PracticeUpdate: Conference Series - EHA 2018

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

23 RD CONGRESS OF THE EUROPEAN HEMATOLOGY ASSOCIATION 14–17 JUNE 2018 • STOCKHOLM, SWEDEN

THE BEST OF EHA 2018 Neither Myeloablative nor Reduced-Intensity Conditioning Impact Overall Survival in T-Cell Lymphoma • Consider Obinutuzumab Plus Chlorambucil for First-Line Treatment for CLL • EUTOS Long-Term Survival Score Superior for Prognosis of Survival in CML • HLH Patients Who Survive First Critical Period May Have Low Relapse Risk

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PracticeUpdate is guided by a world-renowned Editorial and Advisory Board that represents community practitioners and academic specialists with cross-disciplinary expertise. Editor-in-Chief Lee Schwartzberg MD, FACP, Michael Kroll MD Associate Editors Isabel Cunningham MD , Axel Grothey MD Rakhi Naik MD, MHS, Cristhiam Rojas Hernandez MD Advisory Board Benjamin Anderson MD FACS , Roxana Dronca MD , Wilfried Eberhardt MD , Wafiq S. El-Deiry MD PhD FACP , Rafael Fonseca MD , Andre Goy MD, Annette Hasenburg Prof. Dr. med, David Henry MD , Eric Jonasch MD , Jeffrey Kirshner MD FACP , Howard Scher MD , David Straus MD , Roger Stupp MD , Sara M. Tolaney MD MPH Editorial Contributors Neil Majithia MD , Jarushka Naidoo MD , Moshe Ornstein MD , Erin Schenk MD PhD , Basem M. William MD MRCP(UK) , Jeffrey Wiisanen MD, Kelly Casteel MD, Eric Fountain MD, MA PracticeUpdate ® is a registered trademark of Elsevier Inc. 2018 Elsevier Inc. All rights reserved. ABOUT For a complete listing of disclosures for each board member and editorial contributor, please refer to their profile on PracticeUpdate.com PracticeUpdate ’smission is tohelpmedicalprofessionalsnavigate thevast array of available literature and focus on the most critical information for their patients and practice. PracticeUpdate Conference Series is a collection of key research from leading international conferences, reviewed by the PracticeUpdate editorial and advisory board, made available in print format. These news highlights and more are also available online at PracticeUpdate.com PracticeUpdate and the PracticeUpdate Conference Series are commercially supported by advertising, sponsorship, and educational grants. Individual access to PracticeUpdate.com is free. Premium content is available to any user who registers with the site. While PracticeUpdate is a commercially-sponsored product, it maintains the highest level of academic rigour, objectivity, and fair balance associated with all Elsevier products. No editorial content is influenced in any way by commercial sponsors or content contributors. DISCLAIMER The PracticeUpdate Conference Series provides highlights of key international conferences for specialist medical professionals. The ideas and opinions expressed in this publication do not necessarily reflect those of thePublisher.Elsevierwillnotassumeresponsibility fordamages, loss,or claimsofanykindarising fromorrelated to the informationcontained in this publication, including any claims related to the products, drugs, or services mentioned herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. Please consult the full current Data Sheet before prescribing any medication mentioned in this publication. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer. The production and distribution of this publication is sponsored by Janssen New Zealand. It contains content published in accordance with the editorial policies of Elsevier’s PracticeUpdate.com Content was produced by Elsevier with no involvement by Janssen New Zealand. Allcontentprinted in thispublicationcanbe foundonPracticeUpdate.com SALES Fleur Gill fleur.gill@elsevier.com Linnea Mitchell-Taverner l.mitchell@elsevier.com PRODUCTION Content was originally published on PracticeUpdate.com Production of this issue was executed by: Editorial Manager A nne Neilson anne.neilson@elsevier.com Editorial Project Manager Carolyn Ng Designer Jana Sokolovskaja Cover: illustration of a cancer cell and lymphocytes/istock.com ISSN 2208-150X (Print) • ISSN 2208-1518 (Online)

© EHA 2018

Contents

EHA 2018 • 14–17 June 2018 • Stockholm, Sweden BY THE PRACTICEUPDATE EDITORIAL TEAM

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3 Neither Myeloablative nor Reduced- Intensity Conditioning Impact Overall Survival in T-Cell Lymphoma 4 Tisagenlecleucel Improves Quality of Life for Young Patients with Refractory B-Cell Acute Lymphoblastic Leukemia 4 Consider Obinutuzumab Plus Chlorambucil for First-Line Treatment for CLL 6 Low-Dose Heparin May Be Warranted in Patients Undergoing Lower Limb Surgical Revascularization 7 CLL1-CD33 cCAR T-cell Therapy Promising for AML 8 Erythropoietin Treatment More Effective in Myelofibrosis Patients with Anemia and V617F JAK2 Mutations 9 Nilotinib and Lower-Intensity Chemotherapy Promising Treatment for Ph+ Acute Lymphoblastic Leukemia

10 Consider Interventions to Reduce Weight in Patients With Myeloproliferative Neoplasms 11 EUTOS Long-Term Survival Score Superior for Prognosis of Survival in CML 12 Consider Ibrutinib-Rituximab (IR) as Standard Therapeutic Option for Waldenstrom’s Macroglobulinemia 13 Use of Ruxolitinib–Hydroxyurea Benefits Patients with Myelofibrosis 14 HLH Patients Who Survive First Critical Period May Have Low Relapse Risk 14 Rituximab Yields Durable Response in Adults With Persistent or Chronic Immune Thrombocytopenia

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Neither Myeloablative nor Reduced-Intensity Conditioning Impact Overall Survival in T-Cell Lymphoma Largest cohort of allo-hematopoietic stemcell transplantation patients for T-cell lymphoma provides encouraging results

Encouraging results have been found in both myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) in what is believed to be the largest cohort of allo-hematopoietic stem cell transplantation (HSCT) patients for T-cell lymphoma, according to new research presented at EHA 2018. T he aim of the study, led by Anne- Claire Mamez, MD, with the Department of Internal Medicine

of relapse was 18% after the first year and 22% at 2 years. The median time from transplant to relapse was 94 days and only 10% of the relapse occurred after the first year post-transplant. Non-relapse mortality was 22% at 1 year and 24% at 2 years. The main causes of death were relapse (35%), infection (27%) or GvHD (22%). A multivariate analysis conducted by the research team found that at year 5 OS was significantly adversely influenced by the occurrence of grade III–IV GvHD (HR 2.52 [1.52–4.19], P < .01), low Karnofsky score at the time of transplant (HR 2.22 [1.32–3.71], P = .002), and cord blood transplant compared to bone marrow (HR 2.01 [1.00–4.01], P = .049). The main fac- tors associated with non-relapse mortality were as follows: ƒ ƒ patient’s age (HR 1.02, P = .084 [MTR3]) ƒ ƒ a low Karnofsky score (HR 2.03 [1.08– 3.83], P = .029) ƒ ƒ female donor to male recipient (HR 1.87 [1.07–3.28], P = .027). “The conditioning regimen intensity (RIC or MAC) was not found to have impact on OS,” the researchers stated in their abstract. Among 30 patients transplanted in PD, 50% reached complete remission after allo-HSCT and 2 year-OS was 51% in this subgroup.

response (PR) and 11% in progressive disease (PD). Twenty-eight percent were transplanted in frontline treatment, 36% after 2 lines of treatment, and 35% after 3 or more lines of treatment. After the first autologous HSCT, 23% of patients had relapsed and the Karnofsky Performance Status Scale Index was up to 80% in 94% of the patients. The Index is a widely used assessment tool to measure functional impairment. It can be used to compare the effectiveness of different therapies as well as to evaluate the prognosis in indi- vidual patients. Generally, for most serious illnesses, as the Karnofsky score declines, the likelihood of survival decreases. Donors were matched related in 45% of cases, matched unrelated in 36%, and alternative in 19% (haplo-identical n=7, cord blood n=33, mismatched 9/10 n=13) and the stem cell source was peripheral blood in 71% of the patients. A reduced-intensity regiment was given in 147 patients (52%), myeloablative in 106 (38%), and nonmyeloablative in 27 (10%). Half of all patients received an ex-vivo T cell depletion; only 1% had an ex vivo T depletion. Fourteen patients (14%) developed grade III–IV acute graft versus host disease (GvHD), and 34% developed chronic GvHD (extensive for 13%). The median follow-up was 33 months. The 1- and 2-year OS were 68% (95% CI 0.62–0.73) and 64% (95% CI 0.58–07), respectively. The cumulative incidence

Specialties at the University of Geneva, Switzerland, was to analyze the outcomes in a cohort of nearly 300 patients who had undergone an allo-HSCT for peripheral T-cell lymphoma. Three outcomes were measured: overall survival (OS), relapse/ progression, and non-relapse mortality. Using clinical files and data from the Société Francophone De Greffe De Moelle Et De Thérapie Cellulaire data- base, which has more than 400 members engaged in stem cell transplantation research, the study investigators con- ducted a retrospective analysis of adult patients who underwent an allo-stem cell transplant for non-cutaneous peripheral T-cell lymphoma (PTCL) in 34 centers between 2006 and 2014. Primary cuta- neous T-cell lymphomas were excluded. According to the abstract, a total of 284 patients with PTCL were allo-transplanted in a median time of 12.6 months after diagnosis (3–322 months). This com- prised 39% NOS-T cell lymphomas, 29% angioimmunoblastic T lymphomas, 15% anaplastic T-cell lymphomas, 17% in other categories. The median age at transplant was 50 years (15 to 60 years) and 67% were males. At the time of transplant, 62% were in complete remission (CR), 27% in partial

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Tisagenlecleucel Improves Quality of Life for Young Patients with Refractory B-Cell Acute Lymphoblastic Leukemia Improvements in QOL were sustained at both 9 and 12months

A fter tisagenlecleucel infusion, mean- ingful, even dramatic, improvements in quality of life (QOL) have been observed in pediatric and young adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) who achieved complete remission with or without blood count recovery. The research team, led by André Baruchel, with the Pediatric Hematology- Immunology Department at Robert Debré University Hospital in Paris, found improvements in QOL observed at day 28 and months 3 and 6 were still sustained 9 and 12 months later. A global trial, ELIANA, evaluated the efficacy and safety of tisagenlecleu- cel (formerly CTL019) in pediatric and young adult patients with R/R B-ALL. Tisagenlecleucel is an autologous T-cell

chimeric antigen receptor therapy target- ing CD19+ cells. The goal of this study was to evaluate patient-reported QOL before and after infusion with tisagenlecleucel. As of April 25 2017, the data cutoff date, an overall remission rate (including both complete remission and complete blood count recovery of 81% at ≤ 3 months was reported. However, the researchers noted in their abstract, Improvement of Patient-Reported Quality of Life Following Tisagenlecleucel Infusion in Pediatric and Young Adult Patients With Relapsed/ Refractory B-Cell Acute Lymphoblastic Leukemia , “Increasingly, patient quality of life has become an important component in evaluating new oncology therapies.” Infused patients were 3–23 years old with CD19+ B-ALL and were chemore- fractory, relapsed after allogeneic stem

cell transplant (SCT), or otherwise inel- igible for SCT. Patients ≥ 8 years old completed the Pediatric Quality of Life Inventory (PedsQL) and the EuroQOL (EQ-5D/EQ-5D-Y) at baseline, day 28, and months 3, 6, 9, and 12 to evaluate QOL. Baruchel et al noted that both instruments are validated measures of QOL and were summarized with descriptive statistics at the cross-sectional level and through changes from baseline. The minimal clinically important differ- ences for the PedsQL and the EuroQOL visual analog scale (EQ-VAS) are 4.4

Consider ObinutuzumabPlus Chlorambucil for First-Line Treatment for CLL Obinutuzumab plus chlorambucil provide clinicallymeaningful benefits in CLL patients with comorbidities A combination of obinutuzumab plus chlorambucil (G-Clb) should be considered a first-line treatment for chronic lymphocytic leukemia (CLL) patients with comorbidities.

A slower-growing form of CLL produces an increased number of lymphocytes, but a normal or slightly below normal level of red cells, platelets, and neutrophils in the blood. This form of the disease can remain stable for years. The faster-grow- ing form of CLL, however, has too many cells in the blood that block normal cell production. As a result, the number of fully functioning red cells and platelet levels drop below normal. This phase III study conducted by Goede et al evaluated the efficacy and safety of obinutuzumab, a glycoengineered type II anti-CD20 monoclonal antibody developed as an effective treatment for CLL, in combination with chlorambucil (Clb) and rituximab (R) plus Clb (R-Clb)

In their abstract, Overall Survival Benefit of Obinutuzumab Over Rituximab When Combined With Chlorambucil in Patients With Chronic Lymphocytic Leukemia and Comorbidities: Final Survival Analysis of the Cll11 Study , the research team stated that G-Clb yields clinically meaningful ben- efits in CLL patients with comorbidities. CLL, the most common form of leukemia in adults, occurs when the DNA of a developing stem cell in the bone marrow is damaged. Because CLL does not com- pletely interfere with the growth of mature red cells, white cells, and platelets, it is generally less severe than acute leukemia.

The investigators, led by Valentin Goede, MD, a hematologist/oncologist in the Department of Internal Medicine with the University Hospital of Cologne in Germany, presented the findings from the final analysis of the CLL11 study. The research team suggested that obinutu- zumab should be the preferred anti-CD20 antibody in future combination regimens for CLL.

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ƒ ƒ Month 6: PedsQL, 17; EQ-VAS, 16 ƒ ƒ Month 9: PedsQL, 18; EQ-VAS, 19 ƒ ƒ Month 12: PedsQL, 27; EQ-VAS, 25 The percentage of patients who achieved the normative mean or greater (PedsQL, ≥ 83; EQ-VAS, ≥ 86.3) increased from 12% at baseline to 64% by month 12 for the PedsQL total score and 18% at base- line to 64% by month 12 for the EQ-VAS total score. “Sustained improvements in patient QOL were observed for each PedsQL subscale,” the researchers stated in their abstract. “Notable decreases in the proportion of problems reported by responding patients in each of the EQ-5D dimensions were observed at each time point.” Updated results for the international ELIANA clinical trial, a single arm, open-label, multi-center, phase II study, were published earlier this year in The New England Journal of Medicine. In the analysis of 75 infused patients with three or more months of follow-up, tis- agenlecleucel, trademarked as Kymriah, demonstrated an overall remission rate of 81% (95% CI 71%–89%). Sixty percent of patients achieved complete remission and 21% of patients achieved complete remission with incomplete blood count recovery, with no minimal residual disease detected among all responding patients. Median follow-up was 13.1 months.

and 7–10, respectively. The normative mean values for healthy children are 83 and 86.2 for the PedsQL and EQ-VAS, respectively. At the EHA Congress, the researchers reported changes in QOL in patients with a best overall response of complete remission with and without blood count recovery. At the data cutoff, 75 of 92 enrolled patients had been infused. Of these infused patients, 58 patients (77%) who were ≥ 8 years old completed QOL instruments; 48 (83%) of whom were responders (CR/CRi). Mean baseline vs Clb alone (Stage 1). As well the use of G-Clb was compared to R-Clb (Stage 2) in patients with previously untreated CLL and comorbidities. Patients were randomized 1:2:2 to receive six 28-day cycles (C) of Clb, R-Clb or G-Clb. The dosing schedule was as follows: ƒ ƒ Clb (0.5 mg/kg) was administered orally on Day 1 and D15 of C1–6. ƒ ƒ R was administered intravenously (IV) at a dose of 375 mg/m 2 on D1 of C1 and 500 mg/m 2 on D1 of C2–6. ƒ ƒ Obinutuzumab (1000 mg) was adminis- tered IV on D1 (dose split over two days; 100 mg D1, 900 mg D2), D8 and D15 of C1, and D1 of C2–6. A total of 781 patients were enrolled and received treatment (median: age, 73 years; CIRS score, 8; CrCl, 62 mL/min). Eligible patients had previously untreated CD20+ CLL, a total cumulative illness rating scale (CIRS) score of > 6 and/or a

scores for responding patients were 58 and 68 for the PedsQL and EQ-VAS, respectively. Mean baseline scores for nonresponding patients (n=10) were 60 and 63 for the PedsQL and EQ-VAS scales, respectively. “Both assessments demonstrated clinically meaningful improvements in the QOL of responders,” the researchers stated. The mean changes from baseline were as follows: ƒ ƒ At day 28: PedsQL, 6; EQ-VAS, 11 ƒ ƒ Month 3: PedsQL, 13.5; EQ-VAS, 16.5

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" Notably, G-Clb also provided a clinically meaningful improvement in overall survival compared with R-Clb. Two- and five-year survival rates were 91% vs 84% and 66% vs 57% for G-Clb vs R-Clb, respectively. "

outcomes compared with R-Clb (n=330). Notably, G-Clb also provided a clinically meaningful improvement in overall sur- vival compared with R-Clb. Two- and five-year survival rates were 91% vs 84% and 66% vs 57% for G-Clb vs R-Clb, respectively. Overall, the study found that fewer patients died in the G-Clb arm (37%) than in the R-Clb arm (45%). During the survival follow-up period, the most common cause of death was disease progression (G-Clb, 10%; R-Clb, 15%).

creatinine clearance (CrCl) of < 70 mL/ min. “The primary endpoint was investi- gator-assessed progression-free survival,” the investigators noted in their abstract. Secondary endpoints included overall survival, time to new treatment and safety. After a median observation time of 62.5 months, treatment with G-Clb (n=238) was associated with improved outcomes compared with Clb alone (n=118). After a median observation time of 59.4 months, G-Clb (n=333) also demonstrated a clinically meaningful improvement in

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Low-Dose Heparin May Be Warranted in Patients Undergoing Lower Limb Surgical Revascularization Prudent to start thromboprophylaxis 3.5–4 days after surgery

The 2012 American College of Chest Physicians (ACCP) guidelines for the prevention of venous thromboembolism in non-orthopedic surgical patients recommend the use of pneumatic compression devices (PCDs), but pharmacological thromboprophylaxis with low-dose heparin may be warranted in patients undergoing lower limb surgical revascularization. T he research team, led by Anmol Baranwal, MD, with the MacNeal Hospital in Berwyn, Illinois, concluded that because bleeding is a potential

of detection was more than a week after surgery,” he added, noting that the authors’ recommenda- tion for delaying chemoprophylaxis for 3–4 days is contradicted by findings from the Michigan Surgical Quality Collaboration. That study, published in the Journal of Vascular Surgery earlier this year, found that approximately 75% of patients received phar- macological chemo prophylaxis after major vascular surgery. In these patients undergoing lower extremity bypass, the incidence of DVT was only 1.1%. “They examined the timing of initiation of chemoprophylaxis post-operatively and found that it was most effec- tive if initiated within 24 hours post-op, the so-called 'early group', rather than at a later time point, and that early chemoprophylaxis was not associated with an increase in the risk of hemorrhagic side effects,” Dr. Eidt said. Javier Vasquez, MD, with Texas Vascular Associates and Medical Director of Surgical Services with the Baylor Scott & White Heart and Vascular Hospital, noted that the average time to identification of DVT noted in the study, 7.6 days, raised questions about the role ambulation and the calf pump effect would have had on the results. He cited a recent large multicenter retrospective review in the United States that found only 30% of hospitalized vascular patients received adequate DVT prophylaxis. “This was certainly surprising considering the recent pres- sure on hospital systems in the US to adhere to this certain ‘core measure.’ [It] certainly points to a need for improvement.” Several obstacles are present in post-operative vascular patients that are unique to this specialty, said Dr. Vasquez. These include the prevalence

complication in patients undergoing lower limb sur- gical revascularization, who are not good candidates for PCDs, it might be prudent to start thromboprophy- laxis 3.5–4 days after the surgery. Charts for 359 patients who had a lower limb surgical revascularization were evaluated for postoperative deep vein thrombosis (DVT) or consequential pulmo- nary embolism (PE). Overall, 5 patients (1.4%) were recognized to have a new DVT/PE within 3 months of the surgery. Patients had a newDVT/PE on average at 7.6 days after surgery. “It has generally been thought by vascular surgeons that the risk of post-operative DVT following lower extremity bypass surgery is relatively low in com- parison to other types of surgery. The basis for this belief is the fact that systemic intravenous heparin is administered during the operation when patients are thought to be at highest risk for venous stasis,” John F. Eidt, MD, vice chair of vascular surgery with the Baylor Scott & White Heart and Vascular Hospital in Dallas, told Elsevier’s PracticeUpdate . With respect to the present study, Dr. Eidt noted that there did not appear to be a standardized imag- ing protocol to detect subclinical DVT. “Thus, only patients with clinical indications for testing would have been evaluated. This would suggest that some cases of asymptomatic DVT would go undetected due to the retrospective nature of this study.” “The absence of a routine screening protocol might also explain the fact that the average time

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CLL1-CD33 cCAR T-cell Therapy Promising for AML CLL1 and CD33may eliminate both AML bulky disease and leukemia stemcells CLL1-CD33 cCAR T is a promising immunotherapy for acute myeloid leukemia (AML), according to new research findings presented at EHA 2018. “We demonstrated the feasibility and safety of targeting both CLL1 and CD33 to achieve complete response (CR). Our findings suggest further exploration of CLL1-CD33 cCAR T therapy as a stand-alone therapy or ‘bridge to transplant’ for patients with aggressive, relapsing/refractory AML leukemia,” the researchers stated in their abstract. This was the first in-human clinical trial for the therapy. CAR T-cell therapy relies on the use of a patient’s own immune system cells to fight the cancer in their body. The process typically involves modifying a specific set of cells from the patient’s blood to strengthen the immune system’s natural response to the disease. Anti-CD19 CAR T-cells have already shown impressive efficacy in acute lymphoblastic leukemia (B-ALL) and lymphoma, and approval from the Food and Drug Administration (FDA) in the United States has now been obtained. However, treatment of relapsed/refractory AML remains a substantial clinical challenge, noted the study team, led by Dr. Fang Liu, with the Department of Hematology at the Chengdu Military Hospital in China. AML bears heterogeneous cells that can offset killing by single CAR- based therapies, resulting in a relapse. Leukemic stem cells associated with CLL1 expression comprise a rare population that also play an impor- tant role in both disease progression and relapse. CD33 is a myeloid marker found on bulk AML disease cells in the majority of these patients. The present study is the first to treat refractory AML in patients using compound CAR T-cells with discrete scFv domains that target two AML antigens at the same time. The goal was threefold: to provide antigen escape, to ensure the process was safe, and to ensure the treatment was well tolerated. “Our findings indicate that targeting both CLL1 and CD33 on AML cells may be an effective strategy for eliminating both AML bulky disease and leukemia stem cells that may potentially prevent relapse due to antigen escape or the persistence of leukemia stem cells,” Liu said during his presentation. A cCAR bearing two complete CAR constructs connected by a self- cleavable peptide linker, P2A, was generated. Then the anti-leukemic activities of CLL1-CD33 cCAR T cells were evaluated in vitro with killing assays using multiple AML cell lines, primary human AML samples and REH cells expressing either CLL1 or CD33. The research team tested cCAR in multiple animal models that involved injecting mice with REH expressing CLL1 or CD33 or U937 cell line. They also tested an alemtuzumab safety switch that allows for rapid cCAR therapy termination in vivo. “Mice treated with CLL1-CD33 cCAR showed significantly improved survival as compared to control-treated mice,” the researchers stated. “We also showed that CLL1-CD33 cCAR promoted sustained in vivo anti-leukemic activity against the AML U937 cell line, as well as supe- rior murine survival in both models.” Next the researchers conducted a single-patient phase I clinical trial. Additional patients are being enrolled in the study. It is anticipated that 20 patients with relapsed/refractory AML will receive the treatment.

of tobacco abuse, incisions on lower extremities that inherently impair post-operative ambulation, high rates of wound complications and soft tissue infections, and concomitant amputations at times of digits that further impair early ambulation. Additionally, he told Elsevier’s PracticeUpdate , cer- tain vascular patients, especially those with metabolic syndrome and uncontrolled diabetes with or without smoking, may harbor an underlying hypercoaguable disorder that has yet to be diagnosed. “All of these risk factors and unique characteristics of vascular bypass patients make them inherently higher risk for thrombo- embolic disease.” “I would like to see more stratification of risk factors and comorbid conditions that exist in these patients,” said Dr. Vasquez. “Ultimately a reliable scoring system could be developed that would deem a patient at a certain risk category for a post-operative DVT/PE event. This may allow the treatment team to be more liberal with adequate perioperative prophylaxis.” " Ultimately a reliable scoring system could be developed that would deem a patient at a certain risk category for a post-operative DVT/ PE event. This may allow the treatment team to be more liberal with adequate perioperative prophylaxis. "

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Erythropoietin Treatment More Effective in Myelofibrosis Patients with Anemia and V617F JAK2 Mutations Myelofibrosis patients who develop transfusion dependence have a lower overall survival rate

Stimulation of the main pathogenic pathway for patients with myelofibrosis may paradoxically contribute to overcoming the issue of anemia for these individuals, according to new research findings presented at EHA 2018. T he research team from Spain found that patients who developed transfu- sion dependence during the course

This reality represents “a clinical challenge without effective therapeutic options,” the research team, led byMaría Isabel Montero, MD, with the Department of Hematology, Hospital Universitario Virgen del Rocio in Seville, Spain, noted in their abstract. “The underlying mechanisms of anemia in this patient population are not well established, although it has been associated with inef- fective hematopoiesis, elevated levels of proinflammatory cytokines, splenomegaly, mutations in several genes such as UAF1 or downregulation of certain proteins such as in the case of GATA1.” The investigators conducted a single- center analysis of the impact of anemia on survival and the response to erythropoietin treatment with JAK2 mutational status in a cohort of 119 patients diagnosed with myelofibrosis between June 1998 and July 2007. The average age at diagnosis was 67 years (range 19–88); 61% of patients were male and 36% had a previous diagnosis of another myeloproliferative neoplasm, specifically polycythemia vera or essential thrombocythemia. A diagnosis of myelofibrosis was made based on bone marrow examination and according to criteria established by the World Health Organization. V617F JAK2 status was assessed through

allele-specific polymerase chain reaction in patients diagnosed after 2005. Every patient who had clinically significant anemia received treatment with erythropoietin, a hormone produced by the kidney that promotes the production of red blood cells by bone marrow. The average leucocyte, hemoglobin, and platelet counts were 12,5 x 10e9/L, 114 g/L and 344 x 10e9/L, respectively. V617F JAK2 mutation was present in 61% of the patients. Of the total study group, 31% had a hemoglobin concentration less than 100 g/L at diagnosis, and 47% went on to develop a transfusion dependence. Overall, the 4-year OS rate was 69%. In patients with a hemoglobin concentration less than 100 g/L, OS was 56%. In those patients with a hemoglobin concentra- tion of at least 100 g/L, this figure rose to 77%. The difference is not statistically significant, the researchers stated in their abstract Is Anemia the Main Survival Marker in Patients With Myelofibrosis in the Ruxolitinib Era? For patients who developed transfusion dependence, the 4-year OS rate was 60%. This compared with 78% in those patients who did not have a transfusion dependence (P = .03). Only 20% of the patients with a V617F JAK2 mutation died compared with 56% of the patients with wild-type mutational status, the research- ers found. “However,” they noted in their abstract, “4-year OS rates among patients developing transfusion dependence were similar irrespective of their mutational sta- tus (65% if V617F JAK2-positive vs 60% if wild-type).”

of their disease had a lower overall survival (OS) rate, a finding that is consistent with published data. In addition, the investiga- tors concluded that patients with anemia and V617F JAK2 mutations responded better to erythropoietin treatment than those with JAK2 wild-type status, which raises the potential for using stimulation of the main pathogenic pathway. Myelofibrosis is an uncommon and seri- ous form of chronic leukemia that affects the body's normal production of blood cells. The disease causes significant scarring in the bone marrow, which often results in severe anemia as well as gen- eral weakness, fatigue, and an enlarged spleen. At diagnosis, roughly 50% of patients with myelofibrosis will have a hemoglobin concentration less than 100 g/L. Approximately 33% of patients will go on to develop transfusion depend- ence over the duration of their disease. Transfusion dependence indicates a condition of severe anemia typically aris- ing when erythropoiesis is reduced so significantly that blood transfusions are required over a specified interval. Being transfusion dependent is strongly corre- lated with decreased survival.

" The underlying mechanisms of anemia in this patient population are not well established, although it has been associated with ineffective hematopoiesis, elevated levels of proinflammatory cytokines, splenomegaly, mutations in several genes… " PRACTICEUPDATE CONFERENCE SERIES • EHA 2018 8

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Nilotinib and Lower-Intensity Chemotherapy Promising Treatment for Ph+Acute Lymphoblastic Leukemia Treatment associated with a highmajor molecular response rate and positive short-termoutcome N ilotinib in combination with low- er-intensity chemotherapy appears to be a promising option to treat In intent to treat analysis, the major molec- ular response rate was 43/54 patients (80%) after cycle 2 and 38/41 patients (93%) after cycle 4. The research team categorized this outcome as “good as expected” and the trial is continuing. In total, 265 patients will be required to assess if using no cytarabine at all is feasible.

arm after cycle 4, defined as BCR-ABL1/ ABL1 ratio < 0.1% in the bone marrow, is equivalent to standard treatment. Secondary endpoints are hematologic complete remission, early mortality, progression-free survival, per protocol event-free survival and overall survival. An interim analysis was scheduled after enrollment of the first 60 patients to ensure the overall major molecular response rate did not significantly differ from the anticipated 80% rate. The current analysis focused on the initial 60 patients, randomized between March 2016 and June 2017 (M/F, 29/31; median age, 47 years; minor BCR-ABL1 breakpoint, 72%). The median follow-up period was 14 months (IQR, 11.6–16.2) and the minimal follow-up of patients who were still alive was 3.8 months. All patients but 1, who early died from a septic shock, achieved hematologic complete remission after cycle 1. During the initial 4-cycle period, 4 additional patients in complete remission discontinued the planned therapy during cycle 1 (1 septic shock, 1 chest pain, 1 par- aplegia, 1 cannabis arteritis) and 1 during cycle 3 (prolonged cytopenia).

adult patients with Philadelphia chromo- some-positive (Ph+) acute lymphoblastic leukemia (ALL). The treatment combination is associated with a high major molecular response rate and a positive short-term outcome, the research team, led by Yves Chalandon, MD, Head of the Oncology Hematology and Allogeneic Hematopoietic Stem Cells Unit at Geneva University Hospitals in Switzerland, said in their abstract. Although Ph+ ALL is a relatively uncom- mon disease, it accounts for approximately 20% to 30% of adults diagnosed with ALL and is the most common cytogenetic abnormality in adult patients with this disease. Compared with Ph-negative ALL, Ph+ ALL has been found to have a poorer prognosis. The use of tyrosine kinase inhibitors (TKIs) to treat patients with Ph+ ALL has resulted in the need for a lower intensity of chemo- therapy to treat the disease. The study investigators previously reported on a randomized GRAAPH-2005 trial with imati- nib that identified better short-term results when patients received lower-intensity chemotherapy during the first treatment cycle (Y. Chalandon et al, Blood 2015). In the current study, part of the ongoing GRAAPH-2014 trial with nilotinib, the researchers conducted a random evalu- ation of reducing chemotherapy intensity by omitting high-dose cytarabine during the second treatment cycle. They also repeated cycles 1 and 2 for a total of 4 cycles to prolong TKI exposure and reach a deeper response prior to allogeneic or autologous stem cell transplantation in these patients. For the purposes of the study, patients 18 to 59 years old with newly diagnosed previously untreated de novo Ph+ ALL and an ECOG-PS ≤ 3 are eligible for ran- domization following a steroid prephase. The primary determinant of effectiveness is confirming that the major BCR-ABL1 molecular response in the no-cytarabine

At the time of the current analysis, the researchers noted, 31 and 13 patients had received allogeneic and autologous stem cell transplants in the first complete remis- sion, respectively (transplant rate, 73%). Seven out of these 59 patients relapsed, however, (including 4 post-transplant relapses) and 3 patients died (including 2 deaths in complete remission, 1 of which occurred after a stem cell transplant). At the 1-year mark, progression-free survival and overall survival were esti- mated at 84.5% (95% CI 75.0–95.2) and 95.9% (95% CI 90.3–100), respectively. The researchers determined that when initiation of unplanned therapies prior to transplants was considered an event (3 dasatinib, 1 imatinib), per protocol event- free survival was estimated at 79.7% (95% CI 69.5–91.4) after 12 months.

www.practiceupdate.com/c/69937

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EHA 2018 • PRACTICEUPDATE CONFERENCE SERIES

Consider Interventions to Reduce Weight in Patients With Myeloproliferative Neoplasms Weight loss in combinationwith traditional therapymay improve symptomatology

myEloproliferative Neoplasms Trial), a large international survey conducted with MPN patients to investigate nutrition, sup- plement use, and symptoms. The goal of the NUTRIENT trial is to help craft dietary interventions for people with MPNs. The secondary analysis presented at EHA 2018 focused on the relationship of BMI to dis- ease characteristics and symptom burden. Symptom burden was assessed using the validated MPN10 symptom assessment ( J Clin Oncol 2012;30:4098-103). Participants in NUTRIENT complete an online survey. For the purposes of this cross-sectional study, a total of 1,025 sur- veys had the necessary data on MPN type, weight, height, and symptom burden. MPN types included essential throm- bocythemia (ET; n=392), polycythemia vera (PV; n=390), and myelofibrosis (MF; n=243). Patients were of typical median age (60.0 years) and female predomi- nance (74.9%) in keeping with previous MPN investigations. The overall self-reported mean BMI of respondents in the study was overweight (25.9, SD = 5.13). Distribution over the study’s four weight categories was as follows: 2.8% underweight, 45.7% normal weight, 32.4% overweight, and 19.1% obese. The mean BMI was not found to be signifi- cantly different amongMPN subtypes (25.8 ET, 26.3 PV, and 25.6 MF; P = .30). Male respondents were significantly more likely to have a BMI > 25 than female

Interventions to reduce weight in patients with myeloproliferative neoplasms may be an effective strategy in combination with traditional therapy to improve symptomatology. M yeloproliferative neoplasms (MPNs), a group of rare, chronic blood cancers that affect bone

marrow function, are chronic hemato- logic malignancies that carry an elevated symptom burden including fatigue and pain. At present, stem cell transplantation is the only way to prevent progression of MPNs. Other factors, such as inflam- mation, can affect the disease, however. This understanding has led researchers to investigate the role that diet may play in influencing and managing this disease. There is a significantly reduced lifespan for patients with MPNs as compared to the general population ( J Clin Oncol 2012;30:2995-3001). Although elevated body mass index (BMI) is a risk factor for MPN disease development, little informa- tion is currently available on the relevance of BMI in MPN symptomatology. “Understanding the relevance of BMI to symptoms may help to guide future efforts regarding disease development, pro- gression, symptom burden or [quality of life],” the research team, led by Robyn M. Scherber, MD, PhD, with the Mays Cancer Center at UT Health San Antonio, Texas, said in their abstract. The researchers used data fromNUTRIENT (NUTRitional Intervention among

" Understanding the relevance of BMI to symptoms may help to guide future efforts regarding disease development, progression, symptom burden or [quality of life]. " PRACTICEUPDATE CONFERENCE SERIES • EHA 2018 10

EUTOS Long-TermSurvival Score Superior for Prognosis of Survival in CML Sokal score allocatedmore patients to high-risk group than the ELTS T he EUTOS long-term survival score (ELTS) is recommended to predict long-term survival in patients with chronic-phase (CP) chronic myeloid leukaemia (CML). The 5,154 patients in the combined reg- istry had a median observation time of 5.3 years. Six-year OS probability was 90% (95% CI 89–91%). Of 429 deceased patients, in 175 CML progression prior to death was confirmed (40%). The 6-year CIP of dying of CML was 4% (95% CI 4–5%).

The ELTS was originally developed to distinguish three groups of patients with different probabilities of dying from CML in a cohort of 2,205 imatinib-treated patients who were part of the European Treatment and Outcome Study (EUTOS) registry. The registry contains data on adult patients with CP CML. Many investigators, however, continue to rely on the Sokal score for the prognostic discrimination of CML patients treated with tyrosine kinase inhibitors (TKIs). Of the original cohort, the Sokal score had allocated 23% of patients to the high-risk group, the ELTS score only 12%. In their abstract, the research team, led by Markus Pfirrmann, MsC, a senior scientist, biometrician, and epi- demiologist with the Ludwig Maximilian University of Munich, Germany, stated that the long-term outcome of TKIs suggests that allocating > 20% CP CML patients into a high-risk group is “too pessimistic.” Due to the success of TKIs, the number of deaths from CML has declined considerably. The current study compared risk group allocations and prognoses between the two scoring systems. The researchers found that the Sokal score allocated 13% (n=671) more patients to the high- risk group than the ELTS score. As these patients had significantly and clinically relevant lower cumulative incidence probabilities (CIPs) of death and higher overall survival (OS) probabilities, the allocation of the Sokal score was not appropriate, they concluded. For this study, an additional 2,949 patients from other registry sections were included in the review, and survival was calculated from the date of start of treatment to death. The CIPs of dying of CML were compared with the Gray test and OS probabilities with the log-rank test. Only death after confirmed disease progression was regarded as death due to CML.

From low- to high-risk groups, the Sokal score resulted in 6-year CIPs of 3% (n=1,982 [38% of 5,154], CI 2–3%), 4% (n=1,975 [38%], CI 3–5%), and 8% (n=1,197 [23%], CI 6–10%). This compared to the ELTS score in 6-year CIPs of 2% (n=3,037 [59%], CI 2–3%), 5% (n=1,449 [28%], CI 4–7%), and 12% (n=668 [13%], CI 9–1 5%). Of the 1,197 patients allocated as high risk by the Sokal score, the ELTS score classified 671 (56%) as non-high risk. Compared to the 526 high-risk patients according to both scores (6-year CIP of dying: 12%, CI 9–16%), the CIPs of dying were lower for the non-high risk patients (P = .0003, 6-year CIP: 5%, CI 3–7%). The Sokal high but ELTS non-high-risk patients (6-year OS: 88%. CI 85–91%) showed higher OS than the 526 com- mon high-risk patients (P = .0036, 6-year OS: 81%, CI 76–85%). Of the 3,037 patients identified as low risk by the ELTS score, the Sokal score allocated 1,200 (40%) to non-low-risk groups. The researchers found that without significant CIP differences to the latter group, at 6 years, the CIP of dying was 2% (CI 1–3%) in the 1,837 low-risk and 2% in the 1,200 non-low-risk patients (CI 2–4%). OS of the Sokal non-low-risk patients (6-year OS: 92%. CI 90–94%) was lower than in the cases classified as low-risk by both scores (6-year OS: 95%. CI 94–96%, P = .0186). Overall survival probabilities but not the CIPs of 1,200 patients assessed as low-risk by the ELTS and non-low-risk by the Sokal score were different from the probabilities of 1,837 assessed as low-risk patients by both scores, the researchers stated. For the prediction of long-term survival, they recommended the use of the ELTS score.

respondents (59.9% vs 48.7%, P = .0018). Among all MPN types, those with a BMI score > 25 showed a significantly higher symptom burden than those with a BMI < 25, the researchers found. This asso- ciation was found among patients with both PV and MF subtypes, but not for patients with ET. However, weak but still significant positive correlations were observed between symptom burden and BMI among all MPN subtypes (r=0.14; P < .001). “When looking within disease sub- types, this correlation was higher for PV patients (r=0.18; P < .001) than for ET (r=0.11; P < .001) or MF patients (r=0.11; P < .001),” the investigators stated. The research team concluded that over- weight or obese BMI is associated with a significantly worsened disease-related symptom burden for most MPN subtypes. This relationship was less clear for ET, where weak but significant correlations were observed between BMI as a contin- uous measure and symptom burden, but not when BMI was evaluated as dichoto- mous variable. One limitation to the data, the researchers pointed out, is that weight and height were self-reported and could not be externally validated. “However,” they noted, “these data suggest that interventions to reduce weight in MPN patients may be a strategy to combine with traditional therapy to improve symptomatology.”

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www.practiceupdate.com/c/69936

EHA 2018 • PRACTICEUPDATE CONFERENCE SERIES 11

Consider Ibrutinib-Rituximab (IR) as Standard Therapeutic Option forWaldenstrom’s Macroglobulinemia Efficacy of the IR combination superior to that of rituximab alone

I brutinib-rituximab (IR) should be considered a standard therapeutic option for patients with Waldenstrom’s macroglobulinemia, according to new research findings presented at EHA 2018. Waldenstrom’s macroglobulinemia (WM) is a rare form of non-Hodgkin’s lymphoma that in Europe affects approximately 7.3 men and 4.2 women per million people. The causes of WM are unknown although it typically affects older adults and is slightly more common in men than women. Since WM is rare, it is difficult to conduct large clinical studies and determine a standard treatment for the disease. Ibrutinib, an oral, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the United States for adults with WM and in the European Union for adults previously treated for WM or those with untreated WM who could not tolerate chemo- therapy. Single-agent ibrutinib is highly active in relapsed WM with reported progression-free survival (PFS) rates of 86% (at 18 months) and 69% (at 24 months). Rituximab, a therapy used to treat other types of blood cancer, is also effective and commonly used in treating WM by itself or in com- bination with other treatments. In this study, led by Meletios A. Dimopoulos, MD, with the National and Kapodistrian University of Athens School of Medicine in Greece, 150 patients with confirmed WM and symptomatic disease requiring treatment were randomized to daily ibrutinib (420 mg) or placebo, both with rituximab (375 mg/m 2 /week IV for infusions at weeks 1–4 and 17–20). The median age of study participants was 69 years, 45% were treatment-naive, and 38% had a high-risk score under the International Prognostic Scoring System for WM. Of the 150 patients, 136 had available mutation data. MYD88L265P and CXCR4WHIM mutations were identified by target exome sequencing assay in

85% and 36%, respectively. At a median follow-up of 26.5 months, IR significantly prolonged PFS compared with rituximab alone. The research team noted that this represented “a five-fold reduction in the risk of progression or death.” More patients had a major response rate to treat- ment with ibrutinib + rituximab (72%) than with placebo plus rituximab (32%). At 30 months after starting treatment, an estimated 82% of patients treated with IR were alive and did not have disease progression versus 28% of patients treated with placebo plus rituximab. Improvements in PFS were consistently reported in all relevant subgroups, including treatment-naive (HR 0.34; 95% CI 0.12–0.95), relapsed (HR 0.17; 95% CI 0.08–0.36), MYD88L265P/CXCR4WT (HR 0.17; 95% CI 0.06–0.49), MYD88L265P/CXCR4WHIM (HR 0.24; 95% CI 0.09–0.66), and MYD88WT/ CXCR4WT (HR 0.21; 95% CI 0.04–1.1). Overall (≥ MR) and major (≥ PR) response rates were significantly higher for IR vs R, 92% vs 47% (P < .0001) and 72% vs 32% (P < .0001), respectively. Improvements in hemoglobin were observed in 73% vs 41% of IR and R patients (P < .0001). Approximately 60% of patients in both treatment groups experienced at least one significant (grade ≥ 3) side effect; the most common grade ≥ 3 side effects with ibrutinib plus rituximab were high blood pressure and atrial fibrillation. However, ending treatment with ibrutinib or placebo because of side effects was uncommon (≤ 5% of patients in both treatment groups). The research team concluded that the efficacy of the ibrutinib plus rituximab combination was supe- rior to that of placebo plus rituximab, producing improvements in PFS for all WM patients regardless of prognostic or genotypic factors. The IR combi- nation was also determined to have a manageable toxicity profile and no new or unexpected adverse effects were observed. The findings presented at the EHA 2018 mirror find- ings from another study presented earlier this year at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting and simultaneously pub- lished in The New England Journal of Medicine . In that study, ibrutinib plus rituximab significantly reduced the risk of disease progression or death by 80% compared to placebo plus rituximab (HR 0.20; CI 0.11–0.38, P < .0001). In late 2017, the Independent Data Monitoring Committee (IDMC) recommended that based on these results the phase III iNNOVATE trial, which is evaluating IR in WM patients, should be unblinded.

" More patients had a major response rate to treatment with ibrutinib + rituximab (72%) than with placebo plus rituximab (32%). At 30 months after starting treatment, an estimated 82% of patients treated with IR were alive and did not have disease progression versus 28% of patients treated with placebo plus rituximab. "

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PRACTICEUPDATE CONFERENCE SERIES • EHA 2018 12