Overview. Myelodysplastic Syndromes: What s on the Horizon? Molecular Mutations in MDS. Refining Risk Models. Incorporating Mutational Data

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1 Myelodysplastic Syndromes: What s on the Horizon? Vu H. Duong, MD, MS Assistant Professor of Medicine University of Maryland July 16, 2016 Overview Refining Risk models Specific Therapeutic Areas of Need New agents in lower-risk disease Optimizing hypomethylating agents in higher-risk disease Treatment options after failure/progression on hypomethylating agents Molecular Mutations in MDS Refining Risk Models 5 mutations independently associated with poor prognosis: TP53 RUNX1 EZH2 ASXL1 ETV6 Bejar R, NEJM 2011 None of the 4 major risk models incorporate molecular data/mutations No consensus on how to combine clinical data with molecular data to risk-stratify patients 508 patients evaluated at the Cleveland Clinic retrospectively analyzed In multivariate analysis: age, IPSS-R score, EZH2, SF3B1 and TP53 mutations were significantly associated with survival Nazha A, Leukemia

2 Characteristic Total (n=508) Training Cohort (n=333) Validation Cohort (n=175) Median Age (y) Males 62% 62% 63% WBC, 10 9 /L (median) ANC, 10 9 /L (median) Hemoglobin, g/dl (median) Platelets, 10 9 /L (median) IPSS-R Category (%) Very Low Low Intermediate High Very High MDS diagnosis (%) De novo MDS Secondary MDS Nazha A, Leukemia 2016 Training Cohort C-Index: 0.67 IPSS-R Validation Cohort C-Index: 0.57 New Molecular Risk Model Therapeutic Areas of Need All currently available therapies have their flaws Lower-risk disease: Anemia after failure of erythropoiesis-stimulating agents Severe thrombocytopenia Training Cohort C-Index: 0.73 Validation Cohort C-Index: 0.65 Higher-risk disease: Improving upon the standard of care: hypomethylating agents Options after progression on hypomethylating agents Lower-Risk Disease Outcomes after ESA failure No response/relapse within 6 months 3-yr incidence of AML (%) Median Overall Survival (months) Relapse after 6 months Kelaidi C, Leukemia

3 Lenalidomide Phase II trial with 214 patients Low or int-1 risk by IPSS Transfusion-dependent anemia No del(5q) Overall response rate 43% 26% achieved RBC transfusion-independence 17% with 50% reduction in transfusions Few cytogenetic responses Lenalidomide Randomized Phase III Trial 239 patients with MDS Low or int-1 risk by IPSS, no del(5q) Transfusion-dependent anemia Ineligible for or refractory to ESAs Randomly assigned (2:1) to treatment with lenalidomide or placebo Raza A et al, Blood 2008;111:86-93 Santini V, JCO 2016 Lenalidomide Lenalidomide Transfusion independence 8 weeks achieved in 26.9% on lenalidomide vs. 2.5% on placebo 90% of patients who achieved RBC-TI responded within 16 weeks Santini V, JCO 2016 Santini V, JCO 2016 Epoetin with Lenalidomide Epoetin with Lenalidomide Hem Improvement Transf Independent Len (n=65) Len + Epo (n=66) P 23.1% 13.8% 39.4% 24.2% Response Duration 18.1 mo 15.1 mo 0.47 Venous Thrombosis Predictors of response: Baseline EPO <100 IU/L Presence of G polymorphism of CRBN Toma A, Leukemia 2016 Toma A, Leukemia

4 Erythropoietin Phase II extension study in IPSS-defined lower risk MDS with anemia Epo > 500 U/L or ESA refractory/intolerant/ unavailable No prior hypomethylating agent Giagounidis A. ASH 2015, #92 Thrombopoetin Agonists Kuter DJ. Cancer

5 Romiplostim Randomized phase II study in patients with low or int-1 risk MDS by IPSS Platelets < 20 x 10 9 /L or 20 x 10 9 /L with a history of bleeding CS bleeding events/patient Plt transfusion units/100 pt-years Romiplostim Placebo P <0.001 HI-P 36.5% 3.6% <0.001 Romiplostim Trial was stopped in 2011 due to increased progression to AML At interim analysis: romiplostim 6.0%, PBO 2.4% Beyond 58 wks Romiplostim Placebo HR AML 6% 4.9% 1.20 Death 18% 20.5% 0.86 * Of 14 patients who progressed to AML, 9 had baseline RAEB-1 or RAEB-2 Giagounidis A et al. ASH Annual Meeting 2011, #117 Giagounidis A et al, Cancer 2014 Eltrombopag Oral Agent Binds to TPO-R at the transmembrane domain Eltrombopag Randomized phase II study in patients with low or int-1 risk MDS by IPSS Platelets < 30 x 10 9 /L Naive to TPO-R agonists Does NOT compete with TPO for receptor binding Eltrombopag Doses up to 300mg daily At 12 weeks: Eltrombopag n=46 Placebo n=24 Mean plt increase 53.2 Gi/L NS Responses 23 (50%) 2 (8%) Progression 5 (11%) 2 (8%) Median Time to Response: 14 days Also improved fatigue Oliva EN. ASH 2015 #91 Oral Azacitidine (CC-486) Lower-risk by IPSS, RBC transfusion dependent and/or thrombocytopenic Parameter 14-day n=26 Phase III study accruing 21-day n=27 Total n=53 ORR 10/26 (38.5%) 8/27 (29.6%) 18/53 (34%) Any HI HI-E HI-P HI-N 6/26 (23.1%) 4/23 (17.4%) 4/17 (23.5%) 2/10 (20%) 7/27 (25.9%) 6/25 (24%) 2/15 (13.3%) 0/6 (0%) 13/53 (24.5%) 10/48 (20.8%) 6/32 (18.8%) 3/12 (25%) Marrow CR 0/7 (0%) 3/5 (60%) 3/12 (25%) Garcia-Manero G, ASH Annual Meeting

6 Low-Dose Hypomethylating Agents Low- or intermediate-1-risk MDS, CMML or MDS/MPN Azacitidine 75 mg/m 2 daily x 3 days or Decitabine 20 mg/m 2 daily x 3 days every 4 weeks 88 patients treated 30 patients (36%) received azacitidine 53 patients (64%) received decitabine Short NJ, ASH Annual Meeting 2015, #94 Low-Dose Hypomethylating Agents Overall response rate: 61% CR: 32 pts (39%) CRi: 11 (13%) Hematologic Improvement: 8 (10%) Median time to best response: 2.2 months Median duration of response not reached with 71% of responders still on study Well-tolerated with only 6 pts (7%) requiring dose reduction Short NJ, ASH Annual Meeting 2015, #94 Hypomethylating Agents Higher-risk Disease The Good Response rates are reasonable Well-tolerated The Bad Treatment is not curative Treatment is indefinite Can be given as an outpatient No FDA-approved options after failure, and patients fare poorly Predicting Response Encodes enzyme that converts 5-methylcytosine to 5- hydroxymethycytosine Leads to DNA demethylation Mutated in ~15% of MDS and AML Probability of Survival 1,8,6,4,2 0 Kaplan-Meier Graphe de Survie Cum. pour FU Variable censure : censureos Facteur : TET2spliceMUT Critère d inclusion : evaluables en réponse medullaire de Mutated WT Predicting Response OR, incl SD with HI Mutated, n=13 WT, n=73 P Value 11 (85%) 34 (47%) 0.01 OR 9 (69%) 23 (31%) 0.01 CR 5 (38%) 15 (21%) Time (months) No significant difference in OS or duration of response Itzykson R et al. Leukemia 2011; 25:1147 Bejar R et al. Blood

7 Azacitidine Combination Studies Drug Target Identifier Durvalumab (MEDI4736) PD-L1 NCT Nivolumab PD-1 NCT Ibrutinib BTK NCT Vosaroxin Topoisomerase II NCT Pevonedistat NEDD8 NCT Volasertib PLK-1 NCT Eltrombopag TPO-R NCT PF (Glasdegib) Hedgehog Pathway NCT Vadastuximab Talirine (SGN-CD33A) CD33 NCT Rigosertib PLK-1 NCT Sirolimus mtor NCT North American Intergroup Randomized Phase 2 MDS Study S1117 North American Intergroup Randomized Phase 2 MDS Study S1117 Overall Response Rate (%) Aza (n=92) Aza+Len (n=93) Aza+Vor (n=92) (p=0.45) 27 (p=0.16) CR/PR/HI (%) 24/0/13 21/1/22 17/1/9 ORR Duration Median (Range, months) 9 (1-26) 11 (2-31) 13 (1-32) CMML ORR (n=52) (p=0.04) 12 (p=0.4) CMML ORR Duration - Median (Range, months) 4 (1-26) 14 (2-31) 21 (1-32) Sekeres M et al. ASH 2015, #908 Sekeres M et al. ASH 2015, #908 Outcomes after HMA Failure Options After HMA Failure? NO STANDARD OF CARE - Clinical trial is preferred Institution No. of Patients Treated MDS & CMML Patients No. of HMA failures AML Progression Median OS (months) OS at 12 months MDACC 1 NR (29%) % GFM NR NR % Moffitt (20.3%) % 1. Jabbour E et al, Cancer 2010; 116: Prébet T et al, JCO 2011; 29: Duong VH, Clin Lymphoma Myeloma Leuk 2013;13:711 Prébet T et al, JCO 2011; 29:3322 7

8 Decitabine after Azacitidine MDACC prospective trial: 28% RR (3/14), median OS 6 months Univ. of Maryland experience: No responses in 25 patients with MDS or AML Median OS: 5.9 m Borthakur G, Leuk Lymphoma 2008 SGI-110 (Guadecitabine) Dinucleotide of decitabine and guanosine Longer half life Longer exposure time Protection from degradation Duong VH, Leuk Lymphoma 2014 SGI-110: Randomized Phase II SGI-110: Randomized Phase II Response Category Prev Treated (n=53) CR 2 (3.8%) mcr 15/34 (44%) HI 11 (20.8%) Garcia-Manero G, EHA 2016, Abstract P249 Rigosertib Binds to the Ras-binding domain of multiple kinases Inhibits signaling pathways controlled by PI3K and PLK (often activated in hematologic malignancies) Randomized, multicenter phase III trial in patients previously treated with azacitidine or decitabine Rigosertib vs. BSC Rigosertib (n=199) BSC (n=100) Number of deaths 161 (81%) 81 (81%) Median Survival (months) 95% Confidence Interval Stratified Hazard Ratio 95% Confidence Interval P-value Garcia Manero, G. Lancet Oncology

9 Rigosertib vs. BSC Rigosertib Acknowledgements Hematology Group: Maria Baer, MD Ashkan Emadi, MD, PhD Arnob Banerjee, MD, PhD Jennie Law, MD Seung Tae Lee, MD Ronald Gartenhaus, MD Ann Zimrin, MD Ashraf Badros, MD Hakan Kocoglu, MD BMT: Aaron Rapoport, MD Nancy Hardy, MD Jean Yared, MD Saul Yanovich, MD Hematopathology: Zeba Singh, MBBS Madhurima Koka, MD, PhD All of our fantastic nurses and staff And to all of our patients!!! 9