Venetoclax, Azacitidine, and Homoharringtonine Regimen Well-Tolerated Among Patients With R/R AML

Results from a Multicenter Phase 2 Trial

The combination of venetoclax, azacitidine, and homoharringtonine was well-tolerated and showed promising efficacy among patients with relapsed/refractory (R/R) acute myeloid leukemia (AML), according to findings from a phase 2 trial recently published in the Journal of Hematology & Oncology. 

Hua Jin, MD, Southern Medical University, Guangzhou, China, and coauthors stated, “The prognosis of refractory/relapsed AML is dismal, with less than 10% overall survival (OS) at 3 years. There is no standard salvage therapy for patients with R/R AML, indicating the urgent need for novel treatment to improve the outcomes.” 

Prior research findings have indicated that the combination of venetoclax, an oral selective small-molecule BCL-2 inhibitor, and hypomethylating agents like azacitidine, improved outcomes among older or unfit patients with AML. Homoharringtonine is an anti-leukemia drug for the treatment of AML and chronic myeloid leukemia (CML), the study authors explained, adding “homoharringtonine reduces MCL1 expression, blocks short-half-life oncoproteins, and induces apoptosis in myeloid leukemia cells.”

This investigators aimed to assess the activity and tolerability of venetoclax plus azacitidine and homoharringtonine among patients with R/R AML. In this trial, 96 patients with R/R AML were enrolled across 10 hospitals in China between May 2020 and June 2021. All patients had an Eastern Cooperative Oncology Group performance status of 0 to 2.

The primary end point was the composite complete remission rate, including complete response (CR) and complete response with incomplete blood count recovery (CRi) after 2 cycles of treatment. Secondary end points included safety and survival outcomes. 

Of the enrolled patients, 37  had primary refractory AML and 59 had relapsed AML, including 16 relapsed after chemotherapy and 43 relapsed after allogeneic hematopoietic stem cell transplantation. Patients received venetoclax at 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3 to 14, azacitidine at 75 mg/m2 on days 1 to 7,  and homoharringtonine at 1 mg/m2 on days 1 to 7. 

The composite complete remission rate was 70.8% (95% confidence interval [CI], 60.8 to 79.2),  indicating a promising response to the VAH regimen. Among these patients, 58.8% achieved measurable residual disease-negative status. The overall response rate, including composite complete remission rate plus partial remission, was 78.1% (95% CI, 68.6 to 85.4).

At a median follow-up of 14.7 months (95% CI, 6.6 to 22.8), the median overall survival was 22.1 months and the event-free survival was 14.3 months (95% CI, 7.0 to not estimated). The 1-year overall survival rate was 61.5% (95% CI, 51.0 to 70.4) and the event-free survival rate was 51% (95% CI, 40.7 to 60.5). As for adverse events, grade 3 to 4 adverse events included febrile neutropenia (37.4%), sepsis (11.4%), and pneumonia (21.9%).  

Dr Jin and coauthors concluded, “[Venetoclax combined with azacitidine plus homoharringtonine] is a promising and well-tolerated regimen in R/R AML, with high [composite complete remission rate] and encouraging survival.”

“Further randomized studies are needed to be explored,” they added. 

Source: 

Jin H, Zhang Y, Yu S, et al. Venetoclax combined with azacitidine and homoharringtonine in relapsed/refractory AML: A multicenter, phase 2 trial. J Hematol Oncol 16, 42 (2023). doi: 10.1186/s13045-023-01437-1