A Phase 1b Study Evaluating the Safety and Efficacy of Venetoclax in Combination with Azacitidine for the Treatment of Relapsed/Refractory Myelodysplastic Syndrome

Background Patients (pts) with relapsed/refractory (RR) higher-risk myelodysplastic syndrome (MDS) have a median overall survival (OS) of less than 6 months. No standard of care exists for these pts. Over-expression of the anti-apoptotic protein BCL-2 in MDS has been implicated in disease progression and drug resistance. Venetoclax (Ven) is a selective, potent, orally bioavailable BCL-2 inhibitor that in combination with azacitidine has been shown to improve overall survival in older or co-morbid pts with newly-diagnosed acute myeloid leukemia.

Aims Here we present an updated analysis of the safety and efficacy of Ven in combination with the HMA azacitidine (Ven+Aza) for the treatment of pts with RR-MDS.

Methods This ongoing phase 1b, open-label, multicenter study (NCT02966782) is evaluating the safety and efficacy of either Ven monotherapy or Ven+Aza combination therapy. Pts enrolled and treated with Ven+Aza were ≥18 years with RR-MDS and had Eastern Cooperative Oncology Group scores ≤2. Pts were excluded if they had myelodysplastic/myeloproliferative neoplasms, had received prior therapy with a BH3 mimetic, or had undergone allogeneic hematopoietic stem cell transplantation or solid organ transplantation. Pts were treated with escalating oral doses of Ven:100, 200, or 400 mg daily for 14 days every 28-day cycle. Aza was administered at 75 mg/m²/day for the first 7 days every cycle. Responses were recorded using the modified International Working Group 2006 criteria. Mutation status was determined in the peripheral blood of 32 (84%) pts by targeted next-generation sequencing.

Results As of August 30, 2019, 38 pts were treated with Ven+Aza [male 84%, median age 74 years (range 44–91)]. Pts received a median of 8 cycles (range 2 – 72)] or prior treatment with an HMA and 63% (24/38) received either RBC or platelet transfusion within 8-weeks prior to first dose of Ven. Fourteen genes were found mutated in ≥ 5%, including TP53, RUNX1, ASXL1, STAG2, and U2AF1. Median follow-up time was 6.8 months (range 0 – 16.6). Common grade 3 or 4 adverse events (AEs) occurring in ≥15% pts were neutropenia (50%), thrombocytopenia (42%), leukopenia (39%), febrile neutropenia (29%), anemia (16%), and pneumonia (16%). Other AEs included low grade constipation (39%) and diarrhea (34%). Serious AEs in >2 pts were febrile neutropenia (n=9) and pneumonia (n=6). Fourteen (37%) pts discontinued the study. Two pts died ≤30 days of first Ven dose and 1 pt died >30 days and ≤60 days of first Ven dose. Thirty-seven pts were response evaluable. Complete remission (CR) + marrow CR (mCR) was 40%, observed in 15 pts (CR 3, mCR12) (Figure). Hematological improvement (HI) was achieved by 25% (9/36) and mCR+HI was achieved by 42% (5/12). Transfusion independence was achieved by 34% (13/38) in either RBC or platelet with median duration of 4.1 months (range 2 – 7). Of 13 pts who completed 4 cycles of Ven+Aza, 9 achieved CR/mCR. Median time to response for CR+mCR was 1.2 months (range 0.7 – 6.3). Overall, median progression free survival (PFS) was 9.1 months (95% CI 5.9 –not estimable) and 12-month OS estimate was 65% (95% CI 37 – 83). Among pts who obtained mCR, median PFS was 10.1 months (95% CI 5.4 – not estimable) and the 12-month estimate of OS was 78% (95% CI 37–94).

Conclusion Ven+Aza combination therapy was well tolerated in pts with RR-MDS and the AEs were manageable. The CR+mCR of 40% and estimated 12-month OS of 65% with Ven+Aza is encouraging. Updated analyses on safety, efficacy, biomarker analyses including associations of genetic mutations and BCL-2 family members expression with clinical outcomes will be presented.

Abstract was previously published at EHA25