JULY/AUGUST 2016 VOLUME 13 ISSUE 4ASH NEWS AND REPORTS®

ASK THE HEMATOPATHOLOGISTS – Drs. Lynch and Foucar walk through their diagnostic approach to monocytosis.

MINI REVIEW – Dr. David Garcia provides an update of ACCP Guidelines for the management of venous thromboembolism.

PRESIDENT’S COLUMN – ASH President Dr. Charles Abrams reports on the ASH Executive Committee Spring retreat.

PROGRAM GENEALOGIES – Dr. Rainer Storb chronicles the history of the “Fred Hutch” bone marrow transplantation program.

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ASH in Cuba: Unmasking Challenges and Opportunities in HematologyJASON GOTLIB, MD, MS, WITH CONTRIBUTIONS BY SUSAN SHURIN, MD

On December 17, 2014, President Barack Obama and President Raúl Castro announced a diplo-matic reboot between the United States and Cuba. This warming

of relations led to the re-opening of each coun-tries’ embassies in the summer of 2015, and a series of intergovernmental dialogues aimed at addressing broad matters of concern such as cooperation in law enforcement and coun-terterrorism, human and civil rights, legal and safe transnational migration, environmental protection, economic development (includ-ing accelerated telecommunications/internet penetration), and expansion of travel and mail service between the two countries. Recently, the first cruise ship in 50 years sailed to Cuba from an American port, and plans have been set for 110 direct round-trip commercial flights a day.

There is renewed hope that a more free exchange of human and economic capital will catalyze reforms across sectors of Cuban soci-ety. However, it remains unclear what the pace and degree of such change will be. Failure of the Cuban economy is multifaceted, includ-ing decades of isolation and sanctions by the U.S. (although relationships with many Latin American countries and some European nations have persisted), loss of subsidized trade and aid from the Soviet Union and former East bloc, and burdens imposed by the authoritarian regime. These factors have contributed to Cuba’s 11 million citizens living in cramped and crumbling dwellings with a resource-poor existence based on rationing of food, medical supplies, and other basic necessities.1 Although the colorful sea of 1950s Fords, Cadillacs, and Oldsmobiles that blanket Cuba’s streets may tug at one’s nos-talgic heartstrings, these temperamental cars, resuscitated by makeshift parts, affirm that the country is largely stuck in the past. Nonetheless, there is a sense of palpable excitement regard-ing Cuba’s future prospects. As ASH President Dr. Charles Abrams notes in his column (see page 2) it is during this dynamic period of rap-prochement with the U.S. that ASH felt a unique

(Cont. on page 5)

D I F F U S I O N

Heparin-Induced Thrombocytopenia: A Preventable Nosocomial DiseaseMcGowan KE, Makari J, Diamantouros A, et al. Reducing the hospital burden of heparin-induced thrombocytopenia: impact of an avoid-heparin program. Blood. 2016;127:1954-1959.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic adverse reaction to heparin that may result in limb- or life-threatening thromboembolism. Traditionally viewed as an inevitable and inexorable complication of treatment with heparin, the primary focus of investigation and management in HIT has been on diagnosis and treatment, and little attention has been given to its prevention. Recently, investigators at Sunnybrook Health Sciences Centre in

Toronto sought to change that.

Capitalizing on the observation that low molecular weight heparin (LMWH) is associated with a five- to 10-fold lower risk of HIT than unfractionated heparin (UFH),1 they implemented the “Avoid-Heparin Initiative” at their institution in 2006 with the lofty goal of preventing HIT. The protocol included four elements: 1) replacement of most prophylactic and therapeutic intensity UFH with LMWH (UFH was retained for hemodialysis and intraoperative anticoagulation during cardiac surgery), 2) replacement of heparinized saline flushes with saline flushes, 3) modification of order sets to exclude UFH, and 4) removal of UFH from most nursing units. Outcomes were compared in the preintervention (2003-2005) and postimplementation (2007-2012) phases.

The avoid-heparin protocol was successful in replacing UFH with LMWH. Overall use of LMWH increased fourfold during the study period. The relative risk reductions (RRRs) in HIT-associated outcomes were dramatic. Compared with the pre-intervention phase, the avoid-heparin protocol was associated with a decreased incidence of suspected HIT (85.5 vs. 49.0 cases per 10,000 admissions; p<0.001; 41.7% RRR), adjudicated HIT (10.7 vs. 2.2 cases per 10,000 admissions; p<0.001; 79.0% RRR), and HIT complicated by thrombosis (4.6 vs. 0.4 cases per 10,000 admissions; p<0.001; 90.7% RRR). The average annual estimated cost (in 2007 Canadian dollars) of HIT-associated care fell 82.8 percent from $322,321 to $55,383 after implementation of the avoid-heparin initiative. Benefits were observed across patient populations. The incidence of HIT was reduced 77 percent in cardiovascular surgery patients, 77 percent in other surgery patients, 75 percent in cardiology patients, and 62 percent in medical patients.

In this elegant quality-improvement study, institutionwide replacement of UFH with LMWH effected dramatic reductions in the incidence of HIT and HIT-associated thrombosis. Several limitations of the study deserve mention. It was carried out in a single center. Only a minority of patients underwent testing with the serotonin release assay (considered the gold standard for diagnosis of HIT). The approximately eightfold greater price tag for LMWH compared with UFH was not accounted for in the cost analysis.2 Despite these limitations, the study provides valuable proof-of-principle that HIT is, indeed, a preventable disease.

Quality metrics and reimbursement are increasingly linked to the incidence of preventable nosocomial diseases. Interventions to forestall selected nosocomial illnesses such as deep vein thrombosis, ventilator-associated pneumonia, central venous catheter–associated bloodstream infections, and pressure ulcers are listed in the Table.3-6 The RRR of the avoid-heparin protocol compares favorably with these widely used interventions, spurring the question as to whether institutions should be doing more to prevent HIT.

The analogy between HIT and the other nosocomial diseases in the Table is imperfect. HIT is probably less common. Therefore any intervention to prevent HIT, no matter how effective, may result in lower reductions in absolute risk and a greater number needed to treat. Moreover, a wholesale switch from UFH to LMWH may be more costly than targeted, less-expensive interventions (e.g., aspiration of subglottic secretions in mechanically ventilated patients). Nevertheless, the message from the study by Dr. Kelly McGowan and colleagues is clear: Institutional adoption of an avoid-heparin protocol is feasible and reduces the incidence of HIT. It may be time for clinicians, administrators, policymakers, and payers to re-envisage HIT, not as an unavoidable iatrogenic disorder, but as a preventable nosocomial disease.

1. Martel N, Lee J, Wells PS, et al. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood. 2005;106:2710-2715.

2. Fowler RA, Mittmann N, Geerts W, et al. Cost-effectiveness of dalteparin vs unfractionated heparin for the prevention of venous thromboembolism in critically ill patients. JAMA. 2014;312:2135-2145.

3. Wein L, Wein S, Haas SJ, et al. Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients: a meta-analysis of randomized controlled trials. Arch Intern Med. 2007;167:1476-1486.

4. Muscedere J, Rewa O, McKechnie K, et al. Subglottic secretion drainage for the prevention of ventilator-associated pneumonia: a systematic review and meta-analysis. Crit Care Med. 2011;39:1985-1991.

5. Climo MW, Yokoe DS, Warren DK, et al. Effect of daily chlorhexidine bathing on hospital-acquired infection. N Engl J Med. 2013;368:533-542.

6. McInnes E, Jammali-Blasi A, Bell-Syer SE, et al. Support surfaces for pressure ulcer prevention. Cochrane Database Syst Rev. 2011;CD001735. 10.1002/14651858.CD001735.pub4.

ADAM CUKER, MD, MS

Dr. Cuker indicated no relevant conflicts of interest.

Table. Relative Risk Reductions Associated with Selected Interventions to Prevent Nosocomial Diseases

Nosocomial Disease Intervention Relative Risk Reduction

Deep vein thrombosis3 Prophylactic intensity LMWH 44%*

Ventilator-associated pneumonia4 Aspiration of subglottic secretions 45%

Central venous catheter-associated bloodstream infection5 Chlorhexidine bathing 55%

Pressure ulcers6 Alternative foam mattress 60%

Heparin-induced thrombocytopenia Avoid heparin protocol 79%

*In medical patients

SPECIAL EDITION: ASH VISITS CUBA

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

Theresa Coetzer, PhDUniversity of the WitwatersrandJohannesburg, South Africa

Adam Cuker, MD, MSUniversity of PennsylvaniaPhiladelphia, PA

Michael DeBaun, MDVanderbilt UniversityNashville, TN

David Garcia, MDUniversity of WashingtonSeattle, WA

Tracy I. George, MDUniversity of New MexicoAlbuquerque, NM

Jonathan Hoggatt, PhDMGH/Harvard UniversityCambridge, MA

Sioban Keel, MDUniversity of WashingtonSeattle, WA

Ann LaCasce, MD, MScDana-Farber Cancer InstituteBoston, MA

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

Elizabeth Raetz, MDUniversity of UtahSalt Lake City, UT

Noopur Raje, MDMassachusetts General HospitalBoston, MA

Managing Editor

Juana Llorens, MS

Editorial Associate

Laura M. Santini

Graphic Designer

grayHouse design

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

©2016 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

President’s Column

Open Borders Open Minds

The ASH Executive Committee Retreat, held each year in the spring, is a wonderful way for committee members and senior staff to work and bond together. It is always rejuvenating and never fails to generate new ways of bettering the mission of ASH. The retreat location is key to stimulating an environment of innovation, inspiration, free communication, and an open and collaborative mindset.

As ASH President, one of my roles is to select the location for this event, and this year, the location I chose was Havana, Cuba, which turned out to be the perfect choice. Cuba is a close neighbor of the U.S., yet vastly different in multiple respects. I think that the experience of immersion into a non-U.S. society (something we typically do not have the chance to experience at these retreats) is part of what spurred many of us to be even more introspective and flexible than usual. Furthermore, the sheer cultural richness of Havana and its people added to the mosaic of personalities, augmented the retreat environment, made a distinct contribution to the dialogues in which we participated, and highlighted the extraordinary diversity among the retreat participants. We have so much to learn from one another, and indeed we did.

It cannot be overstated how much this unique setting allowed us to think about our work as hematologists in new ways. We were limited in our use of the internet and cell phones — a shock at first, but ultimately a gift. “Shutting down” from technology for several days allowed for fertile ground to communicate one-on-one even more effectively and intimately.

If you have followed the news over the past year and a half, you know that this trip would not have been possible for ASH without the improvement and evolution of diplomatic relations between the U.S. and Cuba. Until the retreat, for even the most widely traveled among us, Cuba represented, quite literally, an unfeasible destination. Many of us knew that it would be a place frozen in time in many ways, best symbolized perhaps by the fabulous pre–Cold War automobiles. However, the educational exchange with my counterpart at the Cuban Society of Hematology (CSH), Dr. Antonio Bencomo, and with numerous CSH members, allowed us to look into the future of our field, learning about novel treatment approaches, and identifying much more common ground with our Cuban colleagues than some might have anticipated.

We learned a great deal about the Cuban health-care system, which makes free care and treatment available to all. We talked about the use in Cuba of partial splenectomies for pediatric patients with sickle cell splenic sequestration crisis, and about their treatment inductions and consolidation methods for the management of acute leukemia. The latter conversation, among others, revealed many differences between our approaches and underscored that perhaps “the American way” may be neither the best nor the only. In the case of bone marrow transplantation, the ASH and CSH contingencies were excited by the many similarities we share. Moments like these further spotlighted the critical nature of learning from each other across borders. They make us look forward to engaging in more than just one-way talks and lectures, toward opening up more meaningful discussions and interchanges of ideas.

The very roots of the word retreat mean to pull away or to take a step back. And in fact, we were able to use this occasion to step back and reposition ourselves to get a better view of the big picture of hematologic care and what it means to ASH’s members and those whom we serve. ASH exists to help patients with blood diseases worldwide. This is why we help to educate hematologists on best practices, fund researchers, and advocate for better health-care policy. It is why we strive to help hematologists to better understand everything from clinical trials to the molecular basis of various diseases. Our experience in Cuba solidified that there is an incredible value to “bridging conversations,” in which we examine different approaches all across the globe. The reality is that we can do a lot to effect change by reanalyzing the practices we accept as standard. It also became clear that we must do more to examine and understand the availability of drugs in different places around the world, and how that impacts care for all people. This is what it means to be “a global society,” and ASH is at the forefront of helping to make a difference internationally.

ASH programs such as the International Consortium on Acute Leukemia, (www.hematology.org/Global/206.aspx) exemplify how building collaborative relationships from nation to nation can make tremendous progress toward standardized practices around the world. And in the same way that we as hematologists are in a constant state of growth and place a high premium on lifelong education, hematology as a whole still has plenty of room to mature and expand. Havana and the Cuban hematologists we met illuminated the importance of looking beyond our own backyards, maintaining open minds, and doing everything we can to share our unique experiences with each other.

To learn more about ASH’s global programs and to become involved, visit www.hematology.org/Global.

Charles S. Abrams, MD

LETTERS TO THE EDITOR

The Hematologist welcomes letters of up to 200 words. Please include a postal address, email address, and phone number. Publication will be based on editorial decisions regarding interest to readers and space availability. We may edit letters for reasons of space or clarity. The Hematologist reserves the right to publish your letter, unless it is labeled “not for publication.”

Letters should be sent to:

Juana Llorens, Managing Editor The Hematologist: ASH News and Reports2021 L Street, NW, Suite 900 Washington, DC 20036

jllorens@hematology.org

The Hematologist: ASH NEWS AND REPORTS 3

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

ASH-SAP, Sixth Edition Now Available

The sixth edition of the ASH Self-Assessment Program (ASH-SAP) is now available for ordering. This educational resource will help hematologists and others working in hematology-related fields to stay up to date with the latest advances in the rapidly evolving disciplines of adult and pediatric hematology including benign and malignant disorders.

The program includes multimedia featuring 3D animation and audio, a question and answer book, and six tests, which you can take to earn up to 70 CME/MOC Credits. For pricing, to order your book, and for any additional information, visit www.ash-sap.org.

ASH Award for Leadership in Promoting DiversityThe 2016-2017 Honorific Awards Nomination and Review Cycle is now open. Nominations for the ASH Award for Leadership in Promoting Diversity will be accepted through August 1, 2016. This NEW award is intended to honor an individual who has demonstrated extraordinary commitment to diversity and inclusion in hematology. The scientific accomplishments of this individual are relevant in as much as they are related to diversity and inclusion. Nominees should have a recognized record of accomplishment that has a specifically identifiable focus on promoting inclusion and diversity in hematology. These contributions should be recognized broadly as contributing to hematology research, education, mentorship, clinical practice, administration, advocacy, or a combination of these categories. Nominees should be actively involved in the advancement of diversity and the inclusion of under-represented groups, such as women and racial/ethnic minority populations. The recipient need not be a member of such an under-represented group.

Visit www.hematology.org/Awards/Honorific/ to learn more about this new opportunity to recognize your peers.

Abstract Submission for the 2016 ASH Annual Meeting Now OpenConsider presenting your research at the 58th ASH Annual Meeting, the world’s premier hematology event. Abstract submission across 62 scientific and clinical categories, spanning the entire field of hematology, is now open. The submission deadline is August 4, 2016, at 11:59 p.m. Pacific Time. Visit www.hematology.org/Annual-Meeting/Abstracts/ for more information on attending and presenting at this year’s meeting in San Diego. Please also note that early-bird registration and housing (ASH members only) opens on July 20, 2016, at 11:00 a.m. Eastern Time.

Register for the ASH Meeting on Hematologic MalignanciesThe 2016 ASH Meeting on Hematologic Malignancies (MHM) will take place September 16-17 in Chicago. Top experts in hematologic malignancies will discuss the latest developments in clinical care through “How I Treat” sessions; presentations will showcase the speakers’ evidence-based treatment approaches, including standard of care, specialized disease complications, and novel agents. Peer-reviewed clinical research will also be presented. Learn more at www.hematology.org/Malignancies.

Free CME Summit on Myelodysplastic SyndromeThere are many complexities associated with Myelodysplastic Syndrome (MDS) that a multispecialty team must address as a clinical-care unit. To address educational gaps associated with these complexities, the American Society for Clinical Pathology (ASCP), the American Society of Hematology (ASH), and the France Foundation have designed comprehensive MDS-directed educational summits that feature live events designed by world-class subject matter experts. For more information on these complimentary events and to register, visit www.hematology.org/MDS. UPCOMING DATES AND LOCATIONS:

July 29, 2016 – Washington, DC, ASH Headquarters

November 4, 2016 – Austin, TX, Hyatt Regency Austin

September 15, 2016 – Chicago, IL, Chicago Fairmont (in conjunction with the ASH Meeting on Hematologic Malignancies)

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 Hematopathologists DAVID T. LYNCH, MD,1 AND KATHY FOUCAR, MD2

1. Hematopathology Fellow, University of New Mexico School of Medicine, Albuquerque, NM

2. Distinguished Professor of Pathology, University of New Mexico Health Sciences Center, Albuquerque, NM

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 QuestionWhat is your diagnostic approach to monocytosis?

CaseA 73-year old woman has had monocytosis for at least seven years. She has a history significant for rheumatoid arthritis and anemia of chronic disease. In 2010, her white blood cell count was 9.8 × 109/L with 59 percent neutrophils, 19 percent lymphocytes, and 21 percent monocytes (absolute monocyte count 2.1 × 109/L). Her red blood cell count was 3.2 × 1012/L, hemoglobin was 10.0 g/dL, mean corpuscular volume was 91.5 fL, and platelets were 162 × 109/L. The peripheral smear did not show immature monocytes. A bone marrow biopsy performed at that time was normocellular for age (40%). Significant findings were limited to increased mature mono-cytes (12% by manual differential) and mild dyserythropoiesis (<10%). Flow cytometry showed no increase in blasts (0.3% CD34 positive events), polytypic B-cells, and phenotypically normal T-cells. A concurrent unstimulated karyotype was nor-mal. Six months later, the absolute monocyte count remained elevated at 1.3 × 109/L, and a repeat bone marrow biopsy with flow cytometry and cytogenetics reported similar results.

Our ResponseExamining the Blood SmearPeripheral smear review is essential in cases of sustained monocytosis because morphology is critical to correct classification and diagnostic testing recommendations. Morphology is required to assess maturity in monocytes and to distinguish between monocytes and promonocytes. This difference is crucial since promonocytes are blast equivalents and should be included in the blast count. Additionally, assessment for dysplasia is required, as this provides evidence for hematologic malignancy. This is especially important in the assessment of neutrophils for dysplastic features, such as nuclear hyposegmentation and hypogranular cytoplasm. In the setting of bone mar-row stress, rheumatoid arthritis, and other autoimmune disorders, dyserythropoiesis in blood may be observed, so assessment of red blood cells is not as useful as neutrophil evaluation.1 If clinical correlation fails to explain a case of a sustained peripheral blood monocytosis, a bone marrow specimen (aspirate and biopsy) with cytogenetic karyotyp-ing is indicated.

Reactive MonocytesThe differential diagnosis for reactive monocytosis is broad. Infection is the most common cause of reactive monocytosis. Other common causes of monocytosis include inflammatory conditions such as collagen vascular disease, chronic neutropenia, splenectomy, hemolytic anemia, immune thrombocytopenic purpura, and both hematopoietic and nonhematopoietic neoplasms.

Flow cytometry is capable of unveiling subtle immunophe-notypic aberrancies, but it is not able to reliably distinguish promonocytes (blast equivalents) or monoblasts from mature monocytes. Because of this, flow cytometry is the least reliable modality to assess for a neoplastic monocytic disease. Reactive monocytes may have aberrant expression by flow cytometry, particularly CD56 and/or diminished human leukocyte antigen–DR, CD33, and CD13. The finding of two or more aberrancies favors a neoplastic process, though this is not specific.2 Recently, it was reported that a high fraction of CD14+/CD16– monocytes distinguishes chronic myelomonocytic leukemia (CMML) from reactive causes.3

Neoplastic MonocytesSeveral primary hematologic neoplasms harbor neoplastic monocytes including CMML, acute myeloid leukemia with monocytic differentiation, and myeloproliferative neoplasms such as chronic myelogenous leukemia (CML). While the peripheral smear of CML is usually characteristic,

the findings of CMML and acute leukemia with monocytic differentiation may be similar in peripheral blood. The bone marrow is often the site of increased immature monocytes. For this reason, bone marrow examination is essential when a neoplastic process with monocytic differentiation is suspected.

Morphology is critical to enumerating monoblasts and the blast-equivalent promonocytes, and to distinguishing them from mature monocytes, both reactive and dysplastic. As already mentioned, this distinction is not possible by flow cytometry. Cytochemical staining may be useful since it improves the sensitivity over morphology alone for the detection of monocytic cells.4

Based on World Health Organization (WHO) 2008 criteria, the diagnosis of CMML requires at least three months of monocytosis (>1.0 × 109/L) with dysplasia in at least one myeloid lineage. When dysplasia is absent, the presence of an acquired cytogenetic or molecular clone is required. Other disease-defining translocations, notably BCR-ABL1 fusion, must not be present. In the setting of CMML, one must also be on the lookout for systemic mastocytosis, which may be seen concurrently. CMML is the myeloid malignancy most frequently described in this setting. In the upcoming revision to the 4th edition of the WHO criteria, further subtypes of CMML with prognostic significance will be acknowledged. Based on a WBC count above or below 13 × 109/L, a proliferative and dysplastic subtype, respectively, can be assigned. Additionally, “CMML-0” will be introduced for cases in which the blast count is less than 2 percent in the peripheral blood and 5 percent in the bone marrow.5

Cytogenetic abnormalities are seen in a minority of cases of CMML (approximately 30%). The detection of a clonal cytogenetic abnormality, with few exceptions, confirms a neoplastic process. In contrast, a positive molecular result does not confirm a neoplastic process, since mutations are detected in normal subjects. Mutations in confirmed cases of CMML are found in nearly all cases.6 Many somatic mutations have been described in CMML, although none are specific to the disease. Some of the most common mutations are TET2, ASXL1, SRSF2, and SETBP1. In some studies, SRSF2 is the most common mutation, and it is most often seen in the setting of a normal karyotype.7 SETBP1 and ASXL1 are associated with reduced overall survival.6,8 RUNX1 has been associated with a worse prognosis.9 NPM1 mutations have been linked to a high risk of transformation to AML.10 Interestingly, recent literature has shown that approximately 10 percent of individuals older than 70 years harbor a mutation in peripheral blood, many of which are seen in CMML, including ASXL1 and TET2.11 This finding shows that, in contrast to cytogenetic abnormalities, the detection of an isolated molecular abnormality in a case of monocytosis does not necessarily confirm a neoplastic diagnosis.

The incidence of transformation from CMML to AML is variable, ranging from 15 to 52 percent.12 Sequential karyotyping has prognostic value, in that approximately 25 percent of CMML patients will acquire cytogenetic abnormalities not present at diagnosis. Not surprisingly, the development of a complex karyotype is associated with progression to AML. Those with the addition of del(20q) tend to have stable disease.13

Patient Follow-upIn this patient, the absolute monocyte count has fluctuated but has remained elevated since at least 2010, ranging from 0.9 × 109/L to 3.2 × 109/L. Platelet counts have remained mildly decreased (102 × 109/L - 137 × 109/L), and anemia has never been present. In 2015, the absolute monocyte count was 3.2 × 109/L which triggered a flow cytometry study on peripheral blood. This showed 62 percent monocytes with partial expression of CD56, but without additional immunophenotypic abnormality. A subsequent CBC several months later showed a stable monocyte count of 3.1 × 109/L.

4 The Hematologist: ASH NEWS AND REPORTS

Overall, the findings in this case are consistent with a reactive monocytosis. In rheumatoid arthritis, as in other autoimmune disease, monocytosis is seen in a significant minority of patients and is typically mild.14 The monocytosis has been stable, and sig-nificant dysplasia is not present in the peripheral blood or bone marrow. Repeat bone marrow biopsy with karyotype failed to reveal evidence of a neoplastic process. In this setting, pursuing molecular studies to detect a mutation is not clearly indicated and may even lead to an erroneous diagnosis. Given the rela-tively high prevalence of mutations in this population (e.g., clonal hematopoiesis of indeterminate potential), the finding of one of these mutations would not be diagnostic of a myeloid neoplasm, and could rather represent age-related clonal hema-topoiesis.11 However, the finding of a subsequent cytogenetic abnormality would be of great value in making a diagnosis, and this could be potentially performed on peripheral blood.

Monocytosis is both a common and challenging finding. Accurate diagnosis of the many entities which present as monocytosis requires the integration of clinical history, morphology, and the judicious use of ancillary studies.

1. Hunt KE, Salama ME, Sever CE, et al. Bone marrow examination for unexplained cytopenias reveals nonspecific findings in patients with collagen vascular disease. Arch Pathol Lab Med. 2013;137:948-954.

2. Xu Y, McKenna RW, Karandikar NJ, et al. Flow cytometric analysis of monocytes as a tool for distinguishing chronic myelomonocytic leukemia from reactive monocytosis. Am J Clin Pathol. 2005;124:799-806

3. Selimoglu-Buet D, Wagner-Ballon O, Saada V, et al. Characteristic repartition of monocyte subsets as a diagnostic signature of chronic myelomonocytic leukemia. Blood. 2015;125:3618-3625.

4. Dunphy CH, Orton SO, Mantell J. Relative contributions of enzyme cytochemistry and flow cytometric immunophenotyping to the evaluation of acute myeloid leukemias with a monocytic component and of flow cytometric immunophenotyping to the evaluation of absolute monocytoses. Am J Clin Pathol. 2004;122:865-874

5. Arber D, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016; 127(20):2391-2405.

6. Patnaik MM, Lasho TL, Vijayvargiya P, et al. Prognostic interaction between ASXL1 and TET2 mutations in chronic myelomonocytic leukemia. Blood Cancer J. 2016;6:e385.

7. Federmann B, Abele M, Rosero Cuesta DS, et al. The detection of SRSF2 mutations in routinely processed bone marrow biopsies is useful in the diagnosis of chronic myelomonocytic leukemia. Hum Pathol. 2014;45:2471-2479.

8. Laborde RR, Patnaik MM, Lasho TL, et al. SETBP1 mutations in 415 patients with primary myelofibrosis or chronic myelomonocytic leukemia: independent prognostic impact in CMML. Leukemia. 2013;27:2100-2102.

9. Cervera N, Itzykson R, Coppin E, et al. Gene mutations differently impact the prognosis of the myelodysplastic and myeloproliferative classes of chronic myelomonocytic leukemia. Am J Hematol. 2014;89:604-609.

10. Peng J, Zuo Z, Fu B, et al. Chronic myelomonocytic leukemia with nucleophosmin (NPM1) mutation. Eur J Haematol. 2016;96:65-71.

11. Jaiswal S, Fontanillas P, Flannick J, et al. Age-related clonal hematopoiesis associated with adverse outcomes. N Engl J Med. 2014;371:2488-2498.

12. Mughal TI, Cross NC, Padron E, et al. An International MDS/MPN Working Group’s perspective and recommendations on molecular pathogenesis, diagnosis and clinical characterization of myelodysplastic/myeloproliferative neoplasms. Haematologica. 2015;100:1117-1130.

13. Tang G, Fu B, Hu S, et al. Prognostic impact of acquisition of cytogenetic abnormalities during the course of chronic myelomonocytic leukemia. Am J Hematol. 2015;90:882-887.

14. Buchan GS, Palmer DG, Gibbins BL. The response of human peripheral blood mononuclear phagocytes to rheumatoid arthritis. J Leukoc Biol. 1985;37:221-230.

Drs. Lynch and Foucar indicated no relevant conflicts of interest.

a) Normal (mature) monocyte with many nuclear folds and condensed chromatin. b) Atypical monocyte with less condensed chromatin than normal monocyte but still with a low nuclear to cytoplasmic ratio. c) Promonocyte in a patient with AML showing a high nuclear to cytoplasmic ratio, slight nuclear indentation, and fine chromatin without an obvious nucleolus. d) Monoblast in a patient with AML with a high nuclear to cytoplasmic ratio, fine chromatin, and a visible nucleolus. e) Dysplastic neutrophil with hypogranularity and nuclear hyposegmentation in a patient with CMML. f) Dysplastic neutrophil resembling a monocyte with hypogranular cytoplasm and Döhle body in a patient with CMML.

The Hematologist: ASH NEWS AND REPORTS 5

opportunity existed to visit Cuba to advance its global mis-sion of hematology education, patient care, and research. I accompanied ASH’s Executive Committee and senior staff to the annual Executive Committee Spring Retreat, held this year in Havana.

One of the highlights of the retreat was an educational exchange with some 40 members of the Cuban Society of Hematology (CSH). The CSH consists of 294 members, including 154 hematologists who serve at 39 clinical facilities (25 adult and 14 pediatric hospitals) in all provinces of the island nation. The agenda was comprised of a translator-facilitated discussion of the American and Cuban approaches to the management of three hematologic diseases. Drs. Alexis Thompson and Sergio Machín García discussed sickle cell disease; lectures on acute myeloid leukemia and acute promyelocytic leukemia were delivered by Drs. Marty Tallman and Carlos Hernández-Padrón; and Drs. Alison Loren and Alejandro González Otero gave updates on acute lymphoblastic leukemia. I had the opportunity to learn more about the practice of hematology in Cuba from the President of the CSH, Dr. Antonio Bencomo. I was particularly interested in having him paint a picture of how the decades-long economic squeeze of the Cuban economy has impacted the availability of medicines commonly used in the U.S. as part of standard care approaches to malignant and nonmalignant hematologic disorders.

Dr. Bencomo reiterated that the Cuban health-care system guarantees all of its patients “necessary” medicines according to the precept of universal and free care. Expensive medications that constitute a second- or third-line therapy may be available through treatment protocols established through Cuba’s national system of health and medical specialties. In many cases, access to new drugs is difficult because of the limitations placed upon companies to restrict their sale to Cuba. The U.S. 1992 Cuban Democracy Act made it more difficult to purchase medications from U.S. companies or their foreign subsidaries.1 The 1996 Congressional Helms-Burton Act stipulated that any non-U.S. companies (including pharmaceutical and biotechnology firms) were subject to lawsuits in U.S. courts if they engaged in trade with Cuba.1,2 Because the overwhelming majority of drugs are either produced in the U.S. or by European companies that have merged with U.S. firms, this decimated Cuba’s access to medicines, vaccines, medical devices, and diagnostic equipment. Although the U.S. has provided humanitarian donation of medicines and medical supplies, and authorizations for some medicines have been granted, complicated banking, licensing, and shipping policies frustrate the import of such lifesaving materials.

Cuban resourcefulness and self-reliance have overcome some of the external limi-tations imposed on access to drugs. The Centro de Immunologia Molecular (CIM), which opened in 1994, is Cuba’s premiere research, production, and biotech campus. CIM’s biotechnology focus is on mammalian cells, as well as the production of mono-clonal antibodies and cancer vaccines. Their paradigm is to use treatments such as immunotherapy as a means of making cancer a chronic disease, with less of a focus on cure. It has 1,136 employees and houses laboratories and animal facili-ties. CIM is part of the CUBABIOPHARMA holding group that has 21 products in the pipeline (six registered) and 48 patents, and exports products to 31 countries. There are 78 manufacturing facilities, including several in other countries (such as Japan and Brazil). In all, it has 21,785 workers, of whom 262 have PhDs. The Roswell Park Cancer Institute and Moffitt Cancer Center have existing drug development part-nerships with CIM.

Dr. Bencomo pointed out that Cuban biotechnology also produces and commercializes erythropoietin (ior-EPOCIM®) by CIMAB SA, and filgrastim (Hebervital®) by Heber Biotec SA. Arsenic (Arsenin®) is also produced domestically; it has been added to ATRA, which was incorporated by Cuba into APL therapy in 1991 (one of the first countries to do so). For patients with venous thromboembolism, low-molecular weight heparin and coumadin are available, with the latter

also being produced by the Cuban pharmaceutical industry. The new oral anticoagulants are not widely available, but may be given to patients after failure of initial treatment. Dr. Bencomo provided some additional disease-specific examples of available therapies in Cuba:

• Chronic myeloid leukemia. All patients are treated with imatinib (Gleevec® or generic). Resistant patients are given nilotinib; standard or pegylated forms of interferon-α are available (Heberon Alfa R® ; PEG-Heberon) and produced by Cuban biotechnology (Heberbiotec SA).

• Chronic lymphocytic leukemia. Patients younger than 60 years receive fludarabine, cyclophosphamide, and rituximab; cyclophosphamide, vincristine, and prednisone is administered to patients older than 60 years. Ibrutinib and idelalisib are still not considered front-line therapy and could be made available after an unfavorable response to conventional therapy.

• Myelodysplastic syndromes. In addition to the aforementioned use of Cuban-manufactured erythropoietin and filgrastim, thalidomide is often the first choice for lower-risk MDS, including del(5q) MDS. Azacitidine is the first-line therapy for higher-risk MDS and a second-line option for subjects with lack of response or intolerance to thalidomide. After failure of these “conventional” agents, access to lenalidomide or decitabine is possible. For MDS and other diseases, there are 46 blood banks in the country that provide blood components from voluntary donors.

Flow cytometry, standard karyotyping, fluorescence in situ hybridization, and molecular analyses are all available for the diagnosis of hematologic malignancies. Patient samples are sent for central analysis at the Institute of Hematology and Immunology (IHI) in Havana. The IHI, a research institute created in the 1960s by the Ministry of Public Health, leads the national effort in scientific investigations of hematologic diseases (e.g., sickle cell anemia, hemophilia, leukemias) and immunologic disorders. In addition to establishing quality assurance standards for transfusion medicine, histocompatibility testing, and related fields of immunohematology, IHI's mission is to provide postgraduate training of physicians in hematology and training of health technologists to cover the nation’s needs in these subspecialty areas. The IHI interdigitates well

with Dr. Bencomo’s stated mission of the CSH — to ensure the scientific development of its members so that they can satisfy the needs of their patients. CSH, in conjunction with the IHI and their National Hematology Group (Grupo Nacional de Hematologia) project labor needs in the areas of hematology, immunology, transfusion medicine, and regenerative medicine. He cited that CSH’s area of greatest interest is the use of advanced technology to improve diagnosis and to achieve a greater percentage of cures for patients with hematologic malignancies, including the use of unrelated donor and haploidentical hematopoietic cell transplantation.

Dr. Bencomo touched on the feasibility of conducting clinical trials in Cuba. He indicated that the country has a guiding Center of Clinical Trials (CENCEC) which belongs to the Ministry of Public Health (MINSAP). It is responsible for the coordination and implementation of clinical trials for all medical specialties, including hematology, and ensuring compliance with international clinical trial standards. There is also a public registry of clinical trials that is accessed through the portal of Infomed (http://registroclinico.sld.cu/). Dr. Porfirio Hernández and colleagues from the IHI have led Cuba’s clinical trial efforts in regenerative medicine. Since 2004, they have studied the effects of intramuscular or intra-arterial administration of autologous bone marrow mononuclear cells (BM-MNC) or peripheral blood MNC mobilized from the BM with filgrastim.3 The indications for treatment have included critical lower limb ischemia due to arterial insufficiency with criteria for amputation; lymphedema; orthopedics and trauma (bone cysts, complex bone fractures, aseptic necrosis of the hip and degenerative joint injuries); periodontitis; and paraplegia due to spinal cord injury. Dr. Hernández cited that in 73 percent of patients with critical lower limb ischemia and criteria of major amputation, this intervention was avoided; in patients with intermittent claudication, improvement was obtained in 85 percent of cases.4 Their group has also evaluated the role of platelets in regenerative medicine. By the end of 2014, 5,533 units of platelet components, primarily for orthopedic and “angiology” indications had been used for such trials.4 Other regenerative uses of platelets have included burns; skin ulcers; and in the form of eye drops for treatment of injuries of the cornea and dry eye due to low production of tears. In the decade following treatment of the first patient in 2004, the number of units supplied either with stem cells, platelets, or both combined, reached 13,045, making Cuba among one of the nations with the most widespread application of regenerative medicine.4 Randomized, controlled trials are needed to definitively establish the efficacy and safety of these regenerative medicine efforts.

The highly advanced training of Cuban doctors is widely acknowledged. Cuba has one of the highest ratios of doctors to residents in the world, and the country places a high priority on medical care, like it does for education. However, it is also well known that doctors’ pay, like that of everyone

ASH in Cuba(Cont. from page 1)

(Cont. on page 15)

Pictured (L-R): Dr. Jason Gotlib, Dr. Porfirio Hernández, and Dr. Robert Negrin during the 2016 educational exchange in Havana.

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6 The Hematologist: ASH NEWS AND REPORTS

In early 2016, the latest version of the widely read evidence-based guidelines for the treatment of venous thromboembolism (VTE), sponsored by the American College of Chest Physicians (ACCP) was published in

the journal Chest.1 In this Mini Review, I will highlight some of the clinical recommendations that are most relevant to hematologists.

As in previous iterations of these guidelines, the authors grade each recommendation depending on two factors: the lopsidedness of the risk-benefit tradeoff and the strength of the supporting evidence. The strongest possible recommendation is graded “1A,” where the “1” indicates that the risk-benefit tradeoffs are such that most patients and physicians would, in light of the evidence, choose to follow the recommendation, and the “A” indicates that the quality of evidence on which the recommendation is based is high (e.g., more than one randomized controlled trial showing a similar treatment effect). At the opposite extreme, a “2C” recommendation would correspond to an intervention for which different patients or physicians see the risk-benefit tradeoffs differently and for which the quality of the evidence is low (e.g., data from an observational, noncontrolled study).

1. “For VTE and no cancer, as long-term anticoagulant therapy, we suggest dabigatran (Grade 2B), rivaroxaban (Grade 2B), apixaban (Grade 2B), or edoxaban (Grade 2B) over Vitamin K Antagonist (VKA) therapy.”

This decision to suggest (albeit not strongly) that a direct oral anticoagulant (DOAC) be used preferentially over warfarin is important because many hematologists had been reluctant to choose this class of medications to treat deep vein thrombosis (DVT) or pulmonary embolism (PE). The authors of this guideline, citing numerous large randomized controlled trials that compared DOACs to warfarin in both atrial fibrillation and VTE, explain that their preference for DOACs is based on the evidence that DOACs are as effective as warfarin but cause less bleeding (especially intracranial hemorrhage). They mention the increased convenience (no anticoagulation monitoring and essentially no dietary interactions) afforded by this class of medications. It is noteworthy that the authors made this recommendation despite the fact that, at the time the guideline was written, no reversal agent for any of the factor Xa inhibitors was approved for use. The authors reinforced the need to incorporate a patient’s preferences into the final decision about treatment, and they may have chosen a strength of “2B” (rather than “1B”) partly to recognize the financial burden that DOACs can present for many patients.

2. “For VTE and cancer, we suggest LMWH [low molecular-weight heparin] over VKA (Grade 2B), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C).”

Although prescribing a DOAC to a patient with cancer-associated VTE would not be an “off-label use” in the United States, this recommendation reflects the lack of studies comparing DOACs to long-term LMWH, the current standard of care in this setting. At least one randomized controlled trial of a DOAC (edoxaban) versus LMWH (dalteparin) is underway.2

Management of Venous Thromboembolism: An Update of the ACCP GuidelinesDAVID GARCIA, MD

Professor, Division of Hematology, University of Washington, Seattle, WA

3. “In patients with a first VTE that is an unprovoked proximal DVT of the leg or PE and who have a (i) low or moderate bleeding risk (see text), we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B), and a (ii) high bleeding risk (see text), we recommend 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 1B).”

This recommendation, unchanged from the prior version of these guidelines, highlights the importance of determining whether a clot was provoked or unprovoked when determining duration of anticoagulant therapy. Although the authors are recommending that many VTE patients receive “extended” therapy without a stop date, the absence of the phrase “lifetime anticoagulation” is conspicuous, and the authors emphasize the need to periodically re-assess the risks and benefits of

anticoagulation in all such patients. Some of the factors that have been independently associated with an increased risk of major bleeding on warfarin are listed in the Table. The authors suggest that for patients with unprovoked VTE who have none or one of these bleeding risk factors, the risk of ongoing anticoagulation will likely be outweighed by the benefit.

4. “For DVT, we suggest not using compression stockings routinely to prevent PTS [post-thrombotic syndrome].”

Prior iterations of these guidelines had suggested that compression stockings be used, based on observational studies that were subject to bias. The new recommendation against the use of these stockings reflects the negative result of a randomized trial in which compression stockings were compared to “sham” stockings.3

M I N I R E V I E W

5. “In most patients with acute PE not associated with hypotension, we recommend against systemically administered thrombolytic therapy (Grade 1B).”

This affirmation of a recommendation from the prior guidelines is based, for the most part, on the Pulmonary Embolism Thrombolysis trial, which randomly assigned 1,006 patients with PE and right ventricular dysfunction to tenecteplase and heparin, or to heparin therapy alone (with placebo)4. Although thrombolytic therapy reduced the risk of hemodynamic collapse, it also increased the risk of major (including intracranial) bleeding. The authors of the present guideline concluded that this new evidence was consistent with what had been demonstrated in prior studies: for most PE patients without hypotension, thrombolytic therapy does not confer a net benefit over anticoagulation alone. In associated comments, the authors acknowledged that the PE patients without hypotension

who have signs of significant cardiopulmonary impairment will be best managed in a setting where any deterioration can be detected rapidly. Indeed they suggest that a patient with low bleeding risk who deteriorates while on anticoagulant treatment should receive systemically administered thrombolytic therapy.

1. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149:315-352.

2. van Es N, Di Nisio M, Bleker SM, et al. Edoxaban for treatment of venous thromboembolism in patients with cancer: rationale and design of the Hokusai VTE-cancer study. Thromb Haemost. 2015;114:1268-1276.

3. Kahn SR, Shapiro S, Wells PS, et al. Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial. Lancet. 2014;383:880-888.

4. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014;370:1402-1411.

Dr. Garcia has acted as a consultant for and/or received research funding from Boehringer Ingelheim, Janssen, Daiichi Sankyo, Pfizer, and Bristol Meyers Squibb.

Table. Factors Associated with an Increased Risk of Bleeding on Warfarin*

Older age Antiplatelet therapy

Previous bleeding Poor anticoagulant control

Renal failure Comorbidity and reduced functional capacity

Liver failure Recent surgery

Thrombocytopenia Frequent falls

Previous stroke Alcohol abuse

Diabetes Nonsteroidal anti-inflammatory drug

Anemia

* Adapted from Kearon et al.1 It is unknown which of these factors will be associated with an increased risk of bleeding among patients treated with other anticoagulants (e.g., low molecular-weight heparin or direct oral anticoagulants).

As in previous iterations of these guidelines, the authors grade each recommendation depending on two factors: the lopsidedness of the risk-benefit tradeoff and the strength of the supporting evidence.

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 WashingtonASH Committee on Practice Hits the Hill for Sickle Cell Disease and Access to Affordable Treatments

Following its May 23, 2016, meeting in Washington, DC, the ASH Committee on Practice visited more than 40 congressional offices on May 24 to advocate for issues related to sickle cell disease (SCD) and drug access. ASH advocates encouraged congressional offices to urge the Center for Medicare & Medicaid Innovation (CMMI) to develop a demonstration program focused on improving care for individuals with SCD. The group also asked members of Congress to support legislation (the Patient’s Access to Treatments Act, H.R. 1600; www.congress.gov/bill/114th-congress/house-bill/1600), that establishes patient cost-sharing limits for high-cost drugs in health plans that cover prescription drugs.

Congressional meetings are an important component of ASH’s advocacy efforts and provide an opportunity for members of Congress and their staffs to gain insight on issues of concern to hematologists and their patients. However, the Society needs its members’ help in bringing these important issues to the attention of the U.S. Congress and other governmental agencies.

ASH strongly encourages members to let the ASH Government Relations and Practice department know when you are in Washington, DC, and are available to meet with your congressional delegation. ASH staff can assist by arranging appointments so that your voice is heard in the halls of Congress. You can also participate in the Society’s advocacy efforts by visiting the ASH Advocacy Center and joining the ASH Grassroots Network. Contact ASH Legislative Advocacy Manager Tracy Roades at troades@hematology.org, or visit www.hematology.org/Advocacy for additional information.

(L-R: Dr. Matthew Cheung, Dr. Brenda Grossman, Dr. Kathleen Neville, Senator Tom Cotton [R-AR], Foster Curry, Dr. Richard Lottenberg)

ASH Comments on Plan to Change Payment for Physician-Administered Drugs

In May, ASH submitted detailed comments on the proposed Medicare Part B Drug Payment Model, which would change the formula for physician-administered drugs in much of the United States, reducing payments for expensive drugs, including cancer treatments, and allowing for the use of innovative drug payment models in certain geographic locations. The Medicare Part B demonstration model is proposed to change the payment formula for physician-administered drugs in Medicare in a two-phase program. The first phase would reduce the payment for expensive drugs and increase the payment for inexpensive drugs. The second phase would allow the Centers for Medicare and Medicaid Services (CMS) to use certain value-based tools to pay for drugs in other ways.

ASH has expressed concern about the size and scope of proposed payment cuts, including the potential impact on access to care for patients and encouraged a transparent process in the implementation of the program. The Society’s complete comments may be found on the ASH website at www.hematology.org/Advocacy/Testimony.aspx.

An Early Look at MACRA for Hematology

In late April, CMS released their long-awaited proposed rule for implementing the Medicare Access and CHIP Reauthorization Act (MACRA). The law, passed in April 2015, eliminated annual planned Medicare payment cuts for physicians, replacing it with a system with small predictable updates that are adjusted based on performance. The law also provided a mechanism for physicians to participate in payment models outside of the traditional fee-for-service system. Given the length and complexity of the rule, it will require some time to review and analyze. A few takeaways from the proposed rule are highlighted here; however, given this is a proposed rule, details could change significantly before 2017, when measurement will begin for payment adjustment that begins in 2019.

• Most physicians will not participate in alternative payment models. The legislation envisioned a path by which some physicians were able to participate in payment models such as accountable care organizations instead of the current fee-for-service system embellished with pay-for-performance. However, CMS has proposed to rather rigidly define an alternative payment model and has estimated that more than 90 percent of physicians will not participate in the first year.

• Quality measurement remains paramount. While there are technical changes that are important, failure to report on quality measures will still have a deleterious effect on a pay-for-performance score under the new Merit-Based Incentive Payment System (MIPS). CMS proposes to reduce the number of measures required for reporting from nine to six in many circumstances. All of the mechanisms for reporting such as registries and electronic health records are proposed to still be available.

• Incentive for electronic health record use will be more flexible. Incentives for the so-called “meaningful use” of electronic health records date back to the stimulus bill passed in the first days of the Obama administration. Since that time, an elaborate series of rules has differentiated health information technology (HIT), requiring certification for the technology and demonstration of certain uses of that technology by the physician practice. Over time, vendors have been unable to keep up with rapidly evolving certification standards that some believe do not reflect the current state of technology. The incentive for HIT use was once a bonus but converted into a penalty in recent years, but remained a measure in which one could either pass or fail, and failure resulted in a Medicare payment cut. CMS now proposes to give partial credit for components of HIT use, which should reduce the number who are penalized.

• Physicians will have a new reporting burden, but it may be modest. While most of MIPS is composed of elements of existing programs, the legislation requires assessment of a new category called practice improvement activities. This portion of the MIPS program is an attempt to evaluate and give credit for structures that improve care. CMS proposes a long list of activities (participating in an alternative payment model, being a patient-centered medical home), divided into high and medium value, and proposes to require reaching a score which will likely require reporting on a few activities. Some of these activities may be reported by vendors, and others may be reported by the physician.

The Hematologist: ASH NEWS AND REPORTS 7

JONATHAN HOGGATT, PhD

Dr. Hoggatt indicated no relevant conflicts of interest.

8 The Hematologist: ASH NEWS AND REPORTS

Jedi T CellsAgudo J, Ruzo A, Park ES, et al. GFP-specific CD8 T cells enable targeted cell depletion and visualization of T-cell interactions. Nat Biotechnol. 2015;33:1287-1292.

Hematology research has become increasingly focused on the study of cellular heterogeneity and parsing out the biologic roles of specific cells. For example, such investigations may explore novel T cell subsets mediating immune responses, distinguish pre-leukemic cells from healthy ones, discover the various

roles of uni- or multipotent progenitors to the overall contribution of blood production, and identify the specific stromal cells that govern normal or malignant niches. Early on, the microscope was one of the only tools researchers had to study different cells; it was used to make observations regarding cell morphology, nuclear complexity, and differential staining to basic or acidic dyes. The armamentarium has expanded remarkably since then, with a vast array of antibodies that identify unique markers on cells. The tools even allow for flow cytometric techniques such as CyTOF that can identify dozens of markers on a single cell; for genetic mice with gene-specific reporter systems, or for gene-specific Cre recombinase allowing for deletion; and to live in vivo imaging permitting for the direct observation of cells within their natural environment.

The development of these observational tools has also led to the creation of methods to specifically delete a population of cells in a mouse, allowing a researcher to determine specific biologic functions of that cell population in an intact organism. Infusion of an anti-CD3 antibody to remove T cells can be an effective method of cell ablation. However, this requires a unique surface antigen as well as antibodies with predictable pharmacokinetics and in vivo activity. Sometimes the deletion method is as simple as deleting a specific gene which is unique and necessary for a population of cells. Nevertheless, not every cell type can be deleted in this way, and often there are issues with various genes being ubiquitously expressed during embryogenesis, necessitating floxed alleles and more complicated Cre systems. To allow for cell-specific ablation with temporal control, many researchers develop mice in which a cell-specific promoter region drives expression of the diphtheria toxin receptor. When mice are injected with the toxin, the cell type of interest is killed. In many cases, this alleviates concerns over differences in embryonic versus adult organisms and allows for timed ablation of a cell. However, diphtheria toxin administration and death of cells by this manner can cause significant non-specific effects in the mice. In the blood system, both the diphtheria toxin approach and antibodies also have the disadvantage of needing repeated administrations as the cells are rapidly reconstituted.

Recent work from Dr. Judith Agudo and colleagues now adds another arrow in the quiver of cell ablation techniques that may have unique applicability to the field of hematology. They reasoned that T cell–mediated cell ablation would allow for not only cell specificity, but also for a single administration with sustained effects, unlike antibodies or diphtheria toxin. However, making a cohort of T cells for each cell type of interest would not be very practical, so the researchers cleverly chose to generate T cells with a receptor capable of recognizing EGFP-specific MHC I expression. To generate these EGFP-specific T cells, the authors immunized mice with a lentivirus expressing EGFP, and isolated EGFP-specific

T cells (Figure). These cells were then used as a nuclear donor for somatic cell nuclear transfer. The process created mice that already have the rearranged T cell receptor specific for EGFP, preventing the need for continuous culture of T cell clones. These mice now produce what the authors termed just EGFP death-inducing (Jedi) T cells, that will destroy any cell expressing EGFP.

To test these T cells in in vivo systems, the authors used three separate models. First, they used the readily available CX3CR1-EGFP mice, which express EGFP in macrophage lineages, including microglia. When Jedi T cells were transferred into these mice, within one week of infusion, all of the microglia were eliminated, which suggests the ability of Jedi T cells to cross the blood brain barrier. However, since EGFP is expressed on macrophages, prior to performing the experiment, the authors irradiated the mice and transplanted them with bone marrow from RFP expressing mice in an effort to restrict EGFP expression to only microglia. Therefore, as the authors state in their manuscript, the effects of irradiation in this model on the integrity of the blood brain barrier cannot be ruled out. However, these studies do demonstrate a remarkable ability for efficient and sustained cell ablation within the brain. The authors then used a Foxp3-EGFP mouse, where regulatory T cells express EGFP, and infused them with Jedi T cells to eliminate Tregs. These studies showed robust ablation of the cells, with phenotypes consistent with reports of Foxp3 cell deletion. Finally, to demonstrate the ability to delete a rare population of cells, the authors utilized a hyperpolarization-activated cyclic nucleotide-gated channel (Hcn) EGFP mouse. These cells comprise less than 10,000 of the cells in the heart. Within 10 days of infusion, all of the Hcn+ cells were eliminated, and since they express EGFP, this ablation could be directly visualized and assessed by flow cytometry.

The Jedi mouse could be a remarkable tool to advance hematology research. One caveat to this model is that the recognition is restricted to H-2KD allele, necessitating backcrossing of existing C57Bl/6 strains to either DBA or B10D2 mice. For transplantation studies, or mice with complicated genetics, this could be a barrier to use. Since the cytotoxic T-cell–mediated killing is a natural response of these cells, it is likely that there will be reduced off-target toxicities as compared to diphtheria toxin approaches. Given the abundance of already existing reporter mouse strains that express EGFP, the Jedi mice and their T cells represent a potentially powerful tool for further cell-specific ablation in hematologic research, supporting studies on the hematopoietic niche, as well as cell-specific immune effects. With the ease of adding EGFP to cancer cell lines, one can envision using these as a method to study T-cell–mediated immune surveillance, or even models of minimal residual disease by tracking remaining EGFP-expressing cells after Jedi T-cell infusion.

Isolate GFP-specific T cells

Vaccination against GFP

LV.GFP

CD8

Backcross to B10D2

Injection ofmESC into blastocyst

Jedi mice(GFP-specific TCR)

Generation ofmESC

Enucleate

OocyteIsolate T-cell

nucleus

T-cell

B6 X

BALB/c H-2

Kd -

GFP

200-

208

Implant inpseudo-pregnantfemales

Schematic of the methodology to produce Jedi mice. EGFP, enhanced green fluorescent protein; LV.EGFP, lentivirus expressing EGFP (LV.EGFP); TCR, T cell receptor.

Figure

ANN S. LACASCE, MD

Dr. LaCasce indicated no relevant conflicts of interest.

The Hematologist: ASH NEWS AND REPORTS 9

Understanding Immune Escape in Classical Hodgkin LymphomaRoemer MG, Advani RH, Ligon AH, et al. PD-L1 and PD-L2 genetic alterations define classical Hodgkin lymphoma and predict outcome. J Clin Oncol. JCO664482 [Epub ahead of print].

Genetic and immunohistochemical analyses of the PD-L1 and PD-L2 loci and PD-1 ligand expression. (A) Location and color labeling of the bacterial artificial chromosome (chr) clones on 9p24.1 used for fluorescent in situ hybridization (FISH). RP11-599H20 including PD-L1, labeled red. RP11-635N21 including PD-L2, labeled green. (B) Representative images of FISH results for the various categories. PD-L1 in red, PD-L2 in green, fused (F) signals in yellow, and centromeric probe in aqua (A). In these images, disomy reflects 2A:2F; polysomy, 3A:3F; copy gain, 3A:6F; and amplification, 15+F. (C) The top panel shows PD-L1 (brown)/PAX5 (red) immunohistochemistry (IHC) in the classical Hodgkin lymphoma cases with 9p24.1 disomy, polysomy, copy gain, and amplification from (B). The bottom panel shows PD-L2 (brown)/pSTAT3 (red) IHC in the same cHL cases. Scale bar = 50 μm.©2016 by American Society of Clinical Oncology

Morphologically, Hodgkin lymphoma (HL) is characterized by rare malignant Reed-Sternberg (RS) cells surrounded by an ineffective infiltrate of inflammatory and immune cells. Using checkpoint inhibitors to redirect the immune system to eliminate RS cells is an attractive therapeutic approach.

Nivolumab and pembrolizumab, the monoclonal antibodies directed against PD-1, demonstrated dramatic activity in phase I studies, with the vast majority of patients with refractory disease responding to therapy. In their recent analysis of tissue biopsies from patients with HL, Dr. Margaretha G.M. Roemer and colleagues elucidate the biologic basis for the impressive activity of immunotherapy in this disease.

The investigators analyzed a cohort of 108 HL patients, all of whom were treated with the Stanford V regimen. The median age was 30 years, and the majority of patients had the nodular sclerosis subtype of the disease. Thirty-three and 41 patients had early-stage favorable (as defined by lack of B symptoms or disease bulk) and unfavorable disease, respectively. Thirty-four patients had advanced-stage disease. Using fluorescence in situ hybridization, researchers assessed alterations in chromosome 9p24, which encodes the programmed death 1(PD-1) ligands PDL-1 and PDL-2, as well as JAK2 and related transducers and activators of JAK-STAT signaling. Additionally, given the known increased expression of PD-1 ligands in Epstein-Barr virus–positive HL, EBV-encoded RNA (EBER) status was determined. Approximately 50 RS cells per case were evaluated. Compared with the control signal, cases with a 1:1 ratio were categorized as disomic (n=1), and those with a ratio of 1:1 but with more than two copies of each of the PDL-1 and PDL-2 probes were considered polysomic (n=5). Ratios greater than 1:1 but less than 1:3 were labeled as copy gain (n=61) and those cases with greater than 3:1 were classified as amplified (n=39). Two cases harbored translocations. The highest alteration in 9p24 for each case defined the category. Furthermore, the expression of PD-1 ligands was evaluated using immunohistochemical staining (Figure). All cases were concordant for alterations in PD-L1 and PD-L2. Altogether, 107 of 108 cases harbored alterations in 9p24.

The authors correlated clinical risk and genetic alterations with progression-free survival (PFS). As expected, patients with early-stage disease, both with favorable and unfavorable risk profiles, experienced excellent PFS. Patients with advanced-stage disease, however, were more likely to develop recurrent disease. Importantly, outcome was stratified by copy number alterations of 9p24. No relapses occurred in patients with polysomy. The highest relapse rate was seen in those with amplification, and intermediate PFS was observed in the group with copy gains. Additionally, patients with advanced-stage disease were more likely to harbor amplification compared to those with early-stage disease. On multivariate analysis, only stage was predictive of PFS, with a trend for amplification (p=0.075).

These findings elucidate the mechanism underlying the remarkable clinical activity of nivolumab and pembrolizumab in patients with classical HL. Selecting patients with higher risk disease at baseline based on copy number gain, in addition to clinical risk factors, may be important in identifying those patients most likely to benefit from these agents. In turn, this may facilitate further reductions in the use of chemotherapy and radiation, which are associated with late effects in this group of patients who typically experience long term survival.

Figure

ELIZABETH RAETZ, MD

Dr. Raetz indicated no relevant conflicts of interest.

PAU MOSS, MD, PhD

Dr. Moss indicated no relevant conflicts of interest.

Relapsed Multiple Myeloma: Now a Triad of Triplet CombinationsMoreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374:1621-1634.

The management of multiple myeloma has improved enormously over the past 15 years and has turned the diagnosis into a chronic disease for most patients. Several new drug classes

have emerged, notably the immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies.

For patients with newly diagnosed disease, the triplet combination of bortezomib, lenalidomide, and dexamethasone has shown excellent activity and is standard of care at many centers. In the setting of relapsed or refractory disease, three new drugs are now being assessed in combination with the backbone of lenalidomide and dexamethasone (Len-Dex). This article reports impressive results for ixazomib, the first of a new class of oral proteasome inhibitor.

The trial recruited 722 patients with refractory, relapsed, or relapsed and refractory disease, and half the patients received Len-Dex with placebo, whereas the rest were given ixazomib at days 1, 8, and 15 of each 28-day cycle.

The main outcome was a nearly six-month improvement in progression-free survival, which increased from 14.7 to 20.6 months with the addition of ixazomib. This effect was observed in all cytogenetic groups, though no difference in survival has emerged at this relatively early stage. The adverse effect profile was remarkably impressive, and thrombocytopenia was the only adverse effect of grade 3+ severity that was increased in the treatment group. Even then, there was no significant increase in bleeding episodes. Peripheral neuropathy has been a major concern with proteasome inhibitors, and although the reported rates were high in both groups, no differences were seen between the two treatment arms. Ixazomib, lenalidomide, and dexamethasone is therefore a very well tolerated protocol.

This report is one of three recent studies that have used a new agent in combination with a backbone of Len-Dex. Carfilzomib, also a proteasome inhibitor, and the SLAMF7-specific monoclonal antibody elotuzumab have both been assessed in parallel studies. Of interest, all three triplet regimens showed similar efficacy, with an improvement in the hazard ratio to around 0.7 when compared with Len-Dex alone. One aspect that sets ixazomib apart is that it is the first triplet combination that can be given completely as oral therapy. This, together with the favorable side effect profile, is likely to establish it as an attractive and convenient regimen for relapsed disease. Future studies will assess ixazomib as a component of the initial treatment of myeloma.1

We now have three effective triplet combinations for the treatment of relapsed myeloma. Additional agents, such as antibodies that block PD-1:PD-L1 checkpoint signaling or that bind to CD38, are also under active investigation.2,3 The ambition, which we can now consider with genuine hope, will be to transform multiple myeloma from a chronic disease into a curable disorder.

1. Millennium Pharmaceuticals, Inc. IXAZOMIB plus lenalidomide and dexamethasone versus placebo plus lenalidomide and dexamethasone in adult patients with newly diagnosed multiple myeloma. Last verified: Feb 2016. Available at www.clinicaltrials.gov/ct2/show/NCT01850524.

2. Merck Sharp & Dohme Corp. A study of pembrolizumab (MK-3475) in combination with standard of care treatments in participants with multiple myeloma (MK-3475-023/KEYNOTE-023). Last verified: Apr 2016Available at www.clinicaltrials.gov/ct2/show/NCT02036502.

3. Janssen Research & Development, LLC. Daratumumab in Combination With Lenalidomide and Dexamethasone in Relapsed and Relapsed-refractory Multiple Myeloma. Available at www.clinicaltrials.gov/ct2/show/NCT01615029 Last verified: Apr 2016.

Weighing the Pros and Cons of Dexamethasone Versus Prednisone in Childhood ALL InductionMöricke1 A, Zimmermann M, Valsecchi MG, et al. Dexamethasone vs. prednisone in induction treatment of pediatric ALL: results of the randomized trial AIEOP-BFM ALL 2000. Blood. 2016;127:2101-2112.

Corticosteroids have been a key element of acute lymphocytic leukemia (ALL) induction therapy for decades, yet it has been challenging to reach definitive conclusions about the optimal steroid formulation. Several recent clinical trials in B- and T-lineage ALL have compared dexamethasone versus prednisone during the induction phase of treatment.1 The rationale for using dexamethasone includes greater potency and central nervous

system (CNS) penetration, which is particularly appealing in T-ALL given the higher rates of CNS disease. This has been counterbalanced, however, by higher rates of infectious toxicity and treatment-related mortality with dexamethasone-based induction regimens. Past studies have determined that selecting the optimal steroid is complex, and unique features of the patient population and the other components of the treatment regimen influence the effect of induction corticosteroids. Thus, an overarching consensus about the optimal induction steroid has not been reached.

The AIEOP-BFM ALL 2000 trial conducted by the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) in collaboration with Berlin-Frankfurt-Münster (BFM) ALL study groups from 2000 to 2006 revisited this question with a randomization between dexamethasone vs. prednisone during the induction phase to determine whether treatment with dexamethasone provides a better event-free and overall survival in newly diagnosed childhood B-ALL and T-ALL. Pediatric patients aged one to 17 years participated in this trial at 127 participating sites in Europe. After receiving a seven-day prednisone prephase, children were randomized to receive either prednisone (60 mg/m2/day) or dexamethasone (10 mg/m2/day) for an additional 21 days during a four-drug induction with a subsequent taper. A total of 3,720 patients were randomized: 1,853 were assigned to the dexamethasone arm, and 1,867 patients to the prednisone arm.

Post-induction, children continued treatment with multiagent chemotherapy for a total of two years or with hematopoietic allogeneic stem cell transplantation in first remission for those with very-high-risk features. Prednisone good and poor responses were defined as <1.0 × 109/L or ≥1.0 ×109/L peripheral blood blasts, respectively, after the seven-day prednisone prephase and one intrathecal dose of methotrexate. The primary outcome in this study was event-free survival, with events defined as nonresponse, relapse, secondary neoplasm, or death from any cause. The steroid randomization was halted in October 2004 for patients aged 10 years or older, due to safety concerns.

Strikingly, the overall relapse incidence was reduced by one-third in the dexamethasone arm (10.8% ± 0.7% vs. 15.6% ± 0.8%; p<0.0001), with a proportionally greater reduction in extramedullary versus early bone marrow relapses. However, treatment-related death rates during induction were significantly higher in the dexamethasone arm (2.5% vs. 0.9%; p=0.00013). Among patients ≥ 10 years of age, the reduction in relapse risk was offset by this higher incidence of toxic deaths during induction such that no differences in event-free survival were observed in this older age group. Five-year event-free survival was significantly better for patients randomized to the dexamethasone arm compared with patients assigned to receive prednisone (83.9% ± 0.9% vs. 80.8% ± 0.9%; p=0.024, respectively). However, no difference between the randomization groups could be demonstrated for five-year overall survival (dexamethasone, 90.3% ± 0.7%; prednisone, 90.5% ± 0.7%).

Among prednisone poor responders, there were no differences in event-free or overall survival or relapse incidence in the randomized groups for either B- or T-lineage ALL. Among the patients with a prednisone good response, a significantly lower incidence of relapse and better event-free survival was observed in the dexamethasone arm compared to the prednisone arm for patients with both B- and T-lineage ALL. In the T-ALL patients with a prednisone good response, relapse rates were notably reduced from 17 percent to 7 percent with dexamethasone as the induction steroid and the better event-free survival of the dexamethasone group also translated into significantly better survival of 91.4 percent ± 2.4 percent compared to 82.6 percent ± 3.2 percent; p=0.036 with prednisone. This was in contrast to the patients with prednisone good response and B-ALL, who had an even inferior, though not statistically significant, survival rate in the dexamethasone group, largely attributable to inferior survival rates following relapse (see Table).

The results of this trial have several important implications for the treatment of B- and T-lineage childhood ALL. The benefits of dexamethasone in reducing relapse rates by one-third were notable given that the induction steroid was the only change in an intensive multi-agent treatment regimen; this intervention has had the largest impact on relapse risk reduction in decades. This benefit,

however, was offset by toxicity and treatment-related mortality, especially among patients 10 years or older, which is consistent with the experience of other groups.2 Any benefits of dexamethasone also seemed to be absent in prednisone poor responders, suggesting that a more potent steroid formulation may not be enough to overcome the impact of a steroid-resistant phenotype.

The lack of survival benefit in B-ALL, despite an improvement in event-free survival is another key finding, which could be explained by the observation that dexamethasone had the greatest impact in preventing B-ALL relapses that were more readily salvageable, such as extramedullary or later recurrences. These observations highlight the importance of evaluating the extent to which event-free survival benefits translate into improvements in overall survival as well. One of the most notable findings in this report is the benefit for dexamethasone in T-ALL patients with prednisone good responses. Within this subgroup, relapse rates were markedly reduced and event-free and overall survival improved significantly with dexamethasone as the induction steroid. Notably, overall survival rates exceeded 90 percent in this population that has been challenging to treat and salvage historically. Going forward, the results from this trial continue to suggest that there is not a straightforward answer as to whether one steroid is universally superior to another during childhood ALL induction therapy; rather, there are selective benefits to different formulations among patient subsets and a personalized approach appears warranted, with emphasis on preventing relapses that cannot be salvaged.

1. Teuffel O, Kuster SP, Hunger SP, et al. Dexamethasone versus prednisone for induction therapy in childhood acute lymphoblastic leukemia: a systematic review and meta-analysis. Leukemia. 2011;25:1232-1238.

2. Larsen EC, Devidas M, Chen S, et al. Dexamethasone and high-dose methotrexate improve outcome for children and young adults with high-risk B-acute lymphoblastic leukemia: a report from Children’s Oncology Group Study AALL0232. J Clin Oncol. 10.1200/JCO.2015.62.4544. [Epub ahead of print.]

10 The Hematologist: ASH NEWS AND REPORTS

Table. A Comparison of Dexamethasone Versus Prednisone During Induction

Dexamethasone Prednisone P Value

5-year cumulative incidence of relapse 10.8% ± 0.7% 15.6% ± 0.8% <0.001

Treatment-related deaths in induction 2.5% 0.9% 0.0013

5-year EFS 83.9% ± 0.9% 80.8% ± 0.9% 0.24

5-year OS 90.3% ± 0.7% 90.5% ± 0.7% NA

5-year OS in PGR T-ALL 91.4% ± 2.4% 82.6% ± 3.2% 0.036

5-year survival after relapse in PGR T-ALL 36.4% ± 4.5% 23.1% ± 8.3% 0.62

5-year OS in PGR B-ALL 91.9% ± 0.7% 93.4% ± 0.6% 0.12

5-year survival after relapse in PGR B-ALL 51.9% ± 4.1% 65.7% ± 3.1% 0.0053

EFS, event-free survival; OS, overall survival; PGR, prednisone good response; T-ALL, T-cell acute lymphocytic leukemia; B-ALL, B-cell acute lymphocytic leukemia.

The Hematologist: ASH NEWS AND REPORTS 11

THERESA L. COETZER, PhD

Dr. Coetzer indicated no relevant conflicts of interest.

Unique and Paradoxical Functions of the Tumor Suppressor PTENShojaee S, Chan LN, Buchner M, et al. PTEN opposes negative selection and enables oncogenic transformation of pre-B cells. Nat Med. 2016;22:379-387.

Phosphatase and tensin homolog (PTEN) is a potent tumor suppressor and plays an important role in regulating the phosphatidylinositol-3-kinase (PI3K) and protein kinase B (AKT)

signaling pathway. The development of pre-B cells is tightly controlled and depends on a fine balance of PI3K-AKT activity. A loss of signaling or hyper-activation of the pathway both lead to cell death, whereas an intermediate level of activity allows pre-B cells to pass a tolerance checkpoint that is monitored by PTEN. Point mutations and deletions in PTEN are common in cancer, including hematological malignancies of the T cell lineage and mature B cell lymphomas, implying a tumor suppressor function. To investigate the role of PTEN in immature B cell cancer, Dr. Seyedmehdi Shojaee and colleagues generated mouse models of pre-B acute lymphoblastic leukemia (ALL) driven by the oncogenes BCR-ABL1 or NRASG12D. Cre-mediated inducible deletion of one or both of the loxP-flanked pten alleles in these mice surprisingly prevented malignant transformation and also led to the death of established leukemia cells, indicating that PTEN is required for both the initiation and maintenance of pre-B ALL in vivo. Consistent with these findings, there is no hypermethylation of the PTEN promoter in pre-B ALL patients, resulting in higher levels of PTEN protein and a poor prognosis.

These paradoxical findings prompted reevaluation of genomic data from cancer patients, which confirmed the presence of PTEN mutations in solid tumors and blood cancers, consistent with a tumor suppressor role. However, no point mutations or deletions of PTEN were found in 925 cases of pre-B ALL, and activating mutations in agonists of the PI3K-AKT pathway were also not present, which supports the experimental mouse model evidence of Dr. Shojaee and colleagues. These data suggest that PTEN may have a fundamentally different function in pre-B ALL than in other hematopoietic malignancies. To elucidate the molecular mechanisms underlying the dependency of pre-B ALL on the presence of PTEN, the researchers used their mouse models to show that deletion of the PTEN gene increased phosphorylation of AKT and the activity of the PI3K-AKT cascade. Additional sophisticated gene manipulation experiments demonstrated that the hyperactive PI3K-AKT pathway triggered a checkpoint to eliminate the leukemic cells in a manner similar to the removal of auto-reactive B cells. They further showed that the pro-survival function of PTEN is unique to the B-cell lineage and that myeloid cells did not show this dependency.

These findings prompted an investigation of PTEN as a therapeutic target. Using shRNA technology, researchers knocked down PTEN in cells from four patients with pre-B ALL, which caused the death of the leukemic cells, with no effect on the viability of myeloid leukemia cell lines. Similar results were obtained when they performed pre-clinical testing of SF1670, a small-molecule inhibitor of PTEN. However, since PTEN is an important regulator of several cellular processes, as well as a tumor suppressor in other types of cells, adverse effects may be problematic and would require extensive further evaluation prior to the use of PTEN inhibitors in the clinic.

This exciting and important study has revealed a new and unexpected function of PTEN. Contrary to its normal role as a tumor suppressor, PTEN exhibits a pro-survival function that is unique to immature B cells and is required to initiate and maintain pre-B ALL. This dependency of the tumor cells on PTEN may be exploited for therapeutic intervention. The authors propose that targeted inhibition of PTEN and hyperactivation of the PI3K-AKT signaling pathway triggers a B cell tolerance checkpoint whereby auto-reactive B cells are eliminated. This may offer a new strategy to overcome drug resistance in human pre-B ALL.

OMAR ABDEL-WAHAB, MD, AND JUSTIN TAYLOR, MD

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

Core Circadian Clock Genes Regulate Leukemia Stem Cells

Puram RV, Kowalczyk MS, de Boer CG, et al. Core circadian clock genes regulate leukemia stem cells in AML. Cell. 2016;165:303-316.

The circadian rhythm, defined as daily oscillation in various biological processes, is controlled by an endogenous clock in most normal cells in the body. Prior research has established that hematopoietic stem cells (HSCs) are regulated by a circadian rhythm, which is established by cell-autonomous expression of core circadian clock genes as well as by non-cell autonomous inputs from the nervous system and

microenvironment. Given the importance of circadian regulation of cell proliferation, there has been great interest in understanding the molecular links between the circadian clock and growth regulation, especially in how this regulation might go awry in cancer. However, research linking circadian rhythm and cancer has been fraught with inconsistencies, including the description of a potential tumor suppressor role that was later disputed by null findings.

Now, Dr. Rishi V. Puram and colleagues have identified a leukemia-specific requirement for core circadian clock genes. This finding came about via an in vivo RNA interference screen in mouse acute myeloid leukemia (AML) cells driven by MLL-AF9. This model is enriched for leukemia stem cells (LSCs), and the authors generated short hairpin RNA (shRNA)–targeting genes encoding 152 DNA-binding proteins that have higher expression in HSCs or LSCs versus myeloid progenitors. Besides confirming the importance of established regulators of LSC function (such as HoxA9 and Meis1), the screen also identified genes encoding the core circadian clock proteins Clock and Bmal1 as among the top-scoring hits. This discovery contrasts previous research that showed that these genes were silenced in leukemia and posits that loss of physiologic circadian rhythm contributes to leukemia development.

The molecular mechanisms regulating the circadian clock involves the asynchronous expression of core clock genes CLOCK and BMAL1 with another set of genes (CRY1, CRY2, PER1, PER2, REV-ERB-α, and REV-ERB-β) which reciprocally regulate one another in feedback loops (Figure). In addition to validating the requirement of CLOCK and BMAL1 expression in mouse and human MLL-rearranged AML cells, the authors also evaluated the requirement for these genes in normal hematopoiesis. Despite the fact that both normal and leukemic hematopoiesis have rhythmic, circadian-dependent regulation of gene expression, Bmal1 was not required for normal adult hematopoiesis in mice.

Given the preferential requirement for circadian clock gene expression in malignant relative to normal hematopoiesis, the authors next tested the effect of a small-molecule REV-ERBα agonist compound in MLL-rearranged leukemia. By stimulating REV-ERB activity, this compound reduced BMAL1 expression as well as the expression of other genes required for MLL-rearranged leukemogenesis (Figure). This drug had a less dramatic effect on CD34+ cord-blood cells, indicating that there might be a therapeutic window for inhibiting the circadian clock machinery in leukemia while sparing normal HSCs.

This work advances the understanding of the role of cell intrinsic circadian rhythm mechanisms in LSCs and normal HSCs. It will now be important to validate the preferential requirement for core circadian clock genes in leukemia not dependent on rearranged MLL as well as primary samples from AML patients with wider genetic backgrounds. Moreover, it will be very interesting to directly compare the circadian rhythms of normal HSCs versus LSCs in vivo. However, the models used in this experiment were robust and these experiments set the stage for further research into this area as a novel potential target for anti-leukemic therapy.

A

B

Normal and malignant hematopoietic stem cells have circadian-dependent regulation of gene expression but leukemic stem cells in AML require core circadian clock genes. (A) Circadian rhythm is generated by cyclic expression of BMAL1, which is high at the beginning of a subjective day and low at the beginning of a subjective night. When BMAL1 is expressed it forms a heterodimeric transcription factor with CLOCK to directly promote the expression of CRY, PER, and REV-ERBα. CRY, PER, and REV-ERBα then serve to inhibit the expression of BMAL1 and/or the heterodimerization of BMAL1 to CLOCK. (B) The cyclic expression of these genes are present in normal as well as leukemic stem cells in vivo and Puram et al. have now found that BMAL1 and CLOCK are 1) upregulated by the MLL-AF9 fusion oncoprotein and 2) preferentially required in leukemic stem cells over normal hematopoietic stem cells. Moreover, the malignant cells were preferentially sensitive to the compound SR9011, which is an agonist of REV-ERBα and downregulates BMAL1 expression.

Figure

12 The Hematologist: ASH NEWS AND REPORTS

MICHAEL R. DEBAUN, MD

Dr. DeBaun indicated no relevant conflicts of interest.

When Is a Negative Phase III Trial Positive in Sickle Cell Anemia?Heeney MM, Hoppe CC, Abboud MR, et al. A multinational trial of prasugrel for sickle cell vaso-occlusive events. NEJM. 2016;374:625-635.

The hallmark and most common manifestation of sickle cell disease (SCD) is debilitating, severe acute vaso-occlusive pain often resulting in intravenous morphine given continuously for days to weeks. In more than 50 years, there has been no

evidence-based strategy for maximizing the management of acute vaso-occlusive pain events in children and adults with SCD. For multiple decades, clinicians have offered nonsteroidal anti-inflammatory therapy, typically ibuprofen, to augment acute pain management without evidence that such treatment attenuates current or future pain events. Platelets have been indirectly implicated in vaso-occlusive events based on their activation markers, including, but not limited to, CD63, P-selectin (CD62), and activated glycoprotein (GP)IIb/IIIa. Thus, with the evidence that platelets are activated and mitigate vascular occlusion, the authors postulated that an antiplatelet agent that inhibits adenosine- diphosphate (ADP) release from activated platelets would decrease the incidence of vaso-occlusive events. Based on a strong biological basis and prior promising results demonstrating a decrease in platelet activation biomarkers, as well as a trend toward decreased pain in a multicenter phase II study of prasugrel (a thienopyridine that inhibits ADP-mediated platelet activation),1 the investigators pursued a phase III trial.

Dr. Matthew Heeney and colleagues from 51 sites and 13 countries are to be congratulated in completing one of the few international SCD trials that includes participants from the United Kingdom, Africa, Europe, Brazil, and North America. In this phase III double-blind, placebo-controlled, parallel-group, multinational clinical trial — The Determining Effect of Platelet Inhibition on Vaso-occlusive Events (DOVE) trial — the investigative team tested the hypothesis that prasugrel is effective in reducing the rate of vaso-occlusive events (pain or acute chest syndrome) in children and adolescents with SCD. Each participant was expected to receive either placebo or prasugrel for at least nine months or a maximum of 24 months. There was a 1:1 random assignment of placebo versus prasugrel (initial dose, 0.08 mg/kg; range, 0.04 mg/kg - 0.12 mg/kg titrated to a predetermined level of platelet reactivity). The trial had several unique components, including assessment of platelet reactivity with an assay describing the ADP-induced platelet aggregation and the percentage of inhibition. Another novel component was the use of a handheld, mobile electronic patient-reporting device to remind participants and family members to record secondary outcomes, including a diary to document the rate and intensity of pain.

In 27 months, a total of 341 participants were enrolled, exceeding the target enrollment of 220 participants. The trial had a power of 85 percent to detect a 35 percent lower incidence of vaso-occlusive events in the treatment group compared with the placebo group. The primary outcome was that vaso-occlusive events occurred in 2.30 events per person-year and 2.77 events per person-year (rate ratio, 0.83; 95% confidence interval, 0.66 to 1.05; p=0.12) in the treatment group and placebo group, respectively. Similarly, the secondary endpoints did not reveal any evidence that prasugrel was superior to placebo, including assessments for rates of hospitalization, vaso-occlusive events, transfusions, analgesic use, school absenteeism, and intensity of pain. A major concern in any negative therapeutic trial is that the adherence rate was too low; however, the adherence rates were exceptionally high in both groups, 78.2 percent and 81.2 percent in the prasugrel and placebo groups, respectively.

What lessons did we learn from this multinational, randomized, controlled trial for an antiplatelet agent showing no benefit for the primary endpoint and multiple secondary endpoints? Perhaps the most important lesson is that the international community of families and investigators are eager to participate in a clinical trial attenuating the severity and frequency of pain. Despite being the largest phase III trial ever completed in children and adolescents with SCD, the recruitment goal was reached in 27 months. Another important take-home message is the ability to support adherence to study protocol with an electronic device that prompts family participation. Despite the clear evidence that hydroxyurea therapy decreases vaso-occlusive pain events, only 45 percent of the study population was on hydroxyurea at the time of enrollment. Clearly families of children and adolescents, clinicians, or both, are not enamored with taking hydroxyurea. A better understanding of the barriers for hydroxyurea therapy is needed, as are effective alternatives for this vulnerable population. With the successful completion of the DOVE trial, the SCD community can be optimistic about future phase III trials designed to decrease the frequency and intensity of acute vaso-occlusive events.

1. Wun T, Soulieres D, Frelinger AL, et al. A double-blind, randomized, multicenter phase 2 study of prasugrel versus placebo in adult patients with sickle cell disease. J Hematol Oncol. 2013;6:17.

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The Hematologist: ASH NEWS AND REPORTS 13

P R O G R A M G E N E A L O G I E S

Fred Hutchinson Cancer Research Center’s (“Fred Hutch”) Bone Marrow Transplantation Program, one of the largest in the world, had an inauspicious beginning. The program predates Fred Hutch itself — bone marrow transplantation as we know it has its roots in the vision and perseverance of one physician scientist, and my former mentor, the late Dr. E. Donnall “Don” Thomas. Dr. Thomas came to the University of Washington (UW) from the

Mary Imogene Bassett Hospital in Cooperstown, New York, in late 1963. I came to Seattle as a research fellow in 1965, joining a small team of researchers led by Dr. Thomas: myself; another fellow, Dr. C. Dean Buckner; an Instructor in Medicine, Dr. Bob Epstein; an animal technician, former U.S. Marine Sergeant Ted Graham; a laboratory technician; and Dr. Thomas’ wife and long-term “right hand,” the late Dottie Thomas, who acted as a mother to us all.

In the early 1960s, the field of clinical bone marrow transplantation was nearly dead. Early reported human marrow transplantations had failed. All patients had died from complications, including immune reactions that were not predicted from studies on inbred rodents. Most investigators left the field, and prominent immunologists declared that the barriers between individuals could never be crossed, but Dr. Thomas did not give up. He began to study dogs, the only species to share an unusual phenotypic diversity and a well-mixed gene pool with humans. Most importantly, however, like humans, dogs develop spontaneous cancers including non-Hodgkin lymphoma, which represented a perfect preclinical disease model. When I came to Seattle, there wasn’t room for our team in the UW Medical School, so we occupied a tiny laboratory in a corner of the 10th floor of what used to be the United States Public Health Service Hospital, which later came to brief local fame as Amazon’s original headquarters. At that time, transplantation was not a widely known concept. In fact, when the university’s print shop produced stationery letterhead for us, it said, “Division of Hematology and Transportation.”

To save money, the opposing Cobalt-60 sources used for total body irradiation of lymphoma in dogs and later of human patients were located underground in an abandoned World War II bunker several miles away. Under Dr. Thomas’ guidance, Dr. Epstein and I spent the 1960s in the laboratory tackling the “insurmountable” problems encountered in early human marrow transplantation. We knew that many of these problems would need to be solved in a pre-clinical animal model, so we honed in on the dogs with naturally occurring lymphoma. This

had dual benefits: We were able to answer many pressing clinical problems in a model system that had important similarities to humans, and we provided hope and, in some cases, cures to families with sick pets. We established a collaboration with veterinary offices throughout the Pacific Northwest; more than 1,500 family dogs with lymphoma were brought to us by their owners, sometimes even by plane. We developed high-intensity irradiation and chemotherapy regimens to kill the cancer cells and established the importance of in vitro tissue matching for transplantation outcome. To control and treat graft-versus-host disease (GVHD), we developed drug combinations capable of modifying

immune reactions. For several years, we produced antibodies against human thymocytes, since such antibodies were as yet not commercially available. To that end, we immunized rabbits and horses housed at a farm several miles across Lake Washington. This effort once involved an hour-and-a-half chase, on foot, of an antibody-producing horse.

Don’s leadership always encouraged free, and often heated, exchanges of ideas. Many of the concepts in the early days that later led to improvements in marrow transplantation were put through the wringer in rigorous free-flowing discussions. Everyone on our team was treated as an equal: Nurses and technicians were highly respected and given just as much voice as medical doctors and investigators, and often their input led to important advances. Such a rig-orous and open atmosphere was necessary to advance transplantation to the point of clinical translation. We received new National Institutes of Health (NIH) funding and began our pro-gram’s first patient transplants in 1969 after having addressed some of the most pressing issues, including establishing protocols for irradiation, tissue matching, and control of GVHD. At that time, we were joined by Dr. Paul Neiman, the late Dr. Alex Fefer, and an unusual research technician, the late Reg Clift, who became an integral part of the team. Another hallmark of Dr. Thomas’ team was the indelible partnership between laboratory and clinic. We continuously transferred knowl-edge from the bench to the bedside, and back again.

Our first transplantation did not work. The patient, who had chronic myeloid leukemia in blast crisis phase, developed a severe viral infection of a type that we couldn’t have anticipated from our animal work, but we pressed ahead. Today, there are patients still alive for whom we performed a transplantation in 1971 — 45 years ago. In 1972, a young patient with leukemia to whom all the members of our team had grown attached, developed severe acute GVHD after her transplantation. I had conducted research using antithymocyte serum to treat GVHD in animal models and made antihuman thymocyte globulin in rabbits. After another heated discussion, I convinced the research team and the young woman’s family to try this approach. The patient’s intense swelling at the injection site was frightening for us all, but the treatment worked to rid her of GVHD — she lived until a few years ago when she succumbed to metastatic breast cancer, but her leukemia never returned.

Around this same time, the Public Health Service hospital was shut down by the federal government, and we were faced with an uncertain future. After a few years in a temporary space at Providence Hospital and the UW’s Harborview Medical Center, our team moved to the Fred Hutchinson Cancer Research Center, established in 1975, in part thanks to Dr. Thomas’ relationship with Dr. Bill Hutchinson, who founded the center in his late brother’s

name. We abandoned the World War II bunker. The adjacent Swedish Hospital Medical Center provided the ever-increasing clinical space for our transplantation patients.

In those days, everything was new. Dr. Thomas recognized the importance of recruiting dif-ferent specialists to improve transplantation on multiple fronts. Dr. Dean Buckner led efforts with supportive care. Since the blood center did not provide platelet transfusions, we devel-oped our own transfusion program, which was supervised by Dr. Meera Benaji, with patient families, staff, and investigators donating platelets until we convinced the Puget Sound Blood Center to take over. Dr. John Hansen set up our tissue typing (human leukocyte antigen [HLA] typing) laboratories that continue to this day at the Seattle Cancer Care Alliance, now Fred Hutch’s treatment arm. Dr. Effie Petersdorf conducts molecular research of the HLA region

and its relation to transplantation outcome. Dr. Thomas recruited the late Dr. Joel Myers, an infectious disease expert from the Centers for Disease Control and Prevention, who laid the groundwork for what is now the largest group of infec-tious disease researchers of any cancer center. In 1972, Dr. George McDonald joined the team to address gastrointestinal complications of transplantation. A pulmonary group was also established, now led by Dr. David Madtes. Drs. Kenneth Lerner and George Sale established the pathology group which con-tinues at the Seattle Cancer Care Alliance. Pediatrician Dr. Jean Sanders joined our team from Stanford University in 1975 and was instrumental in broadening the application of transplantation to pediatric patients. In the early 1980s, Drs. Thomas and Hansen, together with the fathers of two of our patients, laid the foundations for the National Marrow Donor Program. As we ourselves grew older, we recognized the need for developing so-called “mini-transplants” — transplant procedures using less toxic conditioning regimens for use in elderly patients who

were not previously eligible for traditional high-intensity transplantations. These rely largely on powerful allogeneic graft-versus-tumor effects for eradicating cancer and are done in an outpatient setting.

More than 160 trainees from all parts of the globe went through my laboratory. The first European trainee, Dr. Hans-Jochem Kolb, pioneered using donor lymphocyte infusions for patients relapsing after transplantation upon his return to Munich. My second European trainee, Dr. Eliane Gluckman, pioneered umbilical cord blood transplantation after returning to her native France. Dr. Paul Weiden published two pivotal papers in the late 1970s/early

1980s in The New England Journal of Medicine, describing allogeneic graft-versus-tumor effects that were instru-

mental in eradicating the last leukemic cells after transplantation. Dr. Brenda Sandmaier plays a

leading role in the mini-transplant effort. Dr. Keith Sullivan, before leaving for Duke University, developed both Fred Hutch’s long-term follow-up group and transplantation for autoimmune diseases — two research areas that he passed on to Drs. Paul Martin and Mary Flowers, more recently joined by Dr. Stephanie Lee, and to

Drs. Richard Nash and George Georges, respec-tively. Dr. Mark Walters, now at Oakland Children’s

Hospital, pioneered transplantation for sickle cell disease. Pediatricians Drs. Ann Woolfrey and Lauri Burroughs are broadening efforts

of transplantation for nonmalignant diseases. Dr. Fred Appelbaum rose to the administra-tive challenges of succeeding Dr. Thomas as Director of the Clinical Research Division. Drs. Joachim Deeg and Bart Scott specialize in transplantation and conventional treatment for myeloproliferative neoplasms and myelodysplastic syndromes, while Dr. Hans-Peter Kiem has established gene therapy at Fred Hutch. My early colleague and friend, Dr. Epstein left Seattle to lead the Division of Oncology at the University of Oklahoma School of Medicine.

It is a testament to the strength of the program Dr. Thomas built that many of the fellows who passed through the program stayed on at Fred Hutch or UW as I did. Many of us, too many to name, continue to work on improving transplantation outcomes, broadening its reach to more patient populations for more diseases other than leukemia and lymphoma, and reduc-

ing transplantation adverse effects. In addition to the fellows, hundreds of visiting physicians trained at Fred Hutch. As one of them said: “Virtually every major transplant center in the world got its start by sending someone to train under Don Thomas.” The observations describing the power of the immune system to elimi-nate cancer by graft-versus-tumor effects are now bearing fruit in the modern field of cancer immunotherapy. Many of today’s leading immunotherapy researchers trained here, including Fred Hutch’s Drs. Phil Greenberg, Stanley Riddell, Cameron Turtle, and David Maloney, and the University of Pennsylvania’s Dr. Carl June. In the end, transplantation’s success and its ripples into other spheres of medicine are due largely to Dr. Thomas’ willingness to take on an adventure as long as it ulti-mately helped the patient. In recognition of his vision and leadership, Dr. Thomas shared the Nobel Prize in in Physiology or Medicine with Joseph E. Murray in 1990. Importantly, transplantation has become a mainstay in medicine. Since 1969, more than 1,000,000 transplants have been performed around the world.

1. Thomas ED, Storb R, Clift RA, et al. Bone-marrow transplantation (second of two parts). N Engl J Med. 1975;292:895-902.

2. Storb R, Prentice RL, Thomas ED. Marrow transplantation for treatment of aplastic anemia. An analysis of factors associated with graft rejection. N Engl J Med. 1977;296:61-66.

3. Weiden PL, Flournoy N, Thomas ED, et al. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med. 1979;300:1968-1073.

4. Storb R, Deeg HJ, Whitehead J, et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med. 1986;314:729-735.

5. Storb R, Gyurkocza B, Storer BE, et al. Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation. J Clin Oncol. 2013;31:1530-1538.

Dr. Bob Epstein

Dr. E. Donnall Thomas

Dr. Rainer Storb

Dr. C. Dean Buckner

Many of the concepts in the early days that later led to

improvements in marrow transplantation were

put through the wringer in rigorous free-flowing

discussions.

Program Genealogies: Bone Marrow Transplantation at Fred HutchRAINER STORB, MD

Head and Member, Transplantation Biology Program, Fred Hutchinson Cancer Research Center; Professor of Medicine, University of Washington, Seattle, WA

Clinical Trials Corner

Is Less More in Therapy for High-Risk MDS in the Elderly?

STUDY TITLE: A Multi-Center Biologic Assignment Trial Comparing Reduced Intensity Allogeneic Hematopoietic Cell Transplant to Hypomethylating Therapy or Best Supportive Care in Patients w/ Intermediate-2 & High Risk Myelodysplastic Syndrome (BMT CTN #1102)

CLINICALTRIALS.GOV IDENTIFIER: NCT02016781

SPONSOR: Medical College of Wisconsin

STUDY DESIGN: Nonrandomized, multicenter, prospective, comparative biologic assignment

ACCRUAL GOAL: approximately 400 patients

PARTICIPATING CENTERS: 36 study sites in North America

STUDY SYNOPSIS: This is a multicenter, prospective trial that compares three-year overall survival and outcomes of older patients with higher-risk myelodysplastic syndromes (MDS) treated with either reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC alloHCT), or nontransplant therapy or best supportive care. Eligible patients will be 50 to 75 years old individuals who have (or who have previously had) intermediate-2 or high-risk de novo MDS. Patients are deemed suitable candidates for a RIC alloHCT at the time of enrollment based on performance status, medical history, physical examination, available laboratory tests, and intent to proceed with RIC alloHCT if a matched sibling or matched unrelated donor is identified, with no requirement as to the timing of the transplantation. Patients and physicians must be willing to comply with treatment assignment and have neither intent to proceed with an alternative donor alloHCT not specified in the protocol nor intent to use myeloablative-conditioning regimens.

To reduce enrollment bias and to optimize the control arm, patients who have had tissue typing initiated for an unrelated donor will not be eligible. Patients who have started a sibling donor search or who have found a matched sibling donor are eligible. Importantly, patients may have received prior therapies for the treatment of MDS, including DNA hypomethylating agent–based therapy and cytotoxic chemotherapy.

All subjects are initially assigned to the nontransplant therapy arm and will be reassigned to the transplantation arm should a suitable donor (HLA-matched related donor or 8/8 HLA well-matched unrelated donor) be identified within 90 days of informed consent. The selection of the RIC alloHCT regimen and nontransplant therapy/best supportive care will be at the discretion of the treating physician. Patients will be evaluated for survival, progression to acute leukemia, and quality of life. Additionally, this study will assess the cost-effectiveness of these two alternative treatment approaches. An important predefined subgroup analysis is to determine the impact of pre-HCT hypomethylating agent–based therapy on study outcomes.

RATIONALE: MDS predominantly affects older individuals. Currently, the only potentially curative therapy for MDS is alloHCT. This approach is considered beneficial in a subset of patients with higher-risk MDS (intermediate-2 and high-risk). However, because of the substantial risk of morbidity and nonrelapse mortality associated with myeloablative allo-HCT, many patients, especially older patients with comorbidities and poor performance status, are deemed candidates for nontransplant therapy. Alternatively, they are never even referred to a transplantation center for consideration as they are thought to be unlikely to benefit from a myeloablative HSCT. The introduction of reduced-intensity conditioning regimens has expanded the age for alloHCT, though data are limited on its use in MDS. There is a lack of definitive prospective data evaluating the relative

14 The Hematologist: ASH NEWS AND REPORTS

Study Design

risks and benefits of alloHCT compared with nontransplant therapies such as hypomethylating agents, which have been shown to prolong progression-free survival and overall survival in patients with higher-risk MDS. BMT CTN #1102 addresses this knowledge gap.

COMMENT: The relative risks and benefits of alloHCT in older patients with higher-risk MDS remain a source of considerable uncertainty. The investigators reasonably expect that most enrolled patients assigned to the nontransplant therapy arm of this study will be treated with hypomethylating agent–based therapies, which have an established therapeutic efficacy in higher-risk MDS and are widely used in clinical practice. By addressing a fundamental question as to whether RIC alloHCT offers a survival advantage compared with this nontransplant therapy among older higher-risk MDS patients who are thought to be transplantation candidates, BMT CTN 1102 has the potential to change practice.

– Sioban Keel, MD

Dr. Keel indicated no relevant conflicts of interest.

Checking Multiple Myeloma with Pembrolizumab

STUDY TITLES: A Phase III Study of Pomalidomide and Low Dose Dexamethasone With or Without Pembrolizumab (MK3475) in Refractory or Relapsed and Refractory Multiple Myeloma (Keynote 183); A Phase III Study of Lenalidomide and Low-dose Dexamethasone With or Without Pembrolizumab (MK3475) in Newly Diagnosed and Treatment Naïve Multiple Myeloma (Keynote 185)

CLINICALTRIALS.GOV IDENTIFIERS: NCT02576977 (in relapsed patients); NCT02579863 (in newly diagnosed patients)

SPONSORS: Merck Sharpe & Dohme Corp.

PARTICIPATING CENTERS: 33 and more centers in the United States and worldwide (in relapsed patients); 39 and more centers in the United States and worldwide (in newly diagnosed patients)

ACCRUAL GOALS: 300 patients (in relapsed patients); 640 patients (in newly diagnosed patients)

STUDY DESIGN: Both of these trials are phase III randomized studies to evaluate the efficacy or progression-free survival of combining the anti-PD1 monoclonal antibody pembrolizumab with standard immunomodulatory therapy in multiple myeloma (MM) in patients with relapsed/refractory or newly diagnosed disease. In the former study, patients who have had two or more prior lines of treatment and who have been previously exposed to an immunomodulatory drug and a proteasome inhibitor are eligible; these criteria are similar to the U.S. Food and Drug Administration indication for pomalidomide. In the latter study, newly diagnosed patients who are not eligible for autologous stem cell transplantation are eligible. In both studies, pembrolizumab is given 200 mg intravenously every three weeks, with the conventional 28-day immunomodulatory drug schedule: pomalidomide 4 mg by mouth on days 1 to 21 with low-dose dexamethasone (40 mg weekly) in relapsed/refractory patients, or lenalidomide 25 mg by mouth on days 1 to 21 with low-dose dexamethasone.

RATIONALE: In cancer initiation and development, tumor cells suppress immune surveillance by using PD-L1 ligand to engage the PD1 receptor on T cells and inhibit T-cell activation (Armand P. Blood. 2015;125:3393-3400). Checkpoint inhibitors targeting PD1 therefore restore

T-cell activity against tumor cells and have emerged as a vital new therapeutic strategy. Two anti-PD1 antibodies, nivolumab and pembrolizumab, are now approved in melanoma and lung cancer. The promise of anti-PD1 antibodies is starting to be explored in hematologic malignancies such as Hodgkin disease (Ansell SM et al. N Engl J Med. 2015;372:311-319).

In MM, myeloma cells have increased levels of PD-L1, and the immunomodulatory drugs lenalidomide and pomalidomide inhibit myeloid-derived suppressor cell–mediated immune suppression in vitro (Görgün G et al. Clin Cancer Res. 2015;21:4607-4618). Furthermore, immunomodulatory drugs activate natural killer cells (Hayashi T et al. Br J Haematol. 2005;128:192-203), and they may augment anti-PD1 antibody enhancement of natural killer cell function against MM (Benson Jr DM et al. Blood. 2010;116:2286-2294). As a single agent, nivolumab had minimal activity in relapsed MM, with a stable disease rate of 67 percent in a phase I trial; partial responses or better were not seen (Lesokhin AM et al. Blood. 2014;124:291). However, in combination, two studies presented at the 57th ASH Annual Meeting showed promising results for pembrolizumab with lenalidomide (San Miguel J et al. Blood. 2015;126:505) or pomalidomide (Badros AZ et al. Blood. 2015;126:506), both with dexamethasone, in relapsed myeloma. The former trial with lenalidomide demonstrated an ORR of 74 percent in patients with two or more prior lines of treatment. In the latter trial with pomalidomide, the ORR was 50 percent, and these patients were heavily pre-treated, with a median of three prior lines of treatment, and 75 percent were refractory to both immunomodulatory drugs and proteasome inhibitors. In both studies, the treatments were tolerated well, and there were no treatment discontinuations for adverse events.

COMMENT: Checkpoint inhibition is emerging as an important new tool in cancer treatment. Its efficacy was first seen in solid tumors such as melanoma and lung cancer, and preclinical work as well as early-stage clinical trials with pembrolizumab in combination with lenalidomide or pomalidomide show auspicious findings for MM. The ongoing randomized studies of pembrolizumab in relapsed and newly diagnosed disease are important studies for validating this type of immuno-oncology as a novel therapeutic platform in MM.

– Andrew J. Yee, MD, and Noopur S. Raje, MD

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

The Hematologist: ASH NEWS AND REPORTS 15

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.

A P R I L 7, 2 0 1 6

Santagostino E, Martinowitz U, Lissitchkov T, et al. Long-acting recombinant coagulation factor IX albumin fusion protein (rIX-FP) in hemophilia B: results of a phase 3 trial. Blood. 2016;127:1761-1769.

In their phase III study, Dr. Elena Santagostino and colleagues demonstrate the efficacy and safety of recombinant factor IX-albumin fusion (rIXFP). Along with the other two extended-half-life FIX products recently approved, this agent heralds a new era for the treatment of hemophilia B.

Bernaudin F, Verlhac S, Arnaud C, et al. Long-term treatment follow-up of children with sickle cell disease monitored with abnormal transcranial Doppler velocities. Blood. 2016;127:1814-1822.

Dr. Françoise Bernaudin and colleagues report that chronic red blood cell transfusions can be safely circumvented with hydroxyurea therapy or bone marrow transplantation for a cohort of children with sickle cell anemia and abnormal transcranial Doppler velocities.

Fujikawa D, Nakagawa S, Hori M, et al. Polycomb-dependent epigenetic landscape in adult T-cell leukemia. Blood. 2016;127:1790-1802.

This report by Dr. Dai Fujikawa et al demonstrates that Tax induces a powerful epigenetics-dependent global modification of host gene expression in adult T-cell leukemia (ATL) through either upregulation or downregulation. These findings provide a strong rationale for directly targeting the Tax global fingerprint on cellular genes in ATL therapy.

A P R I L 1 4 , 2 0 1 6

Jain N, Lamb AV, O’Brien S, et al. Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype. Blood. 2016;127:1863-1869.

Dr. Nitin Jain and colleagues report one of the largest studies that reports clinical data in adult T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma with an immunophenotypically well-characterized cohort. Their study confirms that an early T-cell precursor immunophenotype in adult T-ALL is prognostically relevant.

A P R I L 2 1 , 2 0 1 6

McGowan KE, Makari J, Diamantouros A, et al. Reducing the hospital burden of heparin-induced thrombocytopenia: impact of an avoid-heparin program. 2016;127:1954-1959.

In this article, Dr. Kelly McGowan and colleagues report the outcomes and cost-effectiveness of a hospitalwide strategy to replace unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for prophylactic and therapeutic indications. They report that the use of LMWH markedly reduces the rate of heparin-induced thrombocytopenia (HIT), with a vast cost savings reflecting decreased HIT-related expenditures. (See Diffusion article on p. 1 by Dr. Adam Cuker)

Kanakry JA, Hegde AM, Durand CM, et al. The clinical significance of EBV DNA in the plasma and peripheral blood mononuclear cells of patients with or without EBV diseases. Blood. 2016;127:2007-2017.

Dr. Jennifer Kanakry and colleagues examine the diagnostic power of detection of Epstein-Barr virus (EBV) DNA in plasma versus peripheral blood mononuclear cells to diagnose EBV+ DNA. Reviewing results of more than 2,000 samples from a largely immunocompromised hospital population, they report that detection of cell-free EBV DNA in plasma is more sensitive and specific for the diagnosis of EBV+ disease.

M AY 1 9 , 2 0 1 6

Barr PM, Saylors GB, Spurgeon SE, et al. Phase II study of idelalisib and entospletinib: pneumonitis limits combination therapy in relapsed refractory CLL and NHL. Blood. 2016;127:2411-2415.

Dr. Paul Barr and colleagues report the outcome of a phase II study of the combination of the phosphatidylinositol 3-kinase inhibitor idelalisib and the spleen tyrosine kinase inhibitor entospletinib for the treatment of refractory chronic lymphocytic leukemia and non-Hodgkin lymphoma. Although patients had significant responses, the study was terminated early because of treatment-related pneumonitis occurring in 18 percent of patients with two deaths.

M AY 2 6 , 2 0 1 6

Hubbard N, Hagin D, Sommer K, et al. Targeted gene editing restores regulated CD40L function in X-linked hyper-IgM syndrome. Blood. 2016;127:2513-2522.

In their article, Dr. Nicholas Hubbard et al provide an innovative approach for genome editing to knock in a wild-type cDNA and functionally correct disease-causing mutations in a gene in primary human T cells. The level of gene editing seems high enough to potentially allow therapeutic correction of primary immunodeficiency.

Roccaro AM, Sacco A, Shi J, et al. Exome sequencing reveals recurrent germ line variants in patients with familial Waldenström macroglobulinemia. Blood. 2016;127:2598-2606.

In this article, Dr. Aldo Roccaro and colleagues present the possible contribution of the germ line genetic variants LAPTM5c403t and HCLS1g496a to inherited susceptibility to familial Waldenström macroglobulinemia.

Heestermans M, Salloum-Asfar S, Salvatori D, et al. Role of platelets, neutrophils, and factor XII in spontaneous venous thrombosis in mice. Blood. 2016;127:2630-2637.

Dr. Marco Heestermans and colleagues examined the roles of platelets, neutrophils and FXII in a new genetic mouse model of spontaneous venous thrombosis. Their data profoundly challenge the current notions about these players in venous thrombosis.

Editors’ Choiceelse in society, is exceedingly low and is a major impetus for the exodus of medical trainees to the U.S. and other countries. In 2014, after cutting 100,000 redundant jobs, the Cuban government hiked the monthly salaries of nurses and doctors (all amounts are in USD) by 150 percent: from $13 to $25 for entry-level nurses and up to $60 for nurses with the most experience; and from $20 to $30, up to $60 to $70 for the most highly trained specialty doctors.5,6 Cuba uses its quality doctors, nurses, and ancillary health specialists to feed its biggest generator of foreign revenue (roughly $8 billion), the export of some 50,000 medical workers to 66 countries around the world. These overseas postings provide an opportunity for medical professionals to develop increasing expertise in global health, and to earn more income; however, their salaries are often less than what nationals from other countries receive for similar work. In line with Cuba’s strong global footprint, CSH has made a strong effort to foster partnerships with international medical societies such as the Inter-American Division of the International Society of Hematology; the World Federation of Hemophilia; the Latin American Cooperative Group of Haemostasis and Thrombosis; and the Caribbean Researchers Network on Sickle Cell Disease and Thalassemia.

ASH’s international exchange with CSH was a successful stepping stone for future joint scientific meetings and research projects. However, in order to obtain a more in-depth appreciation of Cuba’s practice of hematology, “in-country” immersion with Cuba’s health-care officials in their practice settings will be critical. To this point, ASH Treasurer Dr. Susan Shurin, who is also senior advisor in the Center for Global Health at the National Cancer Institute, returned to Cuba shortly after the retreat as part of a separate, non-ASH U.S.-Cuba dialogue on health and cancer, sponsored by the American Association for the Advancement of Science (AAAS) and CIM. She had an opportunity to meet with officials from MINSAP, the Dean and faculty of the National School of Public Health, and she toured the National Institute of Oncology of Radiobiology (INOR) with their leadership. INOR is one of the two major tertiary care centers in Havana and specializes in treatment of pediatric and gynecologic cancers. They have radiotherapy facilities including several linear accelerators, and a new PET-CT scanner. Most of the machinery originates from Europe, as do the PhDs earned by their highly educated staff. The Hermanos Ameijeiras Hospital is Cuba’s major referral center for solid tumor and bone marrow transplantation, with almost 300 transplants performed to date primarily for leukemias, myeloma, and lymphomas. Referrals to such secondary or tertiary care centers originate from so-called local “polyclinics,” which are basic, but well-staffed primary care doctors’ offices that dot Cuba’s provinces.

Dr. Shurin came away very impressed with the Cuban infrastructure and personnel. Although the sojourn in Cuba was brief, ASH senior staff and the Executive Committee developed similar impressions, and developed a warm affinity for our brethren Cuban hematologists and the people at large. ASH is energized by the opportunities for clinical and scientific collaboration that lie ahead, especially for trainees, who need only travel 90 miles over the Straits of Florida.

1. Barry M. Effect of the U.S. embargo and economic decline on health in Cuba. Ann Intern Med. 2000;132:151-154.

2. The IMPACT of The U.S. Embargo On The Health And Nutrition In Cuba. American Association for World Health Report. 1997.

3. Hernández P. Generating potential for regenerative medicine in Cuba: Porfirio Hernández MD DrSc. Interviewed by Kathleen Vickery. MEDICC Rev. 2010;12:10-14.

4. Hernández P. Tenth anniversary of the fruitful application of regenerative medicine in Cuba (translated by Dr. Porfirio Hernández). Revista Cubana de Hematol, Inmunol y Hemoter. 2015;31:221-225.

5. Mientka M. Cuban Doctors Get Salary Raises To $67 A Month After Government Cuts 100K Redundant Jobs. Medical Daily. 2014.

6. Cuba Raises MD’s Salaries by up to 150%. Havana Times, March 21, 2014.

Dr. Gotlib wishes to acknowledge the assistance of Drs. Antonio Bencomo and Dr. Porfirio Hernández in producing this feature, and Julie Orlando-Castro, ASH’s Director of Education, for serving as a liaison with the Cuban Society of Hematology.

Dr. Gotlib indicated no relevant conflicts of interest.

ASH in Cuba(Cont. from page 5)

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

July

14-15 ASH Workshop on Genome Editing

Washington, DC www.hematology.org/genome-editing

15 2017 Honorific Awards nominations due

Washington, DC www.hematology.org/awards

29 CME Summit on Myelodysplastic Syndrome

Washington, DC www.hematology.org/meetings

30 Translational Research Training in Hematology letter of intent due

Washington, DC www.hematology.org/awards

30- Clinical Research Training Institute Summer WorkshopAug. 5 Washington, DC www.hematology.org/awards

August

1 Scholar Awards application deadline

Washington, DC www.hematology.org/awards

1 ASH membership application deadline (for consideration during the Annual Meeting in December)

Washington, DC www.hematology.org/membership

25-28 ISEH 45th Annual Scientific Meeting

San Diego, CA www.iseh.org/meeting

September

7 Translational Research Training in Hematology full application deadline

Washington, DC www.hematology.org/awards

14 CME Summit on Myelodysplastic Syndrome

Las Vegas, NV www.hematology.org/meetings

15 ASH Consultative Hematology Course

Chicago, IL www.hematology.org/meetings

15 CME Summit on Myelodysplastic Syndrome

Chicago, IL www.hematology.org/meetings

16-17 ASH Meeting on Hematologic Malignancies

Chicago, IL www.hematology.org/meetings

October

21 ASH annual meeting late-breaking abstract site opens

San Diego, CA www.hematology.org/annual-meeting

31 Deadline to submit late-breaking abstracts for the ASH annual meeting

San Diego, CA www.hematology.org/annual-meeting

Newly Designed ASH Image BankThe Image Bank is a web-based image library which offers a comprehensive collection of images relating to a wide range of hematologic topics. The new website was launched in March of 2016, containing over 2100 images. Content has been completely reorganized for more logical and intuitive browsing, and includes new images and cases including blood and bone marrow smears with the needed supplemental diagnostic material, as well as a new atlas that demonstrates both normal and abnormal cell morphology and differentiation.

This is a free resource for all to use, and ASH encourages new submissions of high quality, peer-reviewed hematologic images for the Image Bank. For comments, questions, and requests, email imagebank@hematology.org. ASH members can log in to the Image Bank with their standard ASH username and password; non-members must create an account at no cost. Access the Image Bank at imagebank.hematology.org.