of America, the National Marrow Donor Program/Be The Match, the American Society of Gene & Cell Therapy, and the Pediatric Hospital Sickle Cell Collaborative, with the goal of educating members of Congress and their staff on scientific advances that could potentially cure this devastating disease.

Speakers included ASH members Drs. Linda Burns and Dan Bauer, who discussed the progress in SCD research as well as curative options such as bone marrow transplantation and gene editing. Constance Benson, a former SCD patient and a transplant recipient concluded the briefing with an inspiring talk about 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.

Thoughts From a ProtégéJOHN G. KELTON, CM, FRSC, MD

Executive Director, Michael G. DeGroote Initiative for Innovation in Healthcare; Dean Emeritus, Michael G. DeGroote School of Medicine; Dean & Vice President Emeritus, Faculty of Health Sciences; McMaster University, Hamilton, Ontario, Canada

I was completing fellowship training in the United States when I became aware of the innovative research studies coming from McMaster University. When I visited the 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,” even long before the actual concept of mentorship became popular. It seemed impossible to me that such a modest person could simultaneously have a crackling intellect, an intense curiosity, and an energy level well beyond the Tasmanian devil of his home country. Jack was also nice — terribly nice.

When I first met Jack, I had a foundation in basic science, but I had not acquired the ability to align bench research with patient care. In the area of translational research, Jack Hirsh was a master without peer. He did not invent the concept of evidence-based medicine, but he was certainly one of the first clinician-scientists to harness its remarkable power to answer important clinical questions. Each week, the clinical and research fellows would update their research at our meetings. The educational experience was remarkable. Jack taught us that a failed experiment was often as informative as a successful one. Above all, he showed us the power 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 characteristic posture: leaning forward, listening intently, one hand under each thigh, legs swinging below the chair. Like bloodied fighters, the research fellows would explain our (often) failed experiments, while Jack asked questions. Throughout this process, our initial pessimism (often a 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 not just the question of that particular experiment, but the value of the research itself. Our ability to ask and answer Jack’s trademark question is what separates workmanlike experimentation from truly important research.

I have learned through a nearly four-decade-long career in medicine that this is not a solo sport. Everything depends on the people around you. They set the circumstances, the examples, and occasionally the limits that define our 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 went into the worlds of academia and medicine and became leaders. He made research a team sport by the sheer force of his example and leadership. I can count at least fifty scientists, half a dozen departmental chairs, and at least three medical school deans scattered across Canada and the United States who owe big parts of their careers to Jack. I am one of them.

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 did Jack’s energy wane. Instead, it would take about a decade for accumulated injuries to impose a switch. Jack’s current sport is golf. I recall playing with Jack in the first few years he took up the sport. He was extoling (with some authority) the value of a natural swing. To the casual observer, the swing could only be called natural if shoulder entrapment prohibits raising the club face higher than waist-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 his age), and his former students receive the frequent news that he has added to his collection of holes-in-one. He’s up to four. From the white tees.

The Hematologist: ASH NEWS AND REPORTS 7

8 The Hematologist: ASH NEWS AND REPORTS

SIMONE DAVION, MD, AND TRACY I. GEORGE, MD

Dr. Davion and Dr. George indicated no relevant conflicts of interest.

CARON A. JACOBSON, MD

Dr. Jacobson indicated no relevant conflicts of interest.

Bone Marrow Fecundity: Turning Over New Stem Cells in Aplastic AnemiaTownsley DM, Scheinberg P, Winkler T, et al. Eltrombopag added to standard immunosuppression of aplastic anemia. N Engl J Med. 2017;376:1540-1550.

An insurmountable limitation in treating bone marrow failure has always been the number of residual stem cells. That is, until now. Dr. Danielle M. Townsley and colleagues from the National Institutes of Health have demonstrated in a nonrandomized historically controlled trial that the ad-

dition of eltrombopag, an oral thrombopoetin-receptor agonist, to standard therapy, improves rates of hematologic response in patients with severe aplastic anemia.

The empty bone marrow seen on trephine core biopsy in aplastic anemia is a stark and accurate indication of depleted hematopoietic precursors; the cells are simply not there. Sensitive flow cytometry designed to enumerate the immature precursor cells corroborates this morphologic impression. Multiple lines of evidence have established immune-mediated destruction of stem cells as the cause of bone marrow failure. Cytotoxic lymphocytes, cytokines, and a relative paucity of 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 cytotoxic T cells, leading to constitutive activation, in combination with the loss of the immune modulating effect of T-regulatory cells. As such, immunosuppression, in the form of horse antithymocyte globulin and cyclosporine, have been the cornerstone of therapy. The historical overall response rate to standard immunosuppressive therapy in aplastic anemia is 66 percent. With the addition of eltrombopag to standard immunosuppressive therapy, Dr. Townsley and colleagues have improved the overall response rate to 94 percent at six months.

The researchers divided patients two years and older with previously untreated severe aplastic anemia into three cohorts. All cohorts were treated with a standard immunosuppression regimen of ATGAM (Pfizer Inc.) and cyclosporine. Eltrombopag was added to the standard regimen in three dosing schedules varying in the timing and duration of eltrombopag therapy. The primary efficacy endpoint was complete hematologic response at six months, defined as an absolute neutrophil count of at least 1,000/mm3, a hemoglobin level of at least 10 g/dL, and a platelet count of at least 100,000/mm3. The primary safety endpoint included overall safety profile in the six months after initiation of therapy. Secondary endpoints included survival and clonal evolution, defined as a new clonal cytogenetic abnormality or characteristic changes in the bone marrow consistent with the myelodysplastic syndrome or acute myeloid leukemia.

The overall complete response rate in all three cohorts was 36 percent — a significant improvement over the historical control cohort (p<0.0001). The cohort with the longest duration of eltrombopag therapy had the highest complete response rate (p<0.0001). Significant adverse events attributed to the drug included grade 2 cutaneous eruptions in two patients. The overall survival rate at two years was 97 percent. Results of bone marrow cellularity and CD34+ cell counts are shown in the Figure (available in the online version of this article at www.hematology.org/thehematologist).

A significant secondary endpoint in this study was clonal cytogenetic evolution. The potential for clonal cytogenetic evolution was of particular interest because of the well-known predisposition of patients with aplastic anemia to experience clonal hematopoiesis. In the milieu of bone marrow failure, the small number of residual stem cells attempt to maintain peripheral counts, which leads to telomere attrition resulting in chromosome instability and increasing the odds of harmful mutations. This eventuality was of particular concern in a trial in which both diminished immunosurveillance and growth promotion were stimulated in tandem. Clonal cytogenetic evolution occurred in seven patients at two years. It is important to note that the rates of clonal evolution in all three cohorts were within the range of what would be anticipated with immunosuppression alone.

The mechanism by which eltrombopag improves recovery of peripheral counts in aplastic anemia is unknown. The results are particularly surprising because endogenous levels of erythropoietin and other hematopoietic growth factors are markedly elevated in patients with aplastic anemia but are clearly unable to promote effective hematopoiesis. Furthermore, therapy with granulocyte colony-stimulating factor in aplastic anemia is usually ineffective. Dr. Townsley and colleagues speculate that improved bioavailability of the synthetic agonist may play a role in its efficacy.

In summary, the potential addition of growth agonist into the immunosuppressive 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.

Expanding Host Tumor Immunity, One Neoantigen at a TimeKhodadoust MS, Olsson N, Wagar LE, et al. Antigen presentation profiling reveals recognition of lymphoma immunoglobulin neoantigens. Nature. 2017;543:723-727.

Dr. Michael Khodadoust and colleagues use liquid chromatography and tandem mass spectrometry to perform direct proteomic analysis of 17 primary mantle cell lymphoma (MCL) samples and two MCL cell lines to identify major histocompatibility complex– (MHC-) presented tumor neoantigens (Figure). Through immunoprecipitation, they

isolated 24,000 unique MHC-I–associated peptides and 12,500 unique MHC-II-associated 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 175 nonsynonymous somatic mutations per patient, only mutated peptides derived from Ig genes were presented by MHC. For all others, only unmutated parts of the protein were presented. Interestingly, MHC presentation was polarized such that nearly all Ig-variable neoantigens were presented by MHC-II, whereas the majority of Ig-constant neoantigens were presented by MHC-I. Of the Ig-variable neoantigens, just about half of them were the result of somatic hypermutation or V-D-J recombination.

Using synthetic neoantigen peptide tetramers with affinity for HLA-DR*0401, they screened the blood of three patients with an HLA-DR*0401 allele for neoantigen-specific CD4+ T cells and found them in one of the three patients. These CD4+ T cells appeared to be memory T cells and lacked PD-1 expression, and were skewed towards a Th2/Th17 phenotype. T-cell receptor (TCR) sequencing identified two dominant T-cell clones, both of which were induced upon neoantigen peptide autologous vaccination. Ex vivo expanded neoantigen specific CD4+ T cells stimulated by autologous neoepitopes resulted in the production of IL-4 and granzyme and could mediate the killing of autologous lymphoma cells in an antigen-specific manner.

Non-Hodgkin lymphomas (NHLs) are susceptible to immune attack, as evidenced by the efficacy of allogeneic stem cell transplantation, but can evade host-immune recognition. Attempts to harness the host’s own immune system against the lymphoma with immune checkpoint blockade

have been less successful than in Hodgkin lymphoma or certain solid tumors. Dr. Khodadoust and colleagues examined a panel of primary MCL samples and cell lines by direct proteomic antigen profiling to identify tumor neoantigens and their potential to elicit an antitumor immune attack. They demonstrate the feasibility of such an approach and identify genes in the Ig-variable region to be the major source of MHC-presented lymphoma neoantigens. Strikingly, these neoantigens are presented almost exclusively in the context of MHC class II, and the cognate neoantigen-specific CD4+ host T cells are skewed to a Th2 phenotype. Why or how is unclear at this point, but it may lead to tumor immune evasion, or even tumor cell progression via support and activation by cognate helper T cells. Despite this, these CD4+ T cells are able to mediate tumor cell killing in an antigen specific manner and autologous tumor vaccination results in induction of anti-tumor CD4+

T cell clones. This has therapeutic potential, especially in a group of diseases with relatively low 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 potential to be a new form of cell therapy for these patients.

Elute peptides

Peptide-MHC IP

Whole exome and lg sequencing

}MCH-IMCH-IINeoantigen

peptide identification

LC-MS/MS analysis

Pool the individual

plexes

Label each sample with TMT10plex Isobaric Mass Tagging Reagents

Figure

Schematic of proteomic and sequencing platform used to identify tumor neoantigens. Tumor samples from 17 patients with mantle cell lymphoma were used to 1) isolate major histocompatibility complex (MHC) ligands through immunoprecipitation (IP) followed by liquid chromatography-tandem mass spectroscopy (LC-MS/MS) and 2) perform whole exome sequencing and immunoglobulin gene sequencing in order to identify neoantigen peptides.

The Hematologist: ASH NEWS AND REPORTS 9

DAMON E. HOUGHTON, MD, MSc, AND STEPHAN MOLL, MD

Dr. Houghton and Dr. Moll indicated no relevant conflicts of interest.

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.

Patients with unprovoked venous thromboembolism (VTE) — deep vein thrombosis (DVT) and/or pulmonary embolism (PE) — have a 30 percent risk of recurrent VTE over five years if anticoagulation is stopped after the initial three to 12 months of acute VTE treatment.1 While men have a higher risk of recurrence than women (over 5 years,

36% vs. 24%, respectively), the risk in both is considered to be high enough that evidence-based guidelines recommend long-term anticoagulation for patients with unprovoked VTE, independent of sex, if they tolerate anticoagulation well and are not at high risk for bleeding.2,3

In 2008, Dr. Marc A. Rodger and colleagues published the “HERDOO2 rule,” created from the results of a prospective multicenter cohort study of 646 participants with a first, unprovoked VTE treated with short-term anticoagulation.4 No predictors for a low risk of recurrence were found in men, but in women, a low-risk group was identified (Table). They concluded that women with unprovoked VTE with a HERDOO2 score of 0 to 1 could discontinue anticoagulation, while women with a score of at least 2, and all men, should continue.

The work of Dr. Rodger and colleagues is a validation study of this HERDOO2 rule. 2,785 subjects (44.3% female) with first unprovoked VTE (proximal DVT or PE) who had completed five to 12 months of anticoagulation were enrolled at 44 medical centers in seven countries. Index VTE events associated with minor or weak risk factors, such as travel, exogenous estrogens, minor immobilization or minor surgery were considered unprovoked and eligible for enrollment; patients with strong thrombophilias were excluded. Women with a HERDOO2 score of at least two and all men were advised to continue long-term anticoagulation; women with a score of zero to one were advised to discontinue anticoagulants. Patients were followed for one year and assessed for the primary outcome, recurrent major VTE (proximal DVT and segmental or greater PE). Not all patients followed the recommendation to discontinue or continue anticoagulation based on the decision rule’s risk assessment, allowing a risk of recurrence assessment in the various groups listed below.

In low-risk women who discontinued anticoagulation (n = 591), VTE recurrence per patient-year was 3.0 percent (95% CI, 1.8-4.8%). In high-risk women and men who discontinued anticoagulation (n = 323), it was 8.1 percent (95% CI, 5.2-11.9%). In high-risk women and men who continued anticoagulation (n = 1,802), it was 1.6 percent (95% CI, 1.1-2.3%), and in high-risk women who discontinued anticoagulation (n = 101), VTE recurrence per patient-year was 7.4 percent (95% CI, 3.0-15.2%).

This study validated the original HERDOO2 rule: Women with a first unprovoked VTE event and a HERDOO2 score of 0 to 1 have a low risk of recurrent VTE and can safely discontinue anticoagulants, whereas women with a score of at least 2, and all men, have a high risk of recurrence and should continue long-term anticoagulation. Noteworthy is that 51.3 percent of women with unprovoked VTE were classified as low risk, appropriate for discontinuation of anticoagulation. Thus, long-term anticoagulation, as recommended by existing guidelines, could be avoided in a substantial number of women if following HERDOO2.

We do not routinely use the HERDOO2 score for decision-making on length of anticoagulation in women with a history of unprovoked VTE, for five reasons. 1) There is equivocal evidence 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 recurrence; while some studies have, similar to Dr. Rodger and colleagues, found that obesity

is a risk factor for recurrence,5-7 others have not confirmed this.8 Discrepant data also exist on whether older age is a risk factor for recurrence; while some studies have found older age to be a recurrence risk factor,8 others have not confirmed this9,10 and even found the opposite (e.g., younger age < 50 years increases risk of recurrence).11 2) The unprovoked VTE group was a mixture of true unprovoked VTE and VTE associated with minor or weak transient risk factors and was treated and analyzed as one homogenous group. However, previous data suggest that 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 inclusion of such patients would have influenced the results. Given that strong thrombophilias are not very prevalent, inclusion would likely not have changed the results. Nevertheless, applying this score to a more general, untested population and using it for clinical decision making has some imponderability factor. 4) Only 25.4 percent of study patients were on a non-warfarin anticoagulant at baseline, but many with VTE are now being treated with a direct 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 predicts recurrent VTE in a similar manner as it does while on warfarin. 5) In this study, the HERDOO2 score was applied after five to 12 months of initial anticoagulation, but it is unclear if the score remains valid if applied earlier after initial VTE (i.e., after 3 months of anticoagulation, a time when many physicians are making the decision to continue or discontinue

anticoagulation). Edema often decreases after the initial DVT, but postthrombotic pigmentation increases, and these changes may influence the HERDOO2 score if obtained at an earlier time.

To discuss and decide with the patient who has a VTE how long to treat with anticoagulation, we use the recurrence triangle depicted in the Figure. In patients at

intermediate risk of recurrence (patient “B”), situations where we or the patient is ambivalent as to whether to stop anticoagulation, or in women with true unprovoked VTE with a strong preference to come off anticoagulation, we use the D-dimer as an aid in decision making. It is also this group of patients in which we contemplate obtaining a thrombophilia work-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 uncommon and a large number of patients would need to be tested to find one case of a strong thrombophilia, and some discrepant data exist on what truly constitutes a “strong thrombophilia.”

Finally, we do apply the HERDOO2 score to women in the intermediate risk of recurrence 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 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 study. Medicine (Baltimore). 2009;88:366-370.

10. Christiansen SC, Lijfering WM, Helmerhorst FM, et al. Sex difference in risk of recurrent venous thrombosis an the risk profile for a second event. J Thromb Haemost. 2010;8:2159-2168.

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.

12. Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med. 2010;170:1710-1716.

Table: HERDOO2 Scoring

Predictor Scoring

H Hyperpigmentation 1 point total, if any one of these criteria is present

E Edema

R Redness of either leg

D D-dimer ≥ 250 μg/L while anticoagulated 1 point

O Obesity with BMI ≥ 30 kg/m2 1 point

O Older age, i.e. ≥ 65 years 1 point

Decision Making:Women: 0-1, discontinue anticoagulation; ≥2, continue anticoagulation.All men: continue long-term anticoagulation.

Recurrence triangle. Patient A: major transient risk factor associated VTE; patient B: minor/weak risk factor associated VTE, such as travel, estrogens, minor immobility, minor surgery; patient C, woman with true unprovoked VTE; patient D, man with unprovoked VTE. Abbreviations: DD, D-dimer; VTE, venous thromboembolism.

ºVTE is a proximal deep vein thrombosis or pulmonary embolism.

*HERDOO2 score is only to be used in women.

Figure

10 The Hematologist: ASH NEWS AND REPORTS

ANDREW J. YEE, MD, AND NOOPUR RAJE, MD

Dr. Yee and Dr. Raje indicated no relevant conflicts of interest.

Is Upfront Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma the Standard?Attal M, Lauwers-Cances V, Hulin C, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376:1311-1320.

High-dose melphalan with autologous stem cell transplantation is an important consolidative strategy for treating multiple myeloma. However, a core question is the timing of intensive treatment when combination regimens such as lenalidomide,

bortezomib, and dexamethasone (RVD) can achieve deep responses with minimal toxicity. Recently, the Intergroupe Francophone du Myélome (IFM) reported the results of a large phase III trial, IFM 2009, that was designed to answer the question of when to undergo autologous stem cell transplantation: upfront as part of the initial treatment, versus at time of relapse.

In this trial, all patients (N=700) received standard induction with RVD for three cycles followed by stem cell collection. The patients were then randomized to upfront transplant with high-dose melphalan and autologous stem cell transplantation, followed by consolidation with two additional cycles of RVD. The other half went on to five additional cycles of RVD for a total of eight cycles. Following completion of initial treatment, both groups received maintenance lenalidomide for one year. The median progression free survival (PFS) was significantly longer in the upfront arm than in the deferred arm, 50 versus 36 months (p<0.001). Depth of response was also higher in patients who received intensive therapy initially, based on achieving complete response (59% vs. 48%; p=0.03) and absence of minimal residual disease (MRD; 79% vs. 65%; p<0.001). (Of note, MRD was measured by a flow cytometry assay with a sensitivity of 1×10-4, which is less sensitive than current assays such as by next- generation sequencing.) Overall, patients who were MRD-negative had improved PFS and overall survival (OS) compared with MRD-positive patients (HR, 0.3 and 0.34, respectively). However, at four years, OS was similar, at 81 percent versus 82 percent between the MRD-negative and MRD-positive arms, respectively. As expected, there were more adverse events related to myelosuppression and gastrointestinal adverse effects in the upfront transplant arm. Also of interest were four cases of acute myelogenous leukemia in the upfront arm versus one case in the deferred arm.

The results from this study are key for helping to frame the discussion with patients about the timing of transplant. The induction regimen of RVD used in the study reflects current practice, especially given the recent SWOG trial showing superiority of the triplet compared with lenalidomide and dexamethasone.1 The trial illustrates the importance of depth of response correlating with improved outcomes, and an upfront approach provides a means for achieving this. Despite the significant improvement in PFS, there was no OS advantage. This is likely a reflection of the evolving maturity of the data. Importantly, in the deferred arm, 21 percent of patients were not able to receive a salvage transplant due to refractory disease, and there were also an increased number of myeloma-related deaths.

The DETERMINATION trial (NCT01208662) is an ongoing investigation in the United States that parallels the IFM study with the same trial design. The DETERMINATION trial is actively accruing patients, and the findings from this study will be an important complement to the IFM study. The main difference in the U.S. arm of the trial is the duration of maintenance lenalidomide. In the U.S. arm, patients are maintained until relapse, whereas in the IFM study, maintenance was for one year only. Maintenance lenalidomide is increasingly becoming adopted as standard practice in the United States based on trials showing improvement in PFS, and in a meta-analysis, improvement in OS.2 Results from DETERMINATION will provide greater clarity on how long to use maintenance lenalidomide and whether longer maintenance will narrow the gap in PFS between upfront and deferred transplant approaches. Additionally, the larger number of patients, when combined with the IFM study, may help identify subgroups who benefit more from upfront transplant. In the IFM study, there was no statistically significant improvement in PFS for patients with high-risk disease, based on International Staging System (ISS) III staging or by cytogenetics, though this may reflect the smaller number of patients in these groupings. Finally, there will be more robust data from MRD assessments using a more sensitive sequencing assay, which is relevant since achieving MRD negative status resulted in improved disease control irrespective of treatment arm. This may help clarify if patients who are MRD negative may consider a deferred transplant approach. Overall, the results from the U.S. arm, combined with the IFM 2009 results, will provide valuable guidance on the place of autologous stem cell transplantation and help individualize treatment for newly diagnosed patients.

1. Durie BG, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389:519-527.

2. Attal M, Palumbo A, Holstein SA, et al. Lenalidomide (LEN) maintenance (MNTC) after 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.

Redefining Induction Failure

O’Connor D, Moorman AV, Wade R, et al. Use of minimal residual disease assessment to redefine induction failure in pediatric acute lymphoblastic leukemia. J Clin Oncol. 2017;35:660-667.

Traditionally, remission status has been determined by bone marrow morphology at the end of the induction phase of treatment in acute lymphoblastic leukemia (ALL). Minimal residual disease (MRD) testing is now routinely performed in conjunction with morphologic assessment to determine the depth of remission, and MRD response is the most powerful prognostic determinant. Although the

vast majority of children achieve a remission (<5% blasts by morphology) with frontline induction therapy, a small percentage fail induction. While in the majority of cases MRD assessments are concordant with morphology, discordance can be observed. This raises the question of how to determine induction response most reliably, as patients with persistence of a high tumor burden at the end induction fare poorly with conventional treatment and may be candidates for alternative therapies.

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 were treated on the Medical Research Council UKALL 2003 trial. All patients underwent routine morphologic assessment of marrow response at individual treating centers at the end of induction (EOI), and response was categorized as M1 (<5% blasts), M2 (5-25% blasts), or M3 (>25% blasts). Induction failure was defined as failure to achieve morphologic complete remission (<5% bone marrow blasts). In parallel, bone marrow MRD was measured at one of five laboratories in the United Kingdom using standardized real-time quantitative polymerase chain reaction for immunoglobulin and T-cell receptor gene rearrangements, with a cutoff of 0.01 percent used to define MRD positivity. All patients underwent routine cytogenetic testing for chromosomal abnormalities of known prognostic significance. Patients lacking established cytogenetic alternations were designated “B-other,” and a representative cohort of these patients underwent additional testing for ABL1, ABL2, PDGFRB, CSF1R, CRLF2, and JAK2 rearrangements.

Fifty-nine patients (1.9%) had morphologic induction failure at the EOI, with 44 M2 and 15 M3 marrow responses. Patients with M2 marrow responses received intensified chemotherapy on protocol, whereas those with M3 marrow responses were taken off protocol to receive salvage therapy. Patients with morphologic induction failure had poor outcomes, with a five-year event-free survival (EFS) of 50.7 percent and a five-year overall survival (OS) of 57.7 percent, and outcomes did not differ significantly among those who underwent hematopoietic stem cell transplantation. Not unexpectedly, induction failure was associated with high-risk clinical and cytogenetic features.

The authors analyzed the relationship between morphologic response and molecular MRD at the EOI. While there was concordance between MRD and morphologic responses in the vast majority of cases, 61 patients (2.3%) were identified with M1 marrow morphologic responses but with discordantly high MRD levels of 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 common in children with T-cell ALL (8%) than B-lineage ALL (1.5%), p<0.001. Conversely, another very small group of six discordantly low MRD patients was identified with morphologic induction failures (M2) but with MRD less than 0.01 percent and this group had a five-year EFS of 100 percent.

Approximately one third of the induction failure patients defined by both morphology and MRD levels of 5 percent or greater fell into the “B-other” cytogenetic group, where expanded testing for genetic fusions was performed. Notably, EBF1-PDGFRB fusions, which have been successfully targeted with imatinib, were

detected in approximately 10 percent of induction failure patients overall. Based on the findings in this report, the UK group has revised their definition of induction failure to include at least 5 percent residual disease by either MRD or morphology. Thus the new definition doubles the number of induction failures (Figure). Given the high proportion of adverse cytogenetic alterations in this group, patients with induction failure now also undergo expanded cytogenetic testing for targetable fusions.

This report provides important new insight into improving the accuracy of induction response assessment by incorporating MRD. While this report suggests that treatment response may be more accurately determined by MRD alone, given the relatively small number of discordant cases, confirmatory studies using different MRD methodologies and therapeutic backbones are presently underway. Additionally, the MRD threshold that optimally defines a poor risk group remains to be defined. This work is anticipated to lead to a revised universal definition of induction failure in the future, identifying an expanded group of patients with poor outcomes, who may benefit from alternative treatment approaches.

Figure

Event-free survival (EFS) in 120 patients with induction failure on the basis of new criteria (M2 and M3 marrow and/or end of induction minimal residual disease ≥5%) compared with those patients who achieved complete remission at the end of induction. Data indicate eight-year EFS estimates. Numbers within each group are indicated in the at-risk table beneath the graph. O/E, observed/expected. Reprinted with permission. © 2017 American Society of Clinical Oncology. All rights reserved.

ELIZABETH RAETZ, MD

Dr. Raetz indicted no relevant conflicts of interest.

Cellular Heterogeneity Based on Microniches

Oyler-Yaniv A, Oyler-Yaniv J, Whitlock BM, et al. A tunable diffusion-consumption mechanism of cytokine propogation enables plasticity in cell-to-cell communication in the immune system. Immunity. 2017;46:609-620.

Hematologists and immunologists are often focused on cellular heterogeneity. New markers or transcriptome profiles are ever increasing, breaking down blood and tissue resident cells into smaller and more discrete “cell types.” With the emergence of single-cell RNA sequence profiling, heterogeneity is

being discovered in what were thought to be more or less homogenous cell populations.

Recent work from Dr. Alon Oyler-Yaniv and colleagues outlines research strategies for the future, and may help to explain some of this heterogeneity. The premise of their work is that cell-to-cell communication via cytokines in tissues is dependent on the ability of that cytokine to diffuse from the source, and on the number of cells consuming the cytokine. Therefore, in a tissue with a high number of cells that have a receptor for the cytokine (consumers), the relative distribution of a cytokine produced 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.

To test the effect of diffusion-consumption on cytokine responses, the authors chose to use a model of regulatory T cells (Treg) as the consumers, as they have high levels of the high-affinity IL-2 receptor a chain (IL-2Ra). Because normal tissue culture plates have cells at too low of a density to be representative of solid tissue density and to allow the medium to uniformly mix, the authors fabricated their own 96-well plate that they named “the clusterwell plate.” This allowed cell suspensions to be loaded into the plate and then centrifuged to created densely packed cell cultures. Using this clusterwell plate, the authors created cell suspensions with various ratios of Tregs and of CD4 depleted splenocytes, which do not respond to IL-2 and are thus “inert cells” in their model system. This created scenarios where the total number of cells was the same, but the number of consumers was altered. To measure the effects of diffusion-consumption, the authors intracellularly stained for pSTAT5, which is immediately downstream of the IL-2 receptor. The authors demonstrate that as the density of consumers decreased, a larger fraction of the CD4+ IL-2Ra+cells were exposed to IL-2 and were positively stained for pSTAT5. In contrast, as the consumer density increased, pSTAT5 staining decreased. In fact, labeled cells at the bottom of the well were unable to respond to IL-2 when consumer density was higher, demonstrating a restricted cytokine distribution in these cultures.

To visualize these microniches created by diffusion-consumption of IL-2, the authors developed an imaging assay they called PlaneView imaging. The authors mixed either consuming T cells or a combination of 10 percent consumers and 90 percent inert splenocytes with 0.1 percent IL-2–producing T cells. This mixture was then deposited in a monolayer on a glass slide, and 10 more layers of cells without producers were added, creating a three-dimensional system with a small number of producers on the bottom. When pSTAT5 was then imaged, spherical microdomains of IL-2 response were seen. In settings where 100 percent of the cells were consumers, the length scale of the cytokine niche was approximately 3.5 cell diameters, while the 10 percent consumer setting (with the same total number of cells) was approximately 13.5 cell diameters.

This study demonstrates that spatial heterogeneity, created by diffusion-consumption cytokine gradients, can result in downstream heterogeneity of a cell population that

otherwise would be considered homogenous. In in vivo studies, these microniches were also demonstrated by the authors in immune tissues and could dynamically change depending on stimuli. Given the abundance of single-cell RNAseq profiling being performed in tissues, tumors, etc., spatial organization of the cells within a tissue needs to be considered and may account for transcriptomic differences that are completely independent of underlying genetic differences amongst cells. As the bone marrow hematopoietic niche is densely packed and contains a high variability of cells, it is possible that these same cytokine or growth factor microniches exist, perhaps governing hematopoiesis at very defined locales within the bone marrow space.

MICHAEL R. DEBAUN, MD

Dr. DeBaun indicated no relevant conflicts of interest.

Cautiously Optimistic About Gene Therapy in Sickle Cell Disease: A New Arrow in the Quiver for Cure

Ribeil JA, Hacein-Bey-Abina S, Payen E, et al. Gene therapy in a patient with sickle cell disease. N Engl J Med. 2017;376:848-855.

Until recently, two major barriers limited cure for individuals with sickle cell disease (SCD). First, for both children and adults, there has been a paucity of donors — estimated at only 18 percent of those considering hematopoietic stem cell transplantation (HSCT).1 Second, myeloablative conditioning regimens had typically

been too toxic for adults. Over the past 10 years, however, two strategies have emerged to address these intrinsic challenges, making cure a realistic outcome in an increasing number of children and adults with SCD. The first strategy is nonmyeloablative HSCT; it recently has been successfully applied in adults with SCD, with HLA-matched sibling donors. To increase the pool of donors, the most promising experimental strategy is the use of haploidentical transplantation with posttransplant cyclophosphamide — a nonmyeloablative strategy2 with greater than 90 percent donor availability. Gene therapy is now a second strategy to increase the donor pool, at least in children with SCD.

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 were significant, and the authors clearly addressed each one successfully. Equally laudable

is the bravery of the participant and the participant’s family. The family’s altruism and trust in both their clinical and research teams should not be taken lightly. The gene therapy was designed using the LentiGlobin BB305 (Bluebird Bio) vector, which encodes for the human hemoglobin B genetic variant. Briefly, bone marrow harvest was obtained twice, and CD34+ (stem) cells were transduced with the LentiGlobin BB305 vector (Figure). Next, a myeloablative dose of busulfan with area under the curve 19,363 μmol/min was administered, and after a two-day washout period, the transduced CD34+ cells (5.6 × 106 CD34+ cells/kg) were infused. Fifteen months after completion of the procedure, the participant did not report any vaso-occlusive pain episodes, and the level of donor beta globin production was approximately 50 percent.

Why the optimism? As a proof of principle, gene therapy for SCD is a therapeutic paradigm shift. Theoretically, donor availability is no longer an obstacle for children and adults with SCD. With the rapid pace of transplant biology research, conditioning regimens are expected to evolve from myeloablative to nonmyeloablative approaches. Until such advances, gene therapy will most likely be restricted to children rather than adults with SCD who may not tolerate the current high dose of busulfan.

Why the caution? Children with SCD living in high-income countries no longer have a

life-threatening disease, but rather a chronic disease with disease-associated, life-threatening events. Two large observational studies in children with SCD indicated 15-year–3 and 16-year4 Kaplan-Meier survival estimates of approximately 99 percent with and without hydroxyurea therapy, respectively. A third cohort study of children with SCD from a region in Paris, France, indicated that after introduction of the online guidelines, there was also an increase in the overall five-year survival from 98.3 percent to 99.2 percent.5 In terms of morbidity, the rate of stroke in a population of children with SCD can drop a log-fold at SCD centers screening with transcranial Doppler and subsequently treating those with abnormal values with regular blood transfusions for at least a year, then switching to therapy with hydroxyurea indefinitely. For children with SCD living in low- and middle-income countries, where approximately 90 percent of all children with SCD are born, gene therapy is not an option. In summary, gene therapy to treat children with SCD is currently restricted to those who: 1) have severe disease; 2) have failed blood transfusion or hydroxyurea therapy; 3) require treatment for comorbidities; 5) live in a high-income country; and 6) are not likely to die from the disease in childhood. Given the known short-and long-term toxicities of myeloablative doses of busulfan, the calculated trade-off of gene therapy is that the benefits will outweigh the unknown late potential adverse effects of busulfan in this population.

The bottom line is that gene therapy provides a new option for curing SCD, a disease that 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 challenges with gene therapy for SCD will be overcome with the rapid advancement of transplant immunobiology.

1. Mentzer WC, Heller S, Pearle PR, et al. Availability of related donors for bone marrow transplantation in sickle cell anemia. Am J Pediatr Hematol Oncol. 1994;16:27-29.

2. Bolaños-Meade J, Fuchs EJ, Luznik L, et al. HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood. 2012;120:4285-4291.

3. Lê PQ, Gulbis B, Dedeken L, et al. Survival among children and adults with sickle cell disease in Belgium: benefit from hydroxyurea treatment. Pediatr Blood Cancer. 2015;62:1956-1961.

4. Telfer P, Coen P, Chakravorty S, et al. Clinical outcomes in children with sickle cell disease living in England: a neonatal cohort in East London. Haematologica. 2007;92:905-912.

5. Couque N, Girard D, Ducrocq R, et al. Improvement of medical care in a cohort of newborns with sickle-cell disease in North Paris: impact of national guidelines. Br J Haematol. 2016;173:927-937.

Diagram of simple diffusion-consumption kinetics. Cytokines are secreted by a producing cell and freely diffuse between cells. Upon binding to a receptor, the cytokine is endocytosed, or consumed. This creates a gradient of localized cytokine niche with a typical length scale of lniche. Increasing consumers will lead to a decrease in the lniche, and vice versa. When lniche is small relative to the total organ size, increases in cell-to-cell variability are likely. (Reprinted from Immunity, Vol 46, Oyler-Yaniv A et al, A Tunable Diffusion-Consumption Mechanism of Cytokine Propagation Enables Plasticity in Cell-to-Cell Communication in the Immune System, pp 609-620, Copyright 2017, with permission from Elsevier.)

JONATHAN HOGGATT, PhD

Dr. Hoggatt indicated no relevant conflicts of interest.

The Hematologist: ASH NEWS AND REPORTS 11

Figure

Bone marrow harvest

Modified HSPCs

HSPCs

Gene Therapy(e.g., globin gene insertion,

gene editing, etc.)

Patient

HSPC Transplant

Typical process of gene therapy for hematopoietic disorders. Hematopoietic stem and progenitor cells (HSPCs) can be modified directly, as is the case for currently used therapies. The genetically modified HSPCs are then transplanted back into the patient. When HSPCs are modified directly, modification may not occur in every cell. Goodman MA et al, Ther Adv Hematol. 15(5):302-315, copyright © 2016 by SAGE Publications. Reprinted by Permission of SAGE Publications, Ltd.

Figure

12 The Hematologist: ASH NEWS AND REPORTS

PAUL MOSS, PhD

Dr. Moss indicated no relevant conflicts of interest.

“And Then There Were 10”: Dendritic Cells and Monocytes Undergo a ReclassificationVillani AC, Satija R, Reynolds G, et al. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science. 2017. doi:10.1126/science.aah4573. [Epub ahead of print.]

Taxonomy is a science that struggles to be fashionable. The great evolutionary biologist Steven Jay Gould commented that “Taxonomy is often regarded as the dullest of subjects, fit only for mindless ordering and sometimes denigrated as mere ‘stamp collecting.’” Yet, medicine needs order, and who could deny that the classic chart of “blood cell differentiation,” beloved of scuffed laboratory walls, is imprinted onto the

hippocampal map of all hematologists?

Classification systems reflect current technology, and it is no surprise to witness the inexorable dominance of molecular biology. In this remarkable article, Dr. Alexandra-Chloé Villani and colleagues at the Broad Institute deliver a radical revision of the classification of dendritic cells and monocytes.

The breathtaking capabilities of contemporary molecular biology lie at the heart of the analysis. In particular, the work focuses on the use of RNA-Seq, a procedure in which all of the mRNA sequences inside a cell are sequenced such that a complete map of the transcriptional activity can be generated. This technology is the mRNA equivalent of “next generation DNA sequencing” and is rapidly replacing microarray analysis. Perhaps even more remarkable is that this work was done on single cells. This combination of detailed transcriptional assessment and single-cell analysis offers remarkable possibilities for future biological insights. Of the 30,000 genes available within our DNA, around 5,000 are expressed at any time in a single cell, and RNA-Seq normally sequences around 1 million reads such that the technology can discover not only which genes are being expressed but also how many mRNA transcripts are present in the cell.

Dendritic cells (DCs) are relative youngsters within hematopoiesis, characterized by Dr. Ralph Steinman in 1973, and broadly classified into conventional DCs (cDCs), which express CD11c, and CD123+ plasmacytoid DCs (pDCs). cDCs are highly efficient at priming T cell immune responses whereas pDCs are potent producers of interferon-a in response to viral infection. Monocytes are a more familiar feature on our blood smears and have also undergone a binary subdivision through immunophenotyping into classical CD14++ and nonclassical CD14+CD16++ subsets.

In this data-rich but wonderfully accessible article, the authors undertook RNA-Seq on 2,400 single DCs (defined as HLA-DR+ lineage–) and monocytes (CD14+ lineage–) from a single individual. Sequence data were analyzed through a statistical approach called principal component analysis (PCA), which categorized dendritic cells into six major 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.

Several novel findings emerge from the reclassification of dendritic cells into six subtypes, termed DC1 to DC6. CD11c+ conventional DCs can be subdivided into those that are CD141+ or CD1C+, or indeed lack both of these molecules. In the new classification, the CD141+ subset becomes DC1 and is renamed CLEC9A+ DC on the basis that CLEC9A is a perfect discriminative marker. The CD1C+ subset is split into two groups, with differential MHC class II or monocytic gene expression (termed DC2 and DC3), while the DC4 group represents the CD1C and CD141 “double negative” group. DC5 is a completely new subset, representing 2 to 3 percent of DCs, and has been termed “AS DC” on the basis of expression of AXL and SIGLEC genes. Finally, DC6 represents the original pDC subset.

Also of note was the finding of a small population of cDC progenitor cells, representing one in 5,000 of the DC population, with a CD100+CD34intermediate phenotype. Morphology plays a role here and shows these cells to possess a high nuclear-to-cytoplasmic ratio with circular or indented nuclei.

The team went on to study monocytes, defined as CD14+lineage–, and delineated four subtypes — two major subsets defined by CD14+ and CD16 expression, and a further two, one with cytotoxic genes and the other with an unknown function.

Several practical lessons are readily apparent from this classification. Functionally, the DC1 through DC5 subsets are capable of stimulating strong T cell responses, whereas DC6 operates primarily for interferon production. The

description of a progenitor pool will allow potential expansion of DC cells in vitro with considerable opportunities for genetic manipulation. Additionally, it will prove possible to understand more closely how DC tumors arise during differentiation, and Dr. Villani and colleagues begin this process by showing that the rare condition of blastic plasmacytoid DC neoplasia is most closely related to the pDC (DC6) subset.

It should be remembered that this classification will itself ultimately be refined and replaced. It is based solely on transcriptional activity, without regard for features such as phenotype and function, and assesses cells in their resting state, without considering factors such as inflammation. Nevertheless, this report represents a considerable advance in our understanding of these important innate immune subsets. We can now expect this approach to be used for all subsets within the hematologic lineage. That hippocampal map of hematopoiesis is going to get a lot more complicated.

group, and broadening the potential to form intergroup trials with the expertise of both pediatric and adult hematologist/oncologists. In November 2013, the COG AYA committee and the SWOG AYA committee formed the NCTN AYA Working 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 have obtained in the past 10 years, hematology/oncology professionals must also structure targeted educational opportunities for physicians.

Greater than 25 percent of AYA patients are treated at community centers.22 The NCI community oncology research program (NCORP) was established to expand access of NCTN trials to patients treated in the community and patients afflicted by health disparities.21 Additionally, as the increase in AYA oncology programs continues,5 we must also lead the charge for recruiting and retaining AYA-focused hematology/oncology professionals. This can be in accomplished in various ways, such as dual training in internal medicine or pediatrics followed by a combined pediatrics and adult hematology/oncology fellowship, or additional AYA-focused fellowship training after initial certification in adult or pediatric hematology/oncology.

The AYA population is a unique, high-risk group of patients facing malignant diseases at an age where they are transitioning to independence. It is a time at which they can emotionally comprehend the burden of their disease, yet may not be as established socially, financially, and emotionally as their adult counterparts, and may not have the comparable support structure as younger patients. Although we should be proud of the progress that has taken place in the past decade, we cannot lose momentum — we need to build the strong and sustainable foundation for treatment that our AYA patients deserve.

Dr. Isenalumhe indicated no relevant conflicts of interest.

1. National Cancer Institute. A snapshot of adolescent and young adult cancers. [Cited 2015, Nov 28]; Access via: www.cancer.gov/research/progress/snapshots/adolescent-young-adult.

2. Albritton K, Caligiuri M, Anderson B, et al. Closing the gap: research and care imperatives for adolescents and young adults with cancer. Natl Cancer Inst. 2006;06-6067.

3. Bleyer WA. Cancer in older adolescents and young adults: epidemiology, diagnosis, treatment, survival, and importance of clinical trials. Med 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.

5. Ferrari A, Barr RD. International evolution in AYA oncology: current status and future expectations. Pediatr Blood Cancer. 2017;e26528. [Epub ahead of print].

6. Keegan THM, Ries LAG, Barr RD, et al. Comparison of cancer survival trends in the United States of adolescents and young adults with those in children and older adults. Cancer. 2016;122:1009-1016.

7. Barr RD, Ries LAG, Lewis DR, et al. Incidence and incidence trends of the most frequent cancers in adolescent and young adult Americans, including “nonmalignant/noninvasive” tumors. Cancer. 2016;122:1000-1008.

8. Tricoli JV, Blair DG, Anders CK, et al. Biologic and clinical characteristics of adolescent and young adult cancers: acute lymphoblastic leukemia, colorectal cancer, breast cancer, melanoma, and sarcoma. Cancer. 2016;122:1017-1028.

9. Tricoli JV, Seibel NL, Blair DG, et al. Unique characteristics of adolescent and young adult acute lymphoblastic leukemia, breast cancer, and colon cancer. J Natl Cancer Inst. 2011;103:628-635.

10. Mullighan CG, Willman CL. Advances in the biology of acute lymphoblastic leukemia-from genomics to the clinic. J Adolesc Young Adult Oncol. 2011;1:77-86.

11. Bleyer WA, Barr RD. Cancer in adolescents and young adults. Springer-Verlag Berlin Heidelberg. 2007. doi:10.1007/978-3-540-68152-6.

12. Heerema NA, Carroll AJ, Devidas M, et al. Intrachromosomal amplification of chromosome 21 is associated with inferior outcomes in children with acute lymphoblastic leukemia treated in contemporary standard-risk children’s oncology group studies: a report from the children’s oncology 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. 2007;10.1007/978-3-540-68152-6.

14. Grassley CE. Living Without Health Insurance: Hearing Before the Committee on Finance, US Senate. DIANE Publishing; 2001 [Cited 2015, Dec 1]. Access via: https://www.congress.gov/108/crpt/srpt31/CRPT-108srpt31.pdf.

15. Martin S, Ulrich C, Munsell M, et al. Delays in cancer diagnosis in underinsured young adults and older adolescents. Oncologist. 2007;12:816-824.

16. Smith JC, Medalia C. Health Insurance Coverage in the United States: 2013. US Department of Commerce, Economics and Statistics Administration, Bureau of the Census. 2014 [Cited 2015, Dec 17]. Access via: www.nber.org/cps/hi/2014redesign/p60-250.pdf.

17. Smith EC, Ziogas A, Anton-Culver H. Association between insurance and socioeconomic status and risk of advanced stage Hodgkin lymphoma in adolescents and young adults. Cancer. 2012;118:6179-6187.

18. Rosenberg AR, Kroon L, Chen L, et al. Insurance status and risk of cancer mortality among adolescents and young adults. Cancer. 2015;121:1279-1286.

19. Wolfson JA, Sun CL, Wyatt LP, et al. Impact of care at comprehensive cancer centers on outcome: Results from a population-based study. Cancer. 2015;121:3885-3893.

20. Wolfson J, Sun CL, Wyatt L, et al. Adolescents and young adults with acute lymphoblastic leukemia and acute myeloid leukemia: impact of care at specialized cancer centers on survival outcome. Cancer Epidemiol 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.

22. Yeager ND, Hoshaw-Woodard S, Ruymann FB, et al. Patterns of care among adolescents with malignancy in Ohio. J Pediatr Hematol Oncol. 2006;28:17-22.

AYA Treatment Disparities(Cont. from page 2)

Establishing a human blood monocyte and dendritic cell atlas. Researchers isolated approximately 2,400 cells enriched from the healthy human blood HLA-DR+ lineage− compartment and subjected them to single-cell RNA sequencing. This strategy, together with follow-up profiling and functional and phenotypic characterization, led them to update the original cell classification to include six dendritic cells (DCs), four monocyte subtypes, and one conventional DC progenitor. From Villani AC et al. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science. 2017. doi:10.1126/science.aah4573. Reprinted with permission from AAAS.

The Hematologist: ASH NEWS AND REPORTS 13

The Division of Kidney, Urologic, and Hematologic Diseases (KUH) of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) supports a consortium of Cooperative Centers of Excellence in Hematology (CCEH). Each

center is composed of three to four biomedical research core facilities providing state-of-the-art cellular and molecular biology tools or reagents and expertise. They each award pilot and feasibility projects as well as providing structured enrichment programs with visiting scholars and instructional presentations.

The NIDDK-supported consortium seeks to build and provide research infrastructure in the field of nonmalignant hematology. This activity helps to achieve the NIDDK director’s vision of maintaining a vigorous investigator-initiated research portfolio; preserving a stable pool of talented new investigators; fostering exceptional research training and mentoring opportunities; and ensuring knowledge dissemination through outreach and communications. The consortium accomplishes its mission primarily by sharing resources of the CCEH consortium and fertilizing collaborations across disciplines. More information is available via www.niddk.nih.gov/about-niddk/meet-the-director/mission-vision/Pages/mission-vision.aspx.

This year (fiscal year 2017) the consortium piloted a Partner Pilot and Feasibility (PPF) program to initiate collaborations by funding projects that use cores located at two different Centers. In the fall of 2017, the PPF program will begin to accept applications from investigators in U.S.-based institutions to partner with one of the center’s core facilities. These PPF projects need to include plans for collaboration and not simply describe use of the core facilities. Interested applicants are strongly encouraged

NIDDK Announcement: Resources and Funding Available for Research in Nonmalignant HematologyTERRY 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

CENTER DIRECTOR PHONE EMAIL WEBSITE

Boston Children’s Hospital

Stuart Orkin 617-919-2042 orkin@bloodgroup.tch.harvard.eduhttp://zfrhmaps.tch.harvard.edu/cemh/

Leonard Zon 617-919-2068 zon@enders.tch.harvard.edu

Fred Hutchinson Cancer Research Center

Beverly Torok-Storb 206-667-4549 btorokst@fredhutch.org http://sharedresources.fredhutch.org/core-facilities/cceh-administration Shelly Heimfeld 604-874-4004 sheimfel@fredhutch.org

Indiana UniversityHal Broxmeyer 317-274-7510 hbroxmey@iu.edu

www.ccehindy.org/ Edward F Srour 317-274-3589 esrour@iu.edu

University of UtahJohn Phillips 801-581-6650 john.phillips@hsc.utah.edu

http://cihd.cores.utah.edu/ James Cox 801-587-7779 jcox@genetics.utah.edu

Yale UniversityDiane Krause 203-737-1678 diane.krause@yale.edu

http://medicine.yale.edu/labmed/ycceh/ Patrick Gallagher 203-688-2896 patrick.gallagher@yale.edu

to contact the core director of the facility prior to submission of the application.

The consortium consists of 17 core facilities that provide:

• CD34 purified primary human hematopoietic stem/progenitor cells, granulocyte colony-stimulating factor mobilized and nonmobilized apheresis collections

• Xenotransplantation studies (including highly engineered humanized mice and large animal models)

• High-resolution microscopy (with cytoskeleton and hematopathology expertise)

• Time-lapse microscopy

• Human induced pluripotent stem cells generation

• Multiple genome editing procedures, predominantly, CRISPR/Cas-9

• Assistance with retroviral/lentiviral design and production

• Assistance with hematopoiesis assays (e.g., murine bone marrow collection, fluorescence-activated cell sorting, colony-forming units)

• CRISPR libraries

• Zebrafish and other model organisms for the study of human hematologic diseases

• Metabolomic profiles on large and small numbers of cells

• Heme and iron quantitative assays

• Angiogenic assays, especially during hematopoietic development in the fetal liver

• Flow cytometry assays.

The table below provides contact information for the currently funded NIDDK CCEHs.

For more information, access each center’s website. The charge for each service is available by contacting the center directly. Additionally, each center is seeking collaborations for new pilot and feasibility projects that will grow into successful NIDDK R01 awards.

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.

14 The Hematologist: ASH NEWS AND REPORTS

Are We Recruiting an Army for Magneto? Optimizing Iron Utilization in Hemodialysis

STUDY TITLE: Proactive IV Iron Therapy for Hemodialysis Patients (PIVOTAL)

CLINICALTRIALS.GOV IDENTIFIER: None (this is a European trial)

EU CLINICAL TRIALS REGISTER: 2013-002267-25. www.clinicaltrialsregister.eu/ctr-search/trial/2013-002267-25/GB.

SPONSOR: King’s College Hospital NHS Foundation Trust

STUDY DESIGN: Multicenter, prospective, open-label, randomized controlled trial

TARGET ENROLLMENT: 2,080

PARTICIPATING CENTERS: 50 clinics in the United Kingdom

ACCRUAL GOAL: 2,080

STUDY DESIGN: PIVOTAL is a multicenter, prospective, open-label, randomized controlled trial investigating the effects of two different doses of intravenous (IV) iron in patients with chronic kidney disease on hemodialysis. The primary study endpoint is to compare the effect of a proactive high-dose IV iron regimen with a reactive low-dose IV iron regimen on all-cause mortality and the incidence of nonfatal cardiovascular events (myocardial infarction, stroke, and hospitalization for heart failure) in patients on hemodialysis. Secondary endpoints include the comparison of the two regimens on erythropoiesis-stimulating agent (ESA) dose requirements, red blood cell transfusion requirements, complications of hemodialysis treatment, and patient quality of life. Safety concerns of IV iron will be analyzed by incidence of vascular access thrombosis, hospitalization for infection, and infectious episodes. Researchers will recruit and randomly assign 2,080 hemodialysis patients from 50 clinics to one of two treatment arms. Patients assigned to the proactive arm will receive 400 mg/month IV iron sucrose, unless their ferritin is greater than 700 µg/L and transferrin saturation (TSAT) is greater than 40 percent. Patients assigned to the reactive arm will receive low-dose IV iron sucrose only if the ferritin is less than 200 µg/L and TSAT is less than 20 percent. Eligible patients are at least 18 years old and newly established (<12 months duration) on hemodialysis for end-stage renal failure receiving an ESA for anemia, and with a ferritin level less than 400 µg/L and TSAT lower than 30 percent. Patients with limited life expectancy or awaiting a renal transplant within the next 12 months are excluded from the study.

RATIONALE: IV iron utilization has increased and ESA utilization has decreased in the United States’ hemodialysis patient population in recent years. A number of factors are associated with these trends. Several trials raised concerns about the safety of ESA dosing in those with renal failure .1-4 These studies led to labeling revisions; concurrently, the U.S. Centers for Medicare and Medicaid Services introduced a bundled payment methodology for dialysis services, including ESA and IV iron, which were previously separately billable (providing incentives to reduce utilization of high-cost items such as ESAs). IV iron treatment, even with high levels of serum ferritin, results in increased hemoglobin levels and reduced ESA dose requirements and cost of care.5 Prior observational studies confirming the safety of IV iron in this setting have produced conflicting results, and moreover, have largely studied outcomes in patients treated at a time when lower cumulative iron doses were used.6,7 Large randomized clinical trials of various doses of IV iron confirming the safety of this more aggressive IV iron repletion and improvement in patient-centered outcomes such as mortality, hospitalization, infectious risk, and quality of life, are lacking. Additionally, IV iron has been implicated in potentially causing oxidative stress and inflammation, as well as endothelial and immune dysfunction. The Dialysis Outcomes and Practice Patterns Study, a recent observational study using data obtained as part of the international prospective cohort study of hemodialysis patients 18 years or older, found all-cause mortality elevated among patients receiving IV iron doses higher

Clinical Trials Corner

than 300 mg/month with hemoglobin levels measured 10 g/dL or greater.8 In light of these uncertainties and associations, well-designed clinical trials are needed to evaluate the safety of different IV iron dosing strategies in hemodialysis patients.

COMMENT: IV iron utilization in hemodialysis patients has increased over time, and higher iron utilization is associated with higher iron stores. The mean serum ferritin of U.S. patients on hemodialysis increased from 300 to 600 ng/mL from 1993 to 2010 and to 799 ng/mL in 2014.9 One large study of hemodialysis patients receiving ESAs and intravenous iron dosed in keeping within current guidelines, demonstrated hepatic iron overload on MRI in the majority of patients.10 Despite this pattern of increased iron utilization, neither the risks nor the benefits of IV iron treatment in hemodialysis patients receiving ESAs are understood sufficiently. The PIVOTAL study will begin to address this fundamental gap in knowledge and should help inform practice not only in the United Kingdom, but also in the United States and elsewhere.

1. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998;339:584-590.

2. Pfeffer MA, Burdmann EA, Chen CY, et al. Baseline characteristics in the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT). Am J Kidney Dis. 2009;54:59-69.

3. Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085-2098.

4. Drüeke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071-2084.

5. Coyne DW, Kapoian T, Suki W, et al. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) study. J Am Soc Nephrol. 2007;18:975-984.

6. Avni T, Bieber A, Grossman A, et al. The safety of intravenous iron preparations: systematic review and meta-analysis. Mayo Clin Proc. 2015;90:12-23.

7. Miskulin DC, Tangri N, Bandeen-Roche K, et al. Intravenous iron exposure and mortality in patients on hemodialysis. Clin J Am Soc Nephrol. 2014;9:1930-1939.

8. Bailie GR, Larkina M, Goodkin DA, et al. Data from the Dialysis Outcomes and Practice Patterns Study validate an association between high intravenous iron doses and mortality. Kidney Int. 2015;87:162-168.

9. Fishbane S, Matthew AT, Wanchoo R. Intravenous iron exposure and outcomes in patients on hemodialysis. Clin J Am Soc Nephrol. 2014;9:1837-1839.

10. Rostoker G, Griuncelli M, Loridon C, et al. Hemodialysis-associated hemosiderosis in the era of erythropoiesis-stimulating agents: a MRI study. Am J Med. 2012;125:991-999.e1.

– Siobán Keel, MD

Dr. Keel indicated no relevant conflicts of interest.

Can Chemoimmunotherapy Be Bettered As Front-Line Therapy for CLL in Fit Patients?

STUDY TITLE: A Phase III Multicenter, Randomized, Prospective, Open-Label Trial of Standard Chemoimmunotherapy (FCR/BR) Versus Rituximab Plus Venetoclax (RVe) Versus Obinutuzumab (GA101) Plus Venetoclax (GVe) Versus Obinutuzumab Plus IbrutinibPlus Venetoclax (GIVe) in Fit Patients With Previously Untreated Chronic LymphocyticLeukemia (CLL) Without del(17p) or TP53 Mutation (CLL13/GAIA)

CLINICALTRIALS.GOV IDENTIFIER: NCT02950051

SPONSOR: German CLL Study Group

COLLABORATING STUDY GROUPS: Nordic CLL Group, HOVON and SAKK

ACCRUAL GOAL: 920 eligible patients

PARTICIPATING CENTERS: 160 centers across Germany, Austria, Switzerland, The Netherlands, Belgium, Denmark, Sweden, Norway, and Finland

STUDY DESIGN: This is a multi-arm phase III, randomized, open-label clinical trial that compares chemoimmunotherapy with three combinations of non-DNA damaging drugs as first-line therapy for fit patients. Standard chemoimmunotherapy is fludarabine, cyclophosphamide, and rituximab (FCR) for patients 65 years or younger, and bendumustine-rituximab (BR) for patients older than 65 years. Two of the experimental arms contain a combination of the BCL2 inhibitor, venetoclax, with an anti-CD20 antibody (either rituximab or obinutuzumab); the third also includes the BTK inhibitor ibrutinib with venetoclax and obinutuzumab. The co-primary endpoints are peripheral blood (PB) minimal residual disease (MRD) negativity at 15 months and progression-free survival (PFS); each will be tested independently, enabling superiority to be established for an experimental arm if either endpoint is significantly different in a favorable direction. The primary comparison for MRD negativity is between the chemoimmunotherapy and the obinutuzumab-venetoclax (GVe) arms. The primary comparison for PFS is between the chemoimmunotherapy and obinutuzumab-ibrutinib-venetoclax (GIVe) arms. The secondary outcomes are multiple and include complete response rates, duration of response, overall survival, safety, and quality-of-life. Efficacy outcomes may be compared among other arms in a predefined hierarchical sequence.

RATIONALE: The chemoimmunotherapy combination FCR was first reported as initial therapy in 20051 and was confirmed as the gold-standard front-line therapy for fit patients in 2010.2 The alternative BR regimen is less effective but is better tolerated and is a standard for older fit patients.3 Both produce significant acute toxicity and carry risks of late complications such as myelodysplastic syndromes or acute myeloid leukemia, and yet, for most patients, the treatment is not curative. Therefore, more effective therapies with less toxicity are needed. New targeted agents avoid some of the toxicities associated with DNA damage, show efficacy as single agents, and preliminary efficacy and tolerability in combination.

Prolonged survival without toxicity is the goal of therapy, but the prognosis of patients with CLL lacking either del(17p) or TP53 mutation is sufficiently favorable to require surrogate measures as primary endpoints in trials. PFS is an established surrogate for overall survival (OS) in this disease setting, and PB MRD–negativity is an independent predictor of PFS and OS with chemoimmunotherapy.4 Venetoclax in combination with an anti-CD20 antibody induces MRD negativity in the majority of patients with CLL in either the relapsed/refractory5 or front-line6 setting. The study therefore tests whether GVe induces a greater rate of PB MRD-negativity than standard therapy, as an early indicator of comparative efficacy. Ibrutinib induces a high rate of durable responses when 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 of relapse. Consequently, PFS is the primary endpoint for comparison between GIVe and chemoimmunotherapy.

COMMENT: Patients with CLL and their doctors are wanting more from first-line therapy. Treatment decisions are becoming increasingly complex and require consideration of disease genetics, age, fitness, comorbidities, and goals of treatment. Add to this the handful of new agents and combinations, and patients and their doctors could well be facing decision matrices akin to a Rubik’s cube as they strive toward personalized medicine. Patients who are fit for chemoimmunotherapy usually are looking to achieve long-term leukemia-free survival (or at least PFS) without the early and late toxicities induced by FCR.

The CLL13/GAIA study led by Dr. Barbara Eichhorst focuses on this large group of patients. While the long-term efficacy of chemoimmunotherapy is well understood, rituximab plus venetoclax (RVe), GVe and GIVe are new regimens, with only RVe having follow-up beyond two years.5 Consequently, the optimal duration of venetoclax in RVe and GVe, or ibrutinib and venetoclax in GIVe, is not known, but investigators are working on the premise that first line therapy for fit patients should be time-limited rather than indefinite until progression. So, the non-DNA damaging combinations chosen are based on preliminary data, including from those tested in ongoing German CLL Study Group trials.

The Hematologist: ASH NEWS AND REPORTS 15

A P R I L 6 , 2 0 1 7

Landier W, Chen Y, Hageman L, et al. Comparison of self-report and electronic monitoring of 6MP intake in childhood ALL: a Children’s Oncology Group study. Blood. 2017;129:1919-1926.

Compliance with 6-mercaptopurine (6MP) during acute lymphoblastic leukemia maintenance therapy is critical for sustained remission. Dr. Wendy Landier and colleagues show that self-reporting markedly overestimates compliance, highlighting a need for better monitoring methods to improve compliance and outcomes.

Riesner K, Shi Y, Jacobi A, et al. Initiation of acute graft-versus-host disease by angiogenesis. Blood. 2017;129:2021-2032.

Dr. Katarina Riesner and colleagues investigate the role of angiogenesis in graft-versus-host disease (GVHD) and show that, rather than occurring as a response to infiltrating leukocytes, angiogenesis occurs very early after transplantation and is involved in the initiation of GVHD.

Hiwarkar P, Amrolia P, Sivaprakasam P, et al. Brincidofovir is highly efficacious in controlling adenoviremia in pediatric recipients of hematopoietic cell transplant. Blood. 2017;129:2033-2037.

Dr. Prashant Hiwarkar and colleagues present encouraging data suggesting that brincidofovir provides excellent activity and safety in controlling adenoviremia during the early lymphopenic phase after hematopoietic stem cell transplantation.

A P R I L 1 3 , 2 0 1 7

Muchtar E, Gertz MA, Kumar SK, et al. Improved outcomes for newly diagnosed AL amyloidosis between 2000 and 2014: cracking the glass ceiling of early death. Blood. 2017;129:2111-2119.andPalladini G, Milani P, Foli A, et al. A phase 2 trial of pomalidomide and dexamethasone rescue treatment in patients with AL amyloidosis. Blood. 2017;129:2120-2123.

The papers by Dr. Eli Muchtar and colleagues, and Dr. Giovanni Palladini and colleagues each reflect the significant progress and challenges associated with treatment of systemic light chain (AL) amyloidosis, based on evolving myeloma-derived cytotoxic therapy.

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Noy A, de Vos S, Thieblemont C, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood. 2017;129:2224-2232.

Dr. Ariela Noy and colleagues present results of a phase 2 trial of ibrutinib for patients with relapsed/refractory marginal zone lymphoma, demonstrating durable responses in approximately half of the patients.

Simão F, Ustunkaya T, Chermont AC, et al. Plasma kallikrein mediates brain hemorrhage and edema caused by tissue plasminogen activator therapy in mice after stroke. Blood. 2017;129:2280-2290.

Dr. Bob Löwenberg (Editor-in-Chief) and Dr. Nancy Berliner (Deputy Editor-in-Chief) have combined efforts to identify some of the most outstanding Blood articles that have appeared either in print or online during the two-month interval between issues of The Hematologist. The goal is to underscore the remarkable research that is published in Blood and to highlight the exciting progress that is being made in the field.

Editors’ ChoiceThe 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 hemorrhagic complications are mediated by tPA-induced upregulation of plasma kallikrein, inhibition of which increases the effectiveness of tPA and reduces hemorrhagic complications.

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Yoshizato T, Nannya Y, Atsuta Y, et al. Genetic abnormalities in myelodysplasia and secondary acute myeloid leukemia: impact on outcome of stem cell transplantation. Blood. 2017;129:2347-2358.

In this plenary paper, Dr. Tetsuichi Yoshizato and colleagues offer a detailed genomic analysis of a substantial cohort of 797 patients with myelodysplastic syndrome and secondary acute myeloid leukemia who received unrelated stem cell transplants, and identify unique predictors of outcome.

Cox TM, Drelichman G, Cravo R, et al. Eliglustat maintains long-term clinical stability in patients with Gaucher disease type 1 stabilized on enzyme therapy. Blood. 2017;129:2375-2383.

Dr. Timothy M. Cox and colleagues report on a cohort of more than 150 adults with type 1 (non-neuronopathic) Gaucher disease who remained clinically stable after switching from recombinant glucocerebrosidase replacement therapy to eliglustat tartrate, an oral inhibitor of glucocerebroside synthase (a substrate reduction therapy).

M AY 4 , 2 0 1 7

Walton BL, Lehmann M, Skorczewski T, et al. Elevated hematocrit enhances platelet accumulation following vascular injury. Blood. 2017;129:2537-2546.

Dr. Bethany L. Walton and colleagues infused red cells into normal mice to demonstrate that elevated hematocrit is an independent contributor to arterial thrombosis, as it increases the frequency and duration of platelet interactions with the growing thrombus.

M AY 1 1 , 2 0 1 7

Fischer K, Al-Sawaf O, Fink AM, et al. Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood. 2017;129:2702-2705.

Dr. Kirsten Fischer and colleagues present efficacy and safety data from a preliminary study of first-line venetoclax and obinutuzumab in older chronic lymphocytic leukemia patients with comorbidities.

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Hovorkova L, Zaliova M, Venn NC, et al. Monitoring of childhood ALL using BCR-ABL1 genomic breakpoints identifies a subgroup with CML-like biology. Blood. 2017;129:2771-2781.

Dr. Lenka Hovorkova and colleagues report that discordant results of DNA-based minimal residual disease monitoring of BCR-ABL1 and immunoglobulin/T-cell receptor gene rear-rangements suggest that an unexpectedly high percentage of childhood acute lymphoblastic leukemias may in fact be chronic myeloid leukemias in lymphoid blast crisis.

The trial’s complex design combines pragmatism with sophistication, reflecting the tension between the large sample sizes needed to compare multiple regimens for multiple endpoints and the imperative to accrue 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 age or younger. The National Cancer Institute-sponsored U.S. intergroup study (NCT02048813) led by Dr. Tait Shanafelt and highlighted in the May/June 2015 issue of The Hematologist, completed accrual in June 2016, and the first interim analysis for its primary endpoint of PFS will be next year, two years after the last accrual.

Once we have the results of the primary analyses for both these trials, physicians and patients will know whether chemoimmunotherapy can be bettered as front-line therapy for CLL without TP53 dysfunction in fit patients. Of course, even if the trials are positive, important questions are likely to remain incompletely answered. For example, which non-DNA damaging regimen is best? What are the optimal durations of use for individual targeted therapy elements (time-limited, until MRD negativity is achieved, or indefinite)? Do the trial outcomes equally apply to specific genetic subgroups, which can be cured with FCR, such as IGHV-mutated CLL? In any case, the CLL13/GAIA trial is likely to shape the future of front-line therapy for fit patients with CLL for many years to come, and accrual should be strongly supported.

1. Keating MJ, O’Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regiment of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23:4079-4088.

2. Hallek M, Fischer K, Fingerle-Rowson G, et al. Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet. 2010;376:1164-1174.

3. Eichhorst B, Fink AM, Bahlo J, et al. First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol. 2016;17:928-942.

4. Böttcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. 2012;30:980-988.

5. Seymour JF, Ma S, Brander DM, et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. Lancet Oncol. 2017;18:230-240.

6. Fischer K, Al-Sawaf O, Fink AM, et al. Venetoclax and obinutuzumab in chronic lymphocytic leukemia. Blood. 2017;129:2702-2705.

7. Cervantes-Gomez F, Lamothe B, Woyach JA, et al. Pharmacological and Protein Profiling Suggests Venetoclax (ABT-199) as Optimal Partner with Ibrutinib in Chronic Lymphocytic Leukemia. Clin Cancer Res. 2015;21:3705-3715.

8. Deng J, Isik E, Fernandes SM, et al. Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia. Leukemia. 2017;doi:10.1038/leu.2017.32. [Epub ahead of print].

– Andrew Roberts, MBBS, PhD, FRACP, FRCPA

Dr. Roberts has received research funding from AbbVie and Genentech (venetoclax), and Janssen (sponsor for ibrutinib outside the United States). He is employed part-time by the Walter and Eliza Hall Institute, which receives milestone and royalty payments for venetoclax but receives no financial benefits personally. Blood Strengthens Its Position As the Top

Journal in Hematology

The newly released 2016 Journal Citation Reports (Clarivate Analytics, 2017) contains excellent news news for Blood:

• Impact Factor increased from 11.847 to 13.164!

• With 161,962 total citations generated in 2016, Blood is the most-cited journal in hematology, #19 out of the 12,085 journals

• 0.31360 Eigenfactor Score ranks Blood #1 in Hematology, #23 out of all journals

“The newly released publication metrics in terms of impact factor, number of citations, and Eigenfactor mark the significance of the Blood journal for hematology and beyond.” – Editor-in-Chief Bob Löwenberg, MD, PhD

M A R K Y O U R C A L E N D A R

July

6 TRTH Letter of Intent Due www.hematology.org/awards

15 2017-2018 ASH Mentor Award nomination packages due www.hematology.org/awards

15 2017-2018 Honorific Awards nominations due www.hematology.org/awards

17 ASH Global Capacity-Building Showcase poster submission deadline www.hematology.org/Annual-Meeting

19 2017 ASH Annual Meeting registration and housing 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) www.hematology.org/Annual-Meeting

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.

Not All Neutrophils Are Created EqualNABEEL R. YASEEN, MD, PhD

Professor, Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL

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 below.

Based on the neutrophil morphology, this patient was likely treated with:

A. Bortezomib, lenalidomide, dexamethasone

B. Carfilzomib, lenalidomide, dexamethasone

C. Autologous stem cell transplantation

D. Allogeneic stem cell transplantation

For the solution to the quiz, visit The Hematologist online, www.hematology.org/Thehematologist/Images.

Dr. Yaseen indicated no relevant conflicts of interest.

Put your fellow readers to the test, and send us your Image Challenge submissions! Email case descriptions and image files to the Managing Editor at jllorens@hematology.org.

I M A G E C H A L L E N G E