Early Data of Azacitidine and Venetoclax Shows Potential in High-Risk CML and MDS

Phase 1 results examining azacitidine and venetoclax in high-risk myelodysplastic syndromes or chronic myelomonocytic leukemia elicited an overall response rate of 87%.

Treatment with azacitidine (Onureg) and venetoclax (Venclexta) elicited safe and encouraging activity in patients with high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CML).

At a median follow-up of 13.2 months (interquartile range, 6.8-18.3), phase 1 results showed the overall response rate (ORR) to be 87% (95% CI 66%–97%) and the maximum tolerated dose (MTD) was not reached. Investigators established the recommended phase 2 dose (RP2D) as 75 mg/m2 azacitidine for 5 days plus 400 mg venetoclax for 14 days.

Findings of these 23 patients who received intravenous or subcutaneous 75 mg/m2 azacitidine for 5 days and oral 100 mg to 400 mg venetoclax for 7 to 14 days were published in Lancet Hematology.

“The combination regimen led to an overall response rate of 87% [13% complete remission, 74% marrow complete remission]. This rate of response was higher than historically reported with azacitidine monotherapy, which yields response rates of roughly 26% [17% complete remission, 9% marrow complete remission]. The majority of responses with the azacitidine plus venetoclax combination were marrow complete remissions, indicating that this regimen is highly effective in reducing the bone marrow blast burden,” wrote the study authors.

Venetoclax is a first-in-class agent which selectively binds to and inhibits the BCL2 protein and prevents some hematologic cancers from undergoing apoptosis. Currently, the agent gained FDA approval in combination with azacitidine, decitabine (Dacogen), or low-dose cytarabine, a regimen known as LDAC, for the treatment of adult patients aged 75 years or older with newly-diagnosed acute myeloid leukemia (AML) who have comorbidities precluding intensive induction chemotherapy.

The University of Texas MD Anderson Cancer Center developed this single-center, dose-escalation, dose-expansion, phase 1/2 trial to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of venetoclax combined with azacitidine in patients with treatment-naive and relapsed or refractory high-risk MDS or CML.

The phase 1 portion of the study utilized a 3 + 3 study design to determine the MTD and RP2D. and the phase 2 dose expansion portion, which is currently ongoing, aims to further evaluate the activity of the RP2D. If 2 or more patients had dose-limiting toxicity at any given dose level, the MTD was considered exceeded.

A total of 23 patients aged 18 years and older with treatment-naive or relapsed or refractory high-risk MDS or CML with bone marrow blasts of more than 5% were enrolled in the trial. There were 17 patients (74%) who were naïve to hypomethylating agents, and 6 (26%) who had failed on a hypomethylating agent. Additionally, 18 patients (78%) were male, 21 patients (91%) were White, and 2 patients (9%) were Asian.

Patients were treated with intravenous or subcutaneous azacitidine at 75 mg/m2 for 5 days in addition to oral venetoclax at 100–400 mg for 7–14 days. The primary end points of the trial were safety, tolerability, and to determine the RP2D and MTD of azacitidine in combination with venetoclax.

Findings showed that the median follow-up was 13.2 months (range 6.8-18.3), and the MTD was not reached. The RP2D established was azacitidine 75 mg/m2 for 5 days plus venetoclax 400 mg for 14 days. The overall response rate was 87% in 20 of the 23 patients (95% CI, 66-97).

The most common grade 3 or 4 treatment-emergent adverse events included neutropenia (39%), thrombocytopenia (39%), lung infection (30%), and febrile neutropenia (17%). Further, there were 3 deaths due to sepsis during the study, which were not deemed to be treatment related.

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