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- Title
MDS-158: Updated Safety and Efficacy of Venetoclax in Combination with Azacitidine for the Treatment of Patients with Treatment-Naïve, Higher-Risk Myelodysplastic Syndromes: Phase 1b Results.
- Authors
Wei, Andrew H.; Garcia, Jacqueline S.; Borate, Uma; Chun Yew Fong; Baer, Maria R.; Nowak, Daniel; Peterlin, Pierre; Jurcic, Joseph; Jacoby, Meagan A.; Platzbecker, Uwe; Odenike, Olatoyosi; Cunningham, Ilona; Ying Zhou; Hoffman, David; Hogdal, Leah; Naqvi, Kiran; Kye, Steve; Garcia-Manero, Guillermo
- Abstract
Venetoclax (Ven), a selective oral BCL-2 inhibitor, demonstrated synergy with azacitidine (Aza) in patients with higher-risk myelodysplastic syndromes (HR-MDS). We report updated safety and efficacy in an ongoing phase 1b study (NCT02942290) evaluating Ven+Aza for treatment-naïve HR-MDS patients. Patients (≥18yrs) with International Prognostic Scoring System (IPSS) intermediate-2 or high-risk MDS, bone marrow (BM) blasts <20% at baseline, and ECOG≤2 performance status were enrolled. Aza 75 mg/m2 was administered on Days (d) 1–7 of each 28-d cycle. Initial Ven dose was 400 or 800 mg daily in 28-d cycles. Due to poor tolerance, the study was amended to examine several dose cohorts (100, 200, and 400 mg x 14-d each 28-d cycle). Primary objectives were assessing Ven+Aza safety profile and establishing RP2D. Key secondary objectives included overall response rate (ORR) and overall survival (OS). At data cutoff (Dec. 15, 2020), 78 patients received Ven+Aza (51 at RP2D 400 mg x 14 d), with median follow-up time of 23 mos. Median age was 70 yrs; 72% male; 90% had excess BM blasts (>5 to 10%, n=21; >10 to 20%, n=49). Grade 3/4 neutropenia (59%) or thrombocytopenia (33%) were present at baseline. All patients experienced ≥1 treatment-emergent adverse event (TEAE), the most common being neutropenia (83%), nausea (55%), and constipation (54%); 96% experienced grade 3/4 TEAEs, with neutropenia (82%), febrile neutropenia (49%), and thrombocytopenia (42%) being most common. Neutropenia (49%), including febrile neutropenia (45%), was the most common serious TEAE. The 30-d mortality rate after first dose was 1%. Intention-to-treat ORR was 80%, including complete remission (CR,40%) and marrow CR (mCR, 40%); 42% mCR had hematologic improvement; no partial remissions recorded. For 31 CR patients, median time to CR and median duration of response was 2.6 and 13.8 mos (95% CI 8.9,–), respectively. Post-baseline transfusion independence rate (defined as no transfusion ≥8 weeks), for patients transfusion-dependent for RBC and/or platelets at baseline, was 46.5%. Median OS was 28.2 mos (95% CI 17.7, –). Median OS for 31 patients achieving CR was 28.6 mos (95% CI 27.5, –). Twenty-three percent moved on to post-study allogeneic HSCT (including BM and peripheral blood stem cells). The combination of Ven+Aza was associated with rapid and durable response, promising efficacy, including remission rates and OS, and an acceptable safety profile for patients with HR-MDS. Additional correlation with disease risk features, including TP53 mutations, will be presented.
- Publication
Clinical Lymphoma, Myeloma & Leukemia, 2021, Vol 21, pS343
- ISSN
2152-2650
- Publication type
Article
- DOI
10.1016/S2152-2650(21)01798-5