Regardless of genotype, venetoclax with a hypomethylating agent (HMA) yields strong response and survival outcomes among patients with treatment-naive or relapsed/refractory acute myeloid leukemia (AML), according to research published in the American Journal of Hematology.

In late 2018, U.S. Food and Drug Administration (FDA) approved venetoclax, a selective inhibitor of B-cell leukemia/lymphoma-2, with an HMA or low-dose cytarabine for patients with newly diagnosed AML who are either older than 75 years or otherwise considered unfit for intensive induction therapy.

Given that the median age at AML diagnosis is 68 years, these combinations have become widely used since approval, and are associated with overall response rates (ORRs) of up to 68%. This contrasts with results of venetoclax monotherapy use in the relapsed/refractory setting, which showed an ORR of only 19% in previous study.

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For this study, researchers evaluated nonclinical trial data to determine the efficacy and safety of venetoclax with an HMA in patients with either treatment-naive or relapsed/refractory AML, and to describe any clinical or genetic biomarkers that might predict patient outcomes.

Data from 86 patients were included in this study: 44 patients had treatment-naive AML and 42 patients had relapsed/refractory disease. Among patients who were treatment-naive, the median age was 73.5 years (range, 37-91), 27 (61.4%) were men, 17 (38.6%) had de novo disease, and the most common AML mutations were TET2 (27.3%) and FLT3 (22.7%). Among patients with relapsed/refractory disease, the median age was 64.5 years (range, 18-79), 25 (59.5%) were men, 20 (47.6%) had de novo disease, and the most common AML mutations were TP53 (28.6%) and ASXL1 (21.4%).

In the treatment-naive group, the complete response (CR)/CR with incomplete hematological recovery (CRi) rate was 50%, which improved in a matched AML cohort treated with HMA only (23%; P =.005). Patients who reached CR/CRi had improved survival compared with patients who did not (17 months vs 3 months, respectively; P =.0009). Mutations in CEPBA and neutropenia appeared to predict CR.

In the relapsed/refractory group, about 50% of patients had received at least 2 prior lines of therapy, and 15 (35.7%) had received a prior HMA. The CR/CRi rate was 33.3% (14 patients), and age older than 65 years, AML with myelodysplasia, and mutations in JAK2, DNMT3A, and BCOR were each predictive of CR. As with the treatment-naive group, patients with CR/CRi had improved survival compared with those who did not (15 months vs 3 months, respectively; P =.0003).

“Future collaborative ventures should focus on identification and validation of clinical and genetic predictive biomarkers for response to venetoclax and HMA based therapy both in treatment naive and relapsed/refractory AML patients,” the authors wrote.


Morsia E, McCullough K, Joshi M, et al. Venetoclax and hypomethylating agents in acute myeloid leukemia: Mayo Clinic series on 86 patients. Am J Hematol. Published online August 24, 2020. doi:10.1002/ajh.25978