Azacitidine Plus Venetoclax Leads to High Response Rates in High-Risk MDS, CML

Azacitidine plus venetoclax was safe and led to an overall response rate of 87% in patients with high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CML), according to results of a phase I clinical trial.

Alexandre Bazinet, MD, of The University of Texas MD Anderson Cancer Center, and colleagues conducted the single-center, dose-escalation, and dose-expansion phase I/II trial. The researchers published the trial’s phase I results in The Lancet Haematology. The phase II portion of the trial is ongoing.

Venetoclax is a small molecule BCL-2 inhibitor and azacitidine is a hypomethylating agent.

The trial included 23 adults with treatment-naïve or relapsed/refractory high-risk MDS or CML who had bone marrow blasts >5%. Most patients (74%) were hypomethylating-agent naïve, while the remainder of patients had post-hypomethylating agent treatment failure. Most patients were male (78%).

Patients received intravenous or subcutaneous azacitidine 75 mg/m² for five days and oral venetoclax 100-400 mg for seven to 14 days. All patients who received at least one dose of the drugs were included in the analysis. The primary endpoints were safety and tolerability of the drug combination, determination of the maximum tolerated dose, and recommended phase II dose. The median follow-up was 13.2 months.

The overall response rate was 87% (95% CI, 66-97). The maximum tolerated dose was not reached, and the phase I study established a recommended phase II dose of azacitidine 75 mg/m² for five days plus venetoclax 400 mg for 14 days.

Neutropenia and thrombocytopenia, each reported in 39% of patients, were the most common grade 3 and grade 4 treatment-emergent adverse events, followed by lung infection (30% of patients) and febrile neutropenia (17%). The researchers reported three treatment-unrelated deaths from sepsis that occurred in patients who were treated with the study drugs.

“Azacitidine with venetoclax is safe and shows encouraging activity in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukemia,” Dr. Bazinet and colleagues concluded.

Bazinet A, Darbaniyan F, Jabbour E, et al. Azacitidine plus venetoclax in patients with high-risk myelodysplastic syndromes or chronic myelomonocytic leukaemia: phase 1 results of a single-centre, dose-escalation, dose-expansion, phase 1-2 study. Lancet Haematol. 2022. doi:10.1016/S2352-3026(22)00216-2