Abstract
Context: In MDS, hypomethylating agents (HMA) remain the standard of care. ASTX727, an oral fixed dose combination of HMA decitabine (35mg) and cytidine deaminase inhibitor cedazuridine (100mg), was recently approved in the US for the treatment of MDS and CMML. Venetoclax (Ven), an orally bioavailable BCL-2 inhibitor in combination with azacitidine has shown preliminary clinical activity in treatment-naïve, higher risk MDS. Objective: To evaluate a total-oral regimen of Ven+ASTX727 combination in pts with higher risk MDS or CMML. Settings/Participants: This single arm Phase I/II study of orally administered ASTX727 in combination with Ven (NCT04655755) is enrolling patients ≥18 years with treatment-naïve, higher risk MDS (intermediate-2- or high-risk categories) per IPSS or CMML with excess blasts ≥5%. Intervention: ASTX727 is administered orally daily on D1-5 and Ven is administered orally daily on D1-14 of 28-d cycles. Main Outcome Measures: The primary objective is to determine the safety and tolerability (phase 1) and overall response rate (ORR, defined as CR+mCR) (phase 2) of Ven+ASTX727 combination. Results: 19 pts have been enrolled to date with a median age of 72 years (range 54-94) with 16 pts aged ≥65 years. These patients had a median bone marrow blast count of 12% (range 6-15%) and harbored a median number of 4 (range 1-9) mutations. Most pts had adverse risk mutations such as ASXL1 (58%) and RUNX1 (42%). There were no deaths during the 30-day and 60-day window. No tumor lysis syndrome was observed. The ORR was 95% with 3 pts achieving CR (16%) and 15 pts achieving marrow CR (79%). All pts achieved a response within 1 cycle among which 7 pts, including one with TP53mut, proceeded to hematopoietic stem cell transplant. At a median follow up of 5.9 months, the median duration of response was not reached (range 0.9-11.1 months), and the median overall survival was not reached (range 1.0-12.1 months). Conclusions: Ven+ASTX727 combination appears safe and demonstrates preliminary efficacy in pts with higher risk MDS or CMML with excess blasts. Total-oral regimen of Ven+ASTX727 combination appears to be a promising strategy for high-risk MDS or CMML pts.