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What’s New and What’s Next in the Treatment of MDS?

What’s New and What’s Next in the Treatment of MDS?. Mikkael A. Sekeres, MD, MS Professor of Medicine Director, Leukemia Program Vice Chair for Clinical Research Cleveland Clinic Cleveland, Ohio. David P. Steensma, MD, FACP Associate Professor of Medicine Harvard Medical School

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What’s New and What’s Next in the Treatment of MDS?

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  1. What’s New and What’s Next in the Treatment of MDS? • Mikkael A. Sekeres, MD, MS • Professor of Medicine • Director, Leukemia Program • Vice Chair for Clinical Research • Cleveland Clinic • Cleveland, Ohio David P. Steensma, MD, FACP Associate Professor of Medicine Harvard Medical School Institute Physician Dana-Farber Cancer Institute Boston, Massachusetts

  2. Use of these Slides • Learners are welcome to use and share these slides in full or in part for educational purposes in noncommercial discussions with colleagues or patients. • The materials presented may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. Readers should verify all information and data before treating patients or using any therapies described in these materials. • The materials published reflect the views of the authors and not those of MediCom Worldwide, Inc. or the companies providing educational grant support. • These slides may not be published, posted online, or used in commercial presentations.  These content slides were current based on the video production date of 3/29/19.

  3. Topics We Will Touch on Today • Personalized risk stratification models beyond IPSS and IPSSR • Is there a benefit to treating iron overload in transfusion dependent MDS? • Newer strategies for treating lower-risk MDS patients who are transfusion dependent • Immunotherapies in MDS • New strategies for treating high-risk MDS

  4. Background • Patients with myelodysplastic syndromes (MDS) have heterogeneous outcomes that can range from months for some patients to decades for others. Although several prognostic scoring systems have been developed to risk stratify MDS patients, survival varies even within discrete categories, which may lead to over- or under-treatment. Deficits in discriminatory power likely derive from analytic approaches or lack of incorporation of molecular data • Here, we developed a model that uses a machine learning approach to analyze genomic and clinical data to provide a personalized overall outcome that is patient-specific Nazha A, et al. ASH 2018. Abstract 793.

  5. Conclusion • A personalized prediction model based on clinical and genomic data that outperformed IPSS and IPSS-R in predicting OS and AML transformation. The new model gives survival probabilities at different time points that are unique for a given patient. Incorporating clinical and mutational data outperformed a mutations only model even when cytogenetics and age were added Nazha A, et al. ASH 2018. Abstract 793.

  6. New Model Building Data Random Survival Forest Important Variables Demographic Training CC + MLL Clinical • 1 Genomics X • 1 Validation Moffitt Nazha A, et al. ASH 2018. Abstract 793.

  7. Mutation Distribution (Training) No. of Patients Mutations Nazha A, et al. ASH 2018. Abstract 793.

  8. Clinical Application Actual Survival Actual Survival Actual Survival Died at 56 months Died at 14 months Died at 30 months Nazha A, et al. ASH 2018. Abstract 793.

  9. Safety and Efficacy, Including Event-free Survival, of Deferasirox Versus Placebo in Iron-Overloaded Patients with Low- and Int-1-Risk Myelodysplastic Syndromes (MDS): Outcomes from the Randomized, Double-Blind TELESTO Study Emanuele Angelucci,1 Junmin Li,2 Peter Greenberg,3 Depei Wu,4 Ming Hou,5 Efreen Horacio Montaňo Figueroa,6 Maria Guadalupe Rodriguez,7 Xunwei Dong,8 Jagannath Ghosh,8 Miguel Izquierdo,9 and Guillermo Garcia-Manero10 1Hematology and Transplant Center, IRCCS Ospedale Policlinico San Martino, Genova, Italy; 2Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; 3Stanford University Medical Center, Stanford, CA, USA; 4Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, China; 5Department of Hematology, Qilu Hospital, Shandong University, Jinan, China; 6Department of Hematology, Hospital General de México, Mexico City, Mexico; 7Department of Hematology, Hospital de Especialidades, Centro Médico Nacional La Raza, IMSS, Mexico City, Mexico; 8Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA; 9Novartis Pharma AG, Basel, Switzerland; 10MD Anderson Cancer Center, University of Texas, Houston, TX, USA

  10. Background and Study Rationale • Although iron chelation therapy (ICT) has been shown to improve outcomes in lower-risk MDS patients, the studies were mainly retrospective analyses and registry studies1-6 • However, considerable debate remained on the clinical utility of ICT in this patient population, and the need for a randomized trial has long been recognized7 Aims The TELESTO (NCT00940602) study prospectively evaluated event-free survival (EFS) and the safety of ICT with deferasirox versus placebo in patients with low/intermediate (Int)-1-risk MDS • AML=acute myeloid leukemia; RBC=red blood cell 1Delforge M, et al. Leuk Res. 2014;38:557-563. 2Leitch HA, et al. Clin Leukemia. 2008;2:205-211. 3Lyons RM, et al. Leuk Res. 2017;56:88-95. 4Neukirchen J, et al. Leuk Res. 2012;36:1067-1070. 5Remacha AF, et al. Ann Hematol. 2015;94:779-787. 6Rose C, et al. Leuk Res. 2010;34:864-870. 7Meerpohl JJ, et al. Cochrane Database Syst Rev. 2014:CD007461.

  11. TELESTO – Study Objectives To evaluate event-free survival (composite endpoint) • Defined as the time from randomization to first documented non-fatal event (worsening cardiac function, hospitalization for congestive heart failure, liver function impairment, liver cirrhosis, transformation to AML), based on review and confirmation by an independent adjudication committee, or death, whichever occurred first Primary To assess: • Overall survival • Change in serum ferritin level • Hematologic improvement in terms of erythroid response (based on International MDS Working Groupcriteria1) • Change in endocrine function (thyroid and glycemic control) • Safety Key secondary 1Cheson BD, et al. Blood. 2006;108:419-425.

  12. Non-fatal Components of the Composite Primary Endpoint Adjudicated by the EAC EAC=Endpoint Adjudication Committee

  13. Key Demographic and Baseline Characteristics SD=standard deviation

  14. Patient Disposition (FAS) EOT=end of treatment; FAS=full analysis set

  15. Exposure to Study Drug Exposure excluding interruption (days) = date of last dose – date of first dose – days with 0 dose + 1 Median time on treatment was 217 days longer with deferasirox (587.5 days) than with placebo (370.5 days) Mean dose was lower with deferasirox (14.9 mg/kg/day) than with placebo (23.5 mg/kg/day), reflecting dose adjustments for SF level changes SF=serum ferritin

  16. Primary Endpoint EFS: Stratified Log-rank Test and Cox Regression Model *Both the log-rank test and Cox proportional hazards model were stratified by stratification factors; †Median time to event and 95% CI generated by Kaplan–Meier estimation; ‡Exploratory P value is one-tailed and based on the stratified log-rank test; §Based on a Wald test from the Cox model A 36.4% risk reduction in EFS was observed in the deferasirox arm compared with the placebo arm (HR: 0.636; 95% CI: 0.42, 0.96; nominal P=0.015) CI=confidence interval; HR=hazard ratio

  17. EFS Events (Non-fatal Events or Deaths) that Occurred First as Confirmed by the EAC (Adjudication Rate 44%) *Investigators were asked to report any event that was even remotely possible to be an event to the EAC; only events confirmed by the EAC are included; †A patient with multiple occurrences of the same event is counted only once in the component category TELESTO was not powered to detect differences between deferasirox and placebo for single-event categories of the composite primary endpoint for EFS

  18. Summary of Overall Survival 100 *Both log-rank test and Cox proportional hazards model were stratified by stratification factors; †Median time to event and 95% CI generated by Kaplan–Meier estimation; ‡Exploratory P value is one-tailed and based on the stratified log-rank test; §Based on a Wald test from the Cox model 80 Median OS was prolonged by 398 days with deferasirox vs placebo Randomized treatment Deferasirox 60 Placebo Censored 40 Probability of overall survival (%) Following study drug discontinuation 52.1% of placebo patients started ICT 20 0 0 364 728 1092 1456 1820 2184 2548 2912 No. of patients still at risk Time (days) 149 113 91 76 40 20 7 1 0 Deferasirox 76 60 45 33 18 4 1 0 Placebo NE=not evaluable

  19. 8637 8637 5776 2915 54 Serum Ferritin Trends Placebo Serum ferritin level (ng/mL) Deferasirox BL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 Time (quarter) Deferasirox 146 141 123 108 94 89 83 76 70 63 60 55 49 39 29 26 22 16 12 10 8 8 4 4 4 4 3 3 2 1 Placebo 76 76 69 56 49 37 30 24 24 18 11 10 9 5 3 3 1 1 1 1 Boxes show lower and upper quartiles, horizontal line shows the median

  20. AEs Regardless of Study Drug Relationship (>15% in Either Arm) AE=adverse event; RTI=respiratory tract infectionAEs occurring more frequently in one group (with ≥5% difference relative to the other) are highlighted in bold

  21. Summary • TELESTO is the first prospective, randomized study of ICT in patients with Low-/Int-1-risk MDS and iron overload • Treatment with deferasirox led to longer EFS compared with placebo • Exposure-adjusted AEs were similar in the two arms with the exception of non-severe increases in serum creatinine, with no new safety signals • Considering the current treatment landscape, it is unlikely that a similar randomized trial will be performed TELESTO provides evidence on the clinical benefit of ICT in lower-risk MDS patients with iron overload

  22. The MEDALIST Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept to Treat Patients with Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) Associated Anemia with Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions Patients with lower-risk (LR)a transfusion-dependent MDS have a poorer prognosis, with greater risk of progression to AML and inferior overall survival compared to transfusion-independent MDS patients RBC transfusion-dependent LR, non-del(5q) MDS patients have a transient response to ESAs, with an attendant risk of iron overload and secondary organ complications Few treatment options exist for LR MDS patients who are either refractory to or become unresponsive to erythropoiesis-stimulating agents (ESAs)1 Pierre Fenaux, Uwe Platzbecker, Ghulam J. Mufti, Guillermo Garcia-Manero, Rena Buckstein, Valeria Santini, María Díez-Campelo, Carlo Finelli, Mario Cazzola, Osman Ilhan, Mikkael A. Sekeres, José F. Falantes, Beatriz Arrizabalaga, Flavia Salvi, Valentina Giai, Paresh Vyas, David Bowen, Dominik Selleslag, Amy E. DeZern, Joseph G. Jurcic, Ulrich Germing, Katharina S. Götze, Bruno Quesnel, Odile Beyne-Rauzy, Thomas Cluzeau, Maria Teresa Voso, Dominiek Mazure, Edo Vellenga, Peter L. Greenberg, Eva Hellström-Lindberg, Amer M. Zeidan, Abderrahmane Laadem, Aziz Benzohra, Jennie Zhang, Anita Rampersad, Peter G. Linde, Matthew L. Sherman, Rami S. Komrokji and Alan F. List a IPSS-R-defined criteria. ESA=erythropoiesis-stimulating agent; IPSS-R=Revised International Prognostic Scoring System; TGF-β=transforming growth factor-beta 1Fenaux P, Ades L. Blood. 2013;121:4280-4286.

  23. MEDALIST Luspatercept Trial Modified extracellular domain ofActRIIB • Luspatercept is a first-in-class erythroid maturation agent that neutralizes select TGF-β superfamily ligands to inhibit aberrant Smad2/3 signaling and enhance late-stage erythropoiesis in MDS models1 • In a phase II study in LR, non-del(5q) MDS, luspatercept yielded a high frequency of transfusion-reduction or RBC-TI in patients with MDS-RS (52%) vs other subtypes (30%)2 Luspatercept ActRIIB/IgG1 Fc recombinant fusion protein HumanIgG1 Fcdomain TGF-β superfamily ligand ActRIIB Smad2/3 Cytoplasm P Complex Nucleus Erythroid maturation ActB=activin B; ActRIIB=human activin receptor type IIB; BMP=bone morphogenetic protein; GDF=growth differentiation factor; IgG1 Fc=immunoglobulin G1 fragment crystallizable; LR=lower-risk; RBC-TI=red blood cell transfusion independence; RS=ring sideroblasts 1Suragani RN, et al. Nat Med. 2014;20:408. 2Platzbecker U, et. A. Lancet Oncol. 2017;18:1338.

  24. MEDALIST TrialStudy Design - A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study Luspatercept 1.0 mg/kg (s.c.) every 21 d n=153 Patient Population • MDS-RS (WHO 2008): ≥15% ring sideroblasts or ≥5% with SF3B1 mutation • <5% blasts in bone marrow • No del(5q) MDS • IPSS-R Very Low-, Low-, or Int-risk • Prior ESA response • Refractory, intolerant • ESA naïve: EPO >200 U/L • Average RBC transfusion burden ≥2 units/8 weeks • No prior treatment with disease modifying agents (eg, IMiDs, HMAs) Randomize 2:1 Dose titrated up to a maximum of 1.75 mg/kg Placebo(s.c.) every 21 days n=76 Disease & Response Assessment week 24 & q 6 months Treatment discontinued for lack of clinical benefit or disease progression per IWG criteria; No crossover allowed Subjects followed ≥3 years post final dose for AML progression, subsequent MDS treatment and overall survival Data cutoff: May 8, 2018 Includes Last Subject Randomized + 48 weeks. EPO=erythropoietin; HMA=hypomethylating agents; IMiD=immunomodulatory drug; IWG=International Working Group; s.c.=subcutaneously; SF3B1=splicing factor 3b subunit 1; WHO=World Health Organization

  25. MEDALIST Trial: Study Endpoints Primary endpoint: • - Red blood cell – transfusion independence ≥8 weeks (weeks 1–24) Key secondary endpoints: - Red blood cell – transfusion independence ≥12 weeks, weeks 1–24 • - Red blood cell – transfusion independence ≥12 weeks, weeks 1–48 Additional secondary endpoints: - HI-E (IWG 2006 criteria1) for any consecutive 56-day period Reduction in transfusion burden ≥4 RBC units/8 weeksa or Mean Hb increase of ≥1.5 g/dL/8 weeksb • Duration of response • Hb change from baseline • Mean serum ferritins a In patients with baseline RBC transfusion ≥4 units/8 weeks. b In patients with baseline RBS transfusion burden <4 units/8 weeks. Hb=hemoglobin; HI-E=hematologic improvement-erythroid 1Cheson B, et al. Blood. 2006;108:419-425.

  26. MEDALIST TrialDemographics and Baseline Disease Characteristics a In the 16 weeks prior to randomization. b 1 (0.7%) patient in the luspatercept arm classified as IPSS-R High. c Data was missing for 1 patient. RARS=refractory anemia with ring sideroblasts; RCMD=refractory cytopenia with multilineage dysplasia; RCMD-RS=RCMD with ring sideroblasts

  27. MEDALIST Trial: Treatment Received a Dose may be titrated up to a maximum of 1.75 mg/kg.

  28. MEDALIST TrialPrimary Endpoint Achieved: Red Blood Cell – Transfusion Independence) ≥8 Weeks a Cochran-Mantel-Haenszel test stratified for average baseline RBC transfusion requirement (≥6 units vs <6 units of RBCs/8 weeks) and baseline IPSS-R score (Very Low or Low vs Intermediate).

  29. MEDALIST TrialPrimary Endpoint: Subgroup Analysis Favors Luspatercept OR=odds ratio

  30. MEDALIST TrialKey Secondary Endpoints: Red Blood Cell – Transfusion Independence ≥12 Weeks a Cochran-Mantel-Haenszel test stratified for average baseline RBC transfusion requirement (≥6 units vs <6 units of RBCs/8 weeks) and baseline IPSS-R score (Very Low or Low vs Intermediate).

  31. MEDALIST Trial: Duration of RBC-TI Response Kaplan–Meier Estimate of Duration of RBC-TI ≥8 Weeks (Weeks 1–24) 1.0 0.9 Luspatercept Placebo Censored 0.8 0.7 Median duration (wks) (95% CI): 30.6 (20.6, 40.6) vs 13.6 (9.1, 54.9) Log-rank P value 0.0629 Hazard ratio (95% CI): 0.467 (0.203, 1.073) 0.6 0.5 0.4 0.3 0.2 Probability of RBC-TI 0.1 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Longest duration of RBC-TI for patients achieving RBC-TI ≥8 weeksa (week) a During indicated treatment period. Patients who maintained RBC-TI at the time of analysis are censored.

  32. MEDALIST TrialSecondary Endpoint Achieved: Erythroid Response (HI-E) a Defined as the proportion of patients meeting the HI-E criteria per IWG 2006 criteria1 sustained over a consecutive 56-day period during the indicated treatment period. b Luspatercept compared with placebo, Cochran-Mantel-Haenszel test. Cheson B, et al. Blood. 2006;108:419-425.

  33. MEDALIST Trial: Safety Summary a In luspatercept arm: sepsis (2), multiple organ dysfunction syndrome, renal failure, hemorrhagic shock; in placebo arm sepsis, urosepsis, general physical health deterioration, respiratory failure TEAE=treatment-emergent adverse event

  34. MEDALIST TrialSafety: TEAEs and Serious TEAEs Overall for thromboembolic events were no significant differences between luspatercept and placebo arm. ALT=alanine aminotransferase

  35. MEDALIST Trial: Conclusions • Luspatercept treatment was well tolerated and yielded a significantly higher proportion of patients who achieved RBC-TI or HI-E (major RBC transfusion reduction, Hb increase) compared with placebo in LR-MDS-RS patients (P<0.0001) • Erythroid responses are durable, with 40% of patients achieving RBC-TI sustained at 12 months of treatment • Luspatercept is a promising novel therapy for the treatment of patients with lower-risk MDS-RS with RBC transfusion-dependent anemia IPSS-R=Revised International Scoring System

  36. Background: MDS and Imetelstat imetelstat NPS oligonucleotide • Patients with TD LR-MDS that has relapsed or is refractory to ESA therapy have limited treatment options • Higher telomerase activity, expression of hTERT and shorter telomeres predict for shorter overall survival in lower-risk MDS • Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomere lengths and active telomerase and has clinical activity in myeloid malignancies1-3 • FDA granted Fast-Track designation for LR-MDS (Oct 2017) • IMerge is an ongoing global phase 2/3 study of imetelstat in RBC TD patients with LR-MDS (IPSS Low or Int-1) • Part 1 consists of an open-label, single-arm design with single-agent imetelstat treatment • Preliminary results have been presented for the first 32 enrolled patients4 lipid tail Imetelstat binds to RNA template of telomerase X telomere Prevents binding by and maintenance of telomeres Htert=human telomerase reverse transcriptase; IPSS=International Prognostic Scoring System; Int-1= Intermediate-1; TD=transfusion dependent • 1Baerlocher GM, et al. N Engl J Med. 2015;373:920-928. 2Tefferi A, et al. N Engl J Med. 2015;373:908-919. 3Tefferi A, et al. Blood Cancer J. 2016;6:e405.4Fenaux P, et al. HemaSphere. 2018;2(S1):S1557 [oral presentation].

  37. Imetelstat Treatment Leads to Durable Transfusion Independence in RBC Transfusion-Dependent, Non-Del(5q) Lower Risk MDS Relapsed/Refractory to Erythropoiesis-Stimulating Agent Who Are Lenalidomide and HMA Naive David P. Steensma, MD1, Uwe Platzbecker, MD2, Koen Van Eygen, MD3, Azra Raza, MD4, Valeria Santini, MD5, Ulrich Germing, MD, PhD6, Patricia Font, MD7, Irina Samarina, MD8, Maria Díez-Campelo, MD, PhD9, Sylvain Thepot, MD10, Edo Vellenga, MD11, Mrinal M. Patnaik, MD, MBBS12, Jun Ho Jang, MD, PhD13, Jacqueline Bussolari, PhD14, Laurie Sherman, BSN15, Libo Sun, PhD14, Helen Varsos, MS, RPh14, Esther Rose, MD14 and Pierre Fenaux, MD, PhD16 1Dana-Farber Cancer Institute, Boston, MA; 2Department of Medicine, University Hospital Carl Gustav Carus, TU Dresden, Dresden, Germany; 3Algemeen Ziekenhuis Groeninge, Kortrijk, Belgium; 4Columbia University Medical Center, New York, NY; 5MDS Unit, AOU Careggi-University of Florence, Florence, Italy; 6Klinik für Hämatologie, Onkologie and Klinische Immunologie, Universitätsklinik Düsseldorf, Heinrich-Heine-Universität, Düsseldorf, Germany; 7Department of Hematology, Hospital General Universitario Gregorio Marañon, Madrid, Spain; 8Emergency Hospital of Dzerzhinsk, Nizhny Novgorod, Russian Federation; 9Hematology Department, The University Hospital of Salamanca, Salamanca, Spain; 10CHU Angers, Angers, France; 11Department of Hematology, University Medical Center Groningen, Groningen, Netherlands; 12Division of Hematology, Mayo Clinic, Department of Internal Medicine, Division of Hematology, Rochester, MN; 13Department of Hematology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, Republic of (South); 14Janssen Research & Development, LLC, Raritan, NJ; 15Janssen Research & Development, LLC, Spring House, PA; 16Hôpital Saint-Louis, Université Paris Diderot, Paris, France This study was funded by Janssen Research & Development LLC and Geron Corporation

  38. Background: IMerge (Part 1) Study Design1 Patients with MDS • IPSS Low or Int-1 • Relapsed / refractory to ESA or ineligible for ESA • Transfusion dependent (≥4u RBC/8 wks) • ANC ≥1.5 x 109/L • Platelets ≥75 x 109/L Imetelstat Treatment 7.5 mg/kg IV q4w (2-hr infusion) single arm open label Pre-medication: diphenhydramine, hydrocortisone 100-200 mg (or equivalent) Supportive care: RBC transfusions, myeloid growth factors per local guidelines 1o Endpoint: 8-Week RBC TI 2o Endpoints: 24-Week RBC TI / Time to TI / TI duration / TR (HI-E: Transfusion Reduction by ≥4 RBC units over 8 weeks) / MDS response per IWG / Overall survival / Incidence of AML / Safety Exploratory: telomerase activity / hTERT / telomere length / genetic mutations • 1Fenaux P, et al. HemaSphere. 2018;2(S1):S1557 [oral presentation].

  39. IMerge: Longest Transfusion-Free Interval 150 Treatment Group: Imetelstat (N=38) 125 100 75 Longest Transfusion Free Interval (Weeks) 50 25 24 8 Among the patients achieving durable TI, all showed a Hb rise of ≥3.0 g/dL compared to baseline during the transfusion-free interval 0 Patients No response 24-week TI 8-week TI HI-E (TR) HI-E=hematologic improvement-erythroid; TI= transfusion independence; TR=transfusion reduction

  40. IMerge: Hemoglobin and Imetelstat Dosing Among Patients with Durable TI ) L 100 / g ( b g 50 H 0 -2 3 7 11 15 19 23 27 31 35 39 43 47 51 55 59 63 67 71 75 79 83 87 91 95 99 103 107 111 115 Hemoglobin Levels (g/L) ) 100 L 6 units / g ( b 50 g H 0 115 -2 3 7 11 15 19 23 27 31 35 39 43 47 51 55 59 63 67 71 75 79 83 87 91 95 99 103 107 111 6 units 150 ) L Prior 8-week RBC Transfusion Burden / 100 g ( b g 50 H 0 98 -3 2 6 10 14 18 22 26 30 34 38 42 46 50 54 58 62 66 70 74 78 82 86 90 94 11 units ) 100 L / g ( b 50 g H 0 71 -2 2 5 8 11 14 17 20 23 26 29 32 35 38 41 44 47 50 53 56 59 62 65 68 4 units

  41. IMerge: Most Common Treatment-Emergent Adverse Events 25 2 1 20 • 19 patients (50%) had dose reductions and 26 patients (68%) had cycle delays • Reversible grade 3 LFT elevations were observed in 3 (8%) patients on study • Independent Hepatic Review Committee, considered these not drug-related 15 Grade 1-2 Events Number of patients with ≥1 TEAE 23 Grade ≥3 Events 21 10 2 0 5 2 3 5 7 7 5 6 6 6 6 4 3 2 1 0 0 0 0 0 Anemia Diarrhea Back pain Headache Bronchitis Leukopenia Neutropenia AST increased ALT increased Nasopharyngitis Peripheral edema Thrombocytopenia Most common TEAEs

  42. Conclusions: Overall Efficacy and Safety • In this cohort of 38 non-del(5q) LR-MDS patients with a high RBC transfusion burden who were ESA relapsed/refractory and naïve to lenalidomide/HMA, single-agent imetelstat yielded: • 8-week TI rate of 37% • 24-week TI rate of 26% • 24-week TI responses were accompanied by Hb rise by 3.0 g/dL • Median duration of TI was not reached • HI-E rate of 71% • Side effects were limited, mainly cytopenias that were both predictable, manageable, and reversible

  43. A Phase II Study of Nivolumab or Ipilimumab with or without Azacitidine for Patients with Myelodysplastic Syndrome Guillermo Garcia-Manero, Koji Sasaki, Guillermo Montalban-Bravo, Naval G. Daver, Elias J. Jabbour, Yesid Alvarado, Courtney D. DiNardo, Farhad Ravandi, Gautam Borthakur, Prithviraj Bose, Naveen Pemmaraju, Kiran Naqvi, Jorge E. Cortes, Tapan M. Kadia, Marina Y. Konopleva, Simona Colla, Hui Yang, Caitlin R. Rausch, Yvonne Gasior, Carlos E. Bueso-Ramos, Rashmi Kanagal-Shamanna, Keyur P. Patel, Hagop M. Kantarjian Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX

  44. ICPI in MDS: Treatment

  45. ICPI in MDS: Patient Characteristics

  46. ICPI in MDS: Response Rates • Not evaluable: 3 patients • Median number of cycles: 4 (range 1-29) • Median number of cycles to response: 3 (range 1-15)

  47. ICPI in MDS: Toxicities • Other G3/4: AKI, 2 in Ipi; hemolysis, 1 in Ipi; colitis, 1 in Nivo • Grade 2 hypophysitis: 1 in Ipi, Ipi+AZA, and Nivo+AZA, respectively

  48. PD-L1 Blockade with Atezolizumab in Higher-Risk Myelodysplastic Syndrome: An Initial Safety and Efficacy Analysis Aaron T Gerds,1 Bart L Scott,2 Peter Greenberg,3 Samer Khaled,4Tara L Lin,5 Daniel A Pollyea,6 Amit Verma,7 Monique Dail,8Cherie Green,8 Connie Ma,8Bruno C Medeiros,8 Patrick Phuong,8 Michael Wenger,9 Mark Yan,10 William Donnellan11 1Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA; 2Fred Hutchinson Cancer Research Center, Seattle, WA, USA;3Stanford Cancer Institute, Stanford, CA, USA; 4City of Hope, Duarte, CA, USA; 5University of Kansas Medical Center, Kansas City, KS, USA; 6University of Colorado School of Medicine, Aurora, CO, USA; 7Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, NY, USA; 8Genentech, Inc., South San Francisco, CA, USA; 9F. Hoffmann-La Roche Ltd, Basel, Switzerland; 10Hoffmann-La Roche Ltd, Mississauga, ON, Canada; 11Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA

  49. Phase Ib trial in HMA-failure and HMA-naive patients with higher-risk MDS (NCT02508870) *21-day cycle; †28-day cycle Study Design COHORT B1 (N=11) INDUCTION Atezo 840 mg IV q2w +AZA 75 mg/m2 SC D1−7 q4w for up to 6 cycles† MAINTENANCE Atezo 1200 mg IV q3w for up to 8 cycles* R/R MDS COHORT A2 Atezo (as Cohort A1) COHORT A1 (N=10) Atezo 1200 mg IV q3w for up to 17 cycles* R COHORT B2 Atezo + AZA (as Cohort B1) COHORT C2 (N=15) Atezo + AZA (as Cohort C1) COHORT C1 (N=6) Atezo 840 mg IV q2w +AZA 75 mg/m2 SC D1−7 q4w until loss of clinical benefit† 1L MDS

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