Phase I/II Combination Study of Azacitidine and Venetoclax Post Hypomethylating Agents Failure in High Risk MDS and CMML

Keywords: High risk MDS, venetoclax , Hypomethylating agent failure , overall response rates (ORR) Introduction: Therapies beyond hypomethylating agents (HMA) such as azacitidine, and decitabine are needed in high-risk myelodysplastic syndromes (HR-MDS). Venetoclax is an orally bioavailable small molecule B-cell leukemia/lymphoma 2 protein (BCL-2) inhibitor that binds to BCL-2, an antiapoptotic protein, ultimately inducing cellular apoptosis. It has been shown to possess synergistic activity with hypomethylating agents in unfit acute myeloid leukemia (AML) patients and HMA naïve HR-MDS patients. We therefore aimed to evaluate the safety, tolerability, and preliminary activity of azacitidine combined with venetoclax for HMA pretreated and relapsed or refractory high-risk myelodysplastic syndromes or chronic myelomonocytic leukemia (CMML). Study Design and Methods: We conducted a single centered, phase I/II trial at the University of Texas MD Anderson Cancer Center (NCT04550442). We enrolled 33 patients (≥18 years) status post-HMA failure (defined as prior receipt of at least 4 cycles of HMA therapy with failure to attain response, or progression/relapse at any time after HMA therapy) having >5% bone marrow blasts with HR-MDS or CMML (IPSS ≥ 1.5). Patients did not receive any prior BCL-2 inhibitor therapy. No specific Eastern Cooperative Oncology Group (ECOG) status restriction was used. Patients were treated with intravenous or subcutaneous azacitidine (IV/SC) (75 mg/m2) for 5 days and oral venetoclax (dose range,100-400 mg) for 14 days of each 28-day cycle. The primary outcome was to determine the safety and tolerability (phase 1) and overall response rate (ORR) (phase 2) of venetoclax in combination with azacitidine in this patient population. All patients who received one dose of study drug were included in the analyses. Results: Between September 2020 and January 2024, 33 patients (32 with HR-MDS and 1 with CMML) were enrolled in the study. The median age was 77 years (range, 55-84), with 20 patients (60%) being male and 26 patients (79%) being white. The median follow-up was 4 months (range, 1-34). At enrollment, 91% of patients were transfusion dependent. The median hemoglobin level was 7.8 g/dL (range, 6.4-11.6), median ANC was 1.2 x 10^9/L (range, 0.1-10.2), median platelet count was 29 x 10^9/L (range, 3-576), median creatinine level was 0.9 mg/dL (range, 0.5-2), and median total bilirubin was 0.8 mg/dL (range, 0.3-1.5).Eighty-five percent of patients had a hemoglobin level <10 g/dL and a platelet count <100 x 10^9/L. Seventy-three percent had intermediate to very poor cytogenetic risk scores, including abnormalities such as del(7q), +8, +19, i(17q), -7, inv(3)/t(3q)/del(3q), and complex cytogenetics. The most common molecular mutations were ASXL1 (45%), RUNX1 (30%), TP53 (30%), and TET2 (27%). One patient had an IDH1 mutation, and another had an IDH2 mutation. The median number of prior treatment lines was 2 (range, 1-3), with a median of 19 prior cycles of HMA therapy (range, 1-23). Patients received a median of 3 cycles of HMA + venetoclax (range, 1-22). Four patients (12%) underwent stem cell transplantation (SCT). The most common grade 3-4 treatment-emergent adverse events were pneumonia (12%), febrile neutropenia (9%), sepsis (9%), and cellulitis (9%). The ORR based on marrow CR + PR according to the International Working Group (IWG) 2006 criteria was 48%. The median overall survival (OS) was 7 months (95% CI, 3.5-10.5), and the median event-free survival (EFS) was 6 months (95% CI, 3.3-8.6). For patients with a TP53 mutation, the median OS was 3 months (95% CI, 0.9-5), while those with an ASXL1 mutation had a median OS of 8 months (95% CI, 3.5-13.4). Of the four patients who underwent a SCT, three were alive at the last follow-up. Conclusion: While adding venetoclax to HMA appears feasible for HR-MDS and CMML patients who have failed prior HMA, this combination seems to only improve outcomes when used as a bridge to transplantation.