Azacitidine Plus Venetoclax Yields Insignificant Outcomes in Higher-Risk MDS Post-HMA Failure

While azacitidine plus venetoclax is a feasible treatment option for patients with higher-risk myelodysplastic syndrome (MDS) after hypomethylating agent (HMA) failure, the combination did not significantly improve patient outcomes in a study published in Leukemia Research.

The phase 1/2, single-center, dose-escalation trial led by Julie S. Braish, MBBCh, of the University of Texas MD Anderson Cancer Center, included 33 patients with higher-risk MDS or chronic myelomonocytic leukemia who progressed after HMA treatment. Patients received intravenous or subcutaneous azacitidine at 75 mg/m² for 5 days, plus venetoclax at 100 to 400 mg for 7 to 14 days in a 28-day cycle.

In the phase 1 portion of the study, the researchers assessed the safety and tolerability of the combination using a 3 + 3 study rule to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (R2PD). In the phase 2 dose expansion portion, the researchers assessed the efficacy of the recommended phase 2 dose (400 mg) through overall response rate (ORR). The study team enrolled 12 patients in phase 1 and 21 patients in phase 2.

Neutropenia (19%) and thrombocytopenia (10%) were some of the most common grade 3-4 adverse events, and hematologic toxicities corresponded with known side effects of venetoclax. A total of 9% of patients died within 4 weeks of starting treatment. The combination yielded an ORR of 49%, a median overall survival (OS) of 7 months (95% CI, 3.5–10.5), and a median progression-free survival (PFS) of 6 months (95 % CI, 3.0–9.0).

“Patients who are refractory or lose response to HMAs have a very poor prognosis with a median OS of 4.3–5.6 months and scarce treatment options,” Dr. Braish and colleagues wrote. “At the present time, there is no therapy that has been shown to have significant activity for this group of patients.”