Emerging Treatment Options for Myelodysplastic Syndromes

Transcription

1 Emerging Treatment Options for Myelodysplastic Syndromes James K. Mangan, MD, PhD Assistant Professor of Clinical Medicine Abramson Cancer Center, University of Pennsylvania Please note that some of the studies reported in this presentation were presented as an abstract and/or presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

2 MDS Epidemiology and Diagnosis Diverse group of clonal hematopoietic stem or progenitor cell disorders characterized by ineffective hematopoiesis, dysplastic cell morphology, and potential for clonal evolution MDS is a malignancy. BMBx and aspirate necessary for diagnosis Must exclude non-mds causes of cytopenias in presence of some combination of dysplasia, increased marrow blasts, or karyotypic abnormality. 30,000 to 40,000 new cases per year in US

3 Therapeutic algorithm for adult patients with primary MDS and intermediate-1 IPSS score. Luca Malcovati et al. Blood 2013;122: by American Society of Hematology

4 Treatment algorithm for patients with higher-risk MDS. Mikkael A. Sekeres, and Corey Cutler Blood 2014;123: by American Society of Hematology

5 IPSS-R (Blood 120:2454, 2012) Improvements over IPSS: -DATA from 7000 MDS pts -5 cytogenetic risk groups (compared to 3) -Severity and type cytopenia taking into account -5 Risk groups; age accounted for -Validated to be effective in treated pts (AJH. 2013;88; )(Blood. 2012; 120(25) ) -Correlates better with outcome (IPSS, WPSS) in one study Voso et al, J Clin Oncol 2013, MDS Gruppo, n=380

6 Prognosis: IPSS-R

7 Somatic mutation in any of the 5 genes (TP53, EZH2, RUNX1, ASLX1, or ETV6) shown in Bejar et al, NEJM 364, 2011 to have prognostic significance independent of the International Prognostic Scoring System (IPSS) identifies patients from that same cohort with shorter overall survival than predicted by the IPSS-R for the 3 lowest IPSS-R risk groups. Bejar R, and Steensma D P Blood 2014;124: by American Society of Hematology

8 IPSS-Rm ASH abstract , Aziz Nazha Et al. 508 patients. Three genes were found to be prognostic: EZH2, p53, SF3B1.

9 2015 by American Society of Hematology Rafael Bejar et al. Blood 2015;126:907

10 2014 by American Society of Hematology Bejar R et al. Blood 2014;124:532

11 Therapies for Lower Risk MDS ESAs: Work well in patients with low transfusion Requirements (<2 units PRBCs/month) and EPO level (<500): 74% response rate. Work poorly in patients with high transfusion Requirements and EPO >500: 7% response rate (Hellstrom- Lindberg et al, BJH 120, 2003). Also clearly inferior responses in higher risk disease.

12 Therapies for Lower Risk MDS Luspatercept (ACE-536): SMAD inhibitor Giagounidis et al, Blood 126: 92, 2015 Phase II PACE-MDS Extension Study 22 patients evaluable, 9 low transfusion burden (<4 units/8 weeks), 13 high transfusion burden (>4 units/8 weeks) Dosing is subcutaneous injection q 3 weeks, at about 1 mg/kg 8/9 Low transfusion patients had erythroid reponse, with median 1.5 g/dl increase In Hbg that lasted for median of 17 weeks 10/13 patients had reduction of > or = 4 transfusion units over 8 weeks and 6 pts achieved transfusion independence and were still on drug as of ASH 2015 No grade 3 or higher AEs.

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14 Can We Beat Vidaza??? Phase II study, SWOG S1117, 277 patients: AZA ALONE VS AZA + LEN VS AZA + VORINOSTAT No winner. Combination arms associated with Increased AEs (NTPc fever, GI sx, rash) Update at ASH: CMML patients did better on AZA + LEN arm compared to Vidaza alone (63% vs 29%), p =.04 Sekkeres et al, ASH abstract 908, 2015

15 Additional Up-Front Therapies: Dacogen vs Dacogen/Carboplatin vs Dacogen/ATO: 10/14 Dac/ATO patients responded (mix of MDS and AML) Kropf PL et al, ASH abstract 3775, 2015 AZA + oral Rigosertib in Up front and HMA failure: 65% of 20 evaluable patients in the phase II study had marrow Complete Responses. Main side effects were nausea and fatigue. Navada SC et al, ASH abstract 910, AZA + Pracinostat vs AZA + Placebo: No improvement with this novel HDAC inhibitor but there was early discontinuation due to AEs. Activity in AML though. Garcia-Manero et al, ASH abstract 911, 2015

16 Patients with MDS for whom hypomethylating agents have failed have poor outcomes overall. Bejar R, and Steensma D P Blood 2014;124: by American Society of Hematology

17 Garcia-Manero G et al. Blood 2014;124: by American Society of Hematology

18 After Hypomethylating Failure Large Randomized Phase III of Rigosertib versus Placebo: OS 8.2 months with rigosertib and 5.8 months for placebo, p =.27 (Raza et al, abstract 7031, ASCO 2013).

19 Additional Therapeutics after Hypomethylating Agent Failure Sapacitabine: 63 patients with median age 73 with 6-19% BM blasts achieved CR rates of around 10-20% depending on dosing scheme. Overall survival around 9 months after hypomethylating agent failure (Garcia-Manero G, Luger SM et al, ASH abstract 2752, Clofarabine and low dose cytarabine: clofarabine 15 mg/m 2 IV daily for 5 days (days 1-5) and cytarabine 20 mg SC twice daily for 7 days (days 1-7). Responding patients proceeded with consolidation therapy with clofarabine 15 mg/m 2 IV daily for 3 days (days 1-3) and cytarabine 20 mg SC twice daily for 5 days (days 1-5) every 4 weeks for a maximum of 12 cycles. 52 patients treated, CR rate 17%, ORR 48%. Median survival around 7 months (Jabbour et al, abstract 534, ASH 2014). SGI-110: Similar to Dacogen. Phase I has been published, 13% CR, 27% HI. O Connell et al, Haematologica, 98, 2013.

20 Clinical Trials for MDS Open At Penn BET inhibitor (Constellation, CPI-0610), phase I dose escalation study, MDS is eligible after failure of HMA Monotherapy with Exjade (AML that has not been treated intensively or MDS IPSS 1.5 or higher with progression/lack of response to hypomethylating Agents) investigator initiated trial by J. Mangan, research funding provided by Novartis

21 Clinical Trials for MDS Open at Penn ECOG 2905: Lenalidomide vs Lenalidomide plus EPO in patients with transfusion dependent low risk MDS and prior EPO failure or poor EPO response profile. Oral Vidaza: A phase 3 multicenter, randomized, doubleblind study to compare the efficacy and safety of oral azacitidine plus best supportive care vs placebo plus best supportive care in subjects with red blood cell transfusion-dependent anemia and thrombocytopenia due to IPSS lower- risk MDS.

22 Clinical Trials for MDS Open at Penn BMT-CTN 1102: Hypomethylating agent/best supportive care versus reduced intensity conditioning allo SCT for MDS ages IPSS 1.5 or greater. *Observational only *Biological randomization based on presence or absence of matched sibling or 10/10 unrelated donor.

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