Older patients with acute myeloid leukemia (AML) respond poorly to standard induction therapy. B-cell lymphoma 2 (BCL-2) overexpression is implicated in survival of AML cells and treatment resistance. We report safety and efficacy of venetoclax with decitabine or azacitidine from a large, multicenter, phase 1b dose-escalation and expansion study. Patients (N = 145) were at least 65 years old with treatment-naive AML and were ineligible for intensive chemotherapy. During dose escalation, oral venetoclax was administered at 400, 800, or 1200 mg daily in combination with either decitabine (20 mg/m2, days 1-5, intravenously [IV]) or azacitidine (75 mg/m2, days 1-7, IV or subcutaneously). In the expansion, 400 or 800 mg venetoclax with either hypomethylating agent (HMA) was given. Median age was 74 years, with poor-risk cytogenetics in 49% of patients. Common adverse events (>30%) included nausea, diarrhea, constipation, febrile neutropenia, fatigue, hypokalemia, decreased appetite, and decreased white blood cell count. No tumor lysis syndrome was observed. With a median time on study of 8.9 months, 67% of patients (all doses) achieved complete remission (CR) + CR with incomplete count recovery (CRi), with a CR + CRi rate of 73% in the venetoclax 400 mg + HMA cohort. Patients with poor-risk cytogenetics and those at least 75 years old had CR + CRi rates of 60% and 65%, respectively. The median duration of CR + CRi (all patients) was 11.3 months, and median overall survival (mOS) was 17.5 months; mOS has not been reached for the 400-mg venetoclax cohort. The novel combination of venetoclax with decitabine or azacitidine was effective and well tolerated in elderly patients with AML (This trial was registered at www.clinicaltrials.gov as #NCT02203773).

Venetoclax‐azacitidine is approved for treatment of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy based on the interim overall survival (OS) analysis of the VIALE‐A study (NCT02993523). Here, long‐term follow‐up is presented to address survival benefit and long‐term outcomes with venetoclax‐azacitidine. Patients with newly diagnosed AML who were ineligible for intensive chemotherapy were randomized 2:1 to receive venetoclax‐azacitidine or placebo‐azacitidine. OS was the primary endpoint; complete remission with/without blood count recovery (CR/CRi) was a key secondary endpoint. This final analysis was conducted when 100% of the predefined 360 OS events occurred. In VIALE‐A, 431 patients were enrolled to venetoclax‐azacitidine (n = 286) or placebo‐azacitidine (n = 145). At 43.2 months median follow‐up, median OS was 14.7 months (95% confidence interval [CI], 12.1–18.7) with venetoclax‐azacitidine, and 9.6 months (95% CI, 7.4–12.7) with placebo‐azacitidine (hazard ratio, 0.58 [95% CI, 0.47–0.72], p < .001); the estimated 24‐month OS rate was 37.5% and 16.9%, respectively. Median OS for patients with IDH1/2 mutations and those with measurable residual disease responses was reached in this final analysis. CR/CRi rate was similar to interim analysis. Any‐grade hematologic and gastrointestinal adverse events were most common in venetoclax‐azacitidine and placebo‐azacitidine arms, including thrombocytopenia (47% and 42%) and neutropenia (43% and 29%). No new safety signals were identified. Long‐term efficacy and safety confirm venetoclax‐azacitidine is an improvement in standard‐of‐care for patients with AML who are not eligible for intensive chemotherapy because of advanced age or comorbidities.

The European LeukemiaNet (ELN) acute myeloid leukemia (AML) genetic risk classification systems are based on response to intensive chemotherapy; their ability to discriminate outcomes in older patients treated with venetoclax-azacitidine may be suboptimal. This pooled analysis of the phase 3 VIALE-A trial (NCT02993523) and phase 1b study (NCT02203773) examined prognostic stratification according to the 2017 and 2022 ELN risk classifications and derived new molecular signatures differentiating venetoclax-azacitidine–treated patients based on overall survival (OS). Overall, 279 patients treated with venetoclax-azacitidine and 113 patients treated with placebo-azacitidine were analyzed. The ELN 2017 or 2022 prognostic criteria classified most patients as adverse-risk AML (60.2% and 72.8% for venetoclax-azacitidine and 65.5% and 75.2% for placebo-azacitidine, respectively). Although outcomes with venetoclax-azacitidine improved across all ELN risk groups compared with placebo-azacitidine, ELN classification systems poorly discriminated venetoclax-azacitidine outcomes. By applying a bioinformatic algorithm, new molecular signatures were derived differentiating OS outcomes with venetoclax-azacitidine. The mutational status of TP53, FLT3 internal tandem duplication (FLT3-ITD), NRAS, and KRAS categorized patients into higher-, intermediate-, and lower-benefit groups (52%, 25%, and 23% of patients, respectively), each associated with a distinct median OS (26.5 months [95% confidence interval (CI), 20.2-32.7]; 12.1 months [95% CI, 7.3-15.2]; and 5.5 months [95% CI, 2.8-7.6], respectively). ELN prognostic classifiers did not provide clinically meaningful risk stratification of OS outcomes in patients treated with venetoclax-azacitidine. TP53, FLT3-ITD, NRAS, and KRAS mutation status allows the classification of these patients into 3 risk groups with distinct differences in median OS. These trials were registered at www.clinicaltrials.gov as #NCT02993523 and #NCT02203773.

PURPOSE: There is limited evidence on the clinical utility of monitoring measurable residual disease (MRD) in patients with acute myeloid leukemia treated with lower-intensity therapy. Herein, we explored the outcomes of patients treated with venetoclax and azacitidine who achieved composite complete remission (CRc; complete remission + complete remission with incomplete hematologic recovery) and MRD < 10^–3 in the VIALE-A trial. METHODS: The patients included in this report were treated with venetoclax and azacitidine. Bone marrow aspirate samples for multiparametric flow cytometry assessments were collected for central analysis at baseline, end of cycle 1, and every three cycles thereafter. MRD-negative response was defined as < 1 residual blast per 1,000 leukocytes (< 10^–3 or 0.1%) with an estimated analytic sensitivity of 0.0037%-0.0027%. CRc, duration of remission (DoR), event-free survival (EFS), and overall survival (OS) were assessed. A multivariate Cox regression analysis identified prognostic factors associated with OS. RESULTS: One hundred sixty-four of one hundred ninety (86%) patients with CRc were evaluable for MRD. MRD < 10^–3 was achieved by 67 of 164 (41%), and 97 of 164 (59%) had MRD ≥ 10^–3. The median DoR, EFS, and OS were not reached in patients with CRc and MRD < 10^–3, and the 12-month estimates for DoR, EFS, and OS in this group were 81.2%, 83.2%, and 94.0%. Among patients with CRc and MRD ≥ 10^–3, the median DoR, EFS, and OS were 9.7, 10.6, and 18.7 months. Multivariate analysis showed that CRc with MRD < 10^–3 was a strong predictor of OS (adjusted hazard ratio = 0.285; 95% CI, 0.159 to 0.510; P < .001). CONCLUSION: Patients who achieved CRc and MRD < 10^–3 with venetoclax and azacitidine had longer DoR, EFS, and OS, than responding patients with MRD ≥ 10^–3.

Acute myeloid leukemia (AML) is associated with poor outcomes, especially in older patients in whom the disease is most common. B-cell lymphoma 2 (BCL-2) is an antiapoptotic protein involved in the survival and maintenance of AML, and it is overexpressed in the leukemia stem cell population. Venetoclax is an oral BCL-2 protein inhibitor recently approved by the United States Food and Drug Administration (FDA) for use in combination with a hypomethylating agent (HMA) (azacitidine or decitabine) or low-dose cytarabine for front-line treatment of AML in older patients or those unfit for induction chemotherapy. Given that its mechanism of action is unique, it is not surprising that this widely effective therapy presents unique challenges, including but not limited to the rapidity of responses, the rate and depth of cytopenias, and issues related to drug–drug interactions. With the recent FDA approval and increasingly widespread use, we aim here to summarize, based on evidence and experience, emerging management strategies for the combination of HMAs and venetoclax in the treatment of AML.