Combination therapy with venetoclax is commonly used to treat relapsed or refractory acute myeloid leukemia (RR-AML). Molecular characteristics may predict response to these treatments in patients with RR-AML, according to new research published in Blood Advances.

Limited studies have looked at predictors of outcomes for venetoclax combination therapy in RR-AML. This study retrospectively looked at data from 86 patients treated with venetoclax plus azacitidine, decitabine, and low-dose cytarabine at a single center.

The overall response rate (ORR) of all patients was 31%, and 24% of patients achieved a complete response (CR) or complete response with incomplete hematologic recovery (CRi). Of the patients achieving a CR/CRi, 40.7% were measurable residual disease (MRD) negative.

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A total of 45% of patients who responded to therapy relapsed. The median overall survival (OS) of relapsed and refractory patients was 6.1 months.

Patients receiving azacitidine had better response rates than patients receiving decitabine or low-dose cytarabine plus venetoclax. Patients receiving combination therapy with azacitidine had a median OS of 25 months, compared with 5.4 months with decitabine and 3.9 months with low-dose cytarabine.

Patients who achieved a response had improved OS, and patients with MRD-negative responses had a longer OS than those who were not MRD-negative in a 3-month landmark analysis.

Molecular characteristics may predict response to venetoclax combination therapy. Presence of NPM1 or IDH1 mutation was associated with a significantly increased response rate (ORR, 62%; P =.02 and ORR, 67%; P =.03, respectively) and longer OS. A STAG2 mutation was also associated with improved survival.

Adverse cytogenetics predicted a lower response rate (ORR: 21%; P =.03) and decreased OS. TP53, NRAS/KRAS, SF3B1, ASXL1, and EZH2 mutations were associated with lower CR/CRi rates, but the results were not significant. The lack of significance may be due to small sample size.

Patients with a DNMT3A mutation who previously received hypomethylating agent (HMA) therapy had a lower chance of achieving a response to venetoclax combination therapy (ORR: 2 of 12 patients, 17%), compared with patients who did not receive prior HMA therapy (ORR, 10 of 15 patients, 67%; P =.02). 

The authors also observed more complex disease in relapsed patients, with some new mutations in ASXL1, DNMT3A, FLT3, NRAS, and TET2.

Overall, the results suggested azacitidine plus venetoclax may be an effective treatment for patients with RR-AML who have favorable molecular profiles.

Disclosures: Some authors have declared affiliations with or received grant support from the pharmaceutical industry. Please refer to the original study for a full list of disclosures.


Stahl M, Menghrajani K, Derkach A, et al. Clinical and molecular predictors of response and survival following venetoclax therapy in relapsed/refractory AML. Blood Adv. 2021;5(5):1552-1564. doi:10.1182/bloodadvances.2020003734