Venetoclax Plus Azacitidine Shows Benefit in Patients with R/R MDS

The combination of venetoclax and azacitidine in adult patients with relapsed or refractory (R/R) myelodysplastic syndromes (MDS) demonstrated a manageable safety profile with meaningful clinical benefits, according to a phase Ib study.

“Venetoclax plus azacitidine shows activity in patients with R/R MDS following prior [hypomethylating agents (HMA)] therapy failure and provides clinically meaningful benefits, including hematological improvement and transfusion independence, and encouraging overall survival (OS),” the investigators, led by Amer Zeidan, MBBS, MHS, of the Yale School of Medicine, wrote.

The phase Ib study examined 44 patients with R/R MDS aged 18 years and older (median, 74 years). Patients were heavily pretreated with HMA (median, 9 cycles), and most of the patients (73%) had very high or high-risk disease, according to the Revised International Prognostic Scoring System.

Patients were treated with escalating doses of oral venetoclax (100, 200, or 400 mg daily for 14 days during every 28-day cycle). Azacitidine 75 mg/m² was administered intravenously/subcutaneously on days one to seven. The median follow-up was 21.2 months.

Among 37 evaluable patients, the overall response rate (ORR) was 39%, with responses including 7% complete responses (CRs; n=3) and 32% marrow CRs (mCRs; n=14). Six of the 14 patients who achieved mCR also achieved hematological improvement. The median time to CR/mCR was 1.2 months, and the median duration of response for CR plus mCR was 8.6 months. The median OS was 12.6 months. Transfusion independence of red blood counts and/or platelets was seen in 36% of patients.

Patients with IDH2 mutations (n=6) achieved an ORR of 83%, whereas those with TP53 mutations (n=5) achieved an ORR of 20%.

The severity, incidence, and types of adverse events observed with the combination of venetoclax and azacitidine were consistent with the known safety profile of both agents, and no new toxicities for venetoclax were identified, wrote the investigators.

Dr. Zeidan and colleagues reported that grade ≥3 hematological adverse events included febrile neutropenia (34%), thrombocytopenia (32%), neutropenia (27%), and anemia (18%). Pneumonia (23%) was the most common grade ≥3 infection.

The investigators noted several limitations of the study, including the lack of a comparator arm, the small sample size of the dose-escalation and safety-expansion cohorts, and the small number of overall assessed cycles.

To overcome any selection bias of patients enrolled in the study, a randomized study is necessary to confirm the results, Dr. Zeidan and colleagues wrote.

Reference

Zeidan AM, Borate U, Pollyea DA, et al. A phase 1b study of venetoclax and azacitidine combination in patients with relapsed or refractory myelodysplastic syndromes. Am J Hematol. 2022. doi:10.1002/ajh.26771