A Phase I Study of the Combination of Venetoclax and Azacitidine in Relapse/Refractory Higher Risk Myelodysplastic Syndrome (MDS)

Background: The prognosis of patients with HMA refractory MDS is poor with a median OS of 6 months. [Lancet Oncology Apr 2016] The combination of Azacitidine and the Bcl-2 inhibitor Venetoclax has shown significant activity in patients with previously untreated higher risk MDS (Garcia et. al ASH 2019). We hypothesize that addition of venetoclax to Azacitidine will improve outcomes of R/R higher risk MDS.

Methods: The phase I study (NCT04550442) is enrolling patients aged ≥ 18 years with adequate organ function, higher risk MDS with ≥5% blasts, and R/R to HMA therapy. Patients who are R/R to HMA therapy include those who progressed on HMA after 4 cycles or those who had an initial response with subsequent relapse. Prior BCL2 inhibitor therapy and patients with lower risk disease per IPSS-R were excluded. Azacitidine was administered on Days 1-5 at a dose of 75mg/m² IV. Venetoclax was administered daily on days 1-14. Cytoreduction was permitted to lower the white count to ≤ 10,000/µl prior to initiation of venetoclax. A 3+3 study design was applied to the regimen as demonstrated in Table 1. Doses were adjusted based on toxicity and concomitant CYP3A4 inhibitors.

Results: Ten patients have been enrolled in this study to date. Baseline characteristics are shown in Table 2. In this entire cohort, the median age was 77 years (range 67 – 81) with a median bone marrow blast of 9%. The entire cohort was enriched with adverse risk mutations such as ASXL1(60%), TP53(40%), and RUNX1(30%) with a median number of 3 mutations (range, 2-12). Median hemoglobin was 7.5mg/dL, median platelet count was 40.5K/µL, median absolute neutrophil count (ANC) of 1.05K/µL, Cr 0.98mg/dL , and Bili 0.5mg/dL.

No new safety signals were observed. No tumor lysis syndrome was observed. The most common grade ≥ 3 adverse events were cytopenias, predominantly neutropenia (40%) and thrombocytopenia (20%) that did not warrant dose reduction of venetoclax.

Among the 10 patients enrolled, 1 patient is too early for response assessment. Among the 9 evaluable patients, the overall response rate (ORR) was 56%(n=5) with 1 patient achieving complete remission (CR) and 4 patients with marrow CR. All 3 nonresponders harbored TP53 mutation of which 2 had therapy related MDS. Among the responders, the responses were durable with a median duration of response not reached.

Among the 10 patients, the 5 responders remain on therapy, one non-responder was switched to a different therapy, one patient died on day 58 due to pneumonia, and 1 patient each died due to sepsis and refractory disease respectively. At a median follow up of 5.5 months, the median overall survival was 7.1 months (range 1-9.5 months) (Figure 1). The 4- and 8-week mortality was 0% and 10% (n=1) respectively

Conclusion: This study in higher risk patients with R/R MDS suggests potential benefit with the addition of Venetoclax to HMA with a 55% overall response and an OS of 7.1 months. TP53 and complex karyotypes still confer poor prognosis despite the addition of Venetoclax.