Background

Consolidative therapy with high/intermediate-dose cytarabine is standard practice for fit patients with newly diagnosed acute myeloid leukemia (ND-AML) who achieve complete remission (CR) after receiving intensive induction chemotherapy (IC). Oral azacitidine is approved as maintenance therapy in patients who achieve CR after IC but are unable to complete intensive consolidation therapy. A recent single arm, phase 2 study showed that low-dose azacitidine + venetoclax (VEN) is a feasible maintenance strategy in patients with AML who have received IC, with a median relapse-free survival (RFS) that was not reached and a 2-year RFS of 71% (Bazinet et al. Lancet Haematol. 2024). Real-world data on the use of hypomethylating agents (HMA) + VEN as maintenance in patients with ND-AML who received IC is sparse and warrants investigation.

Methods

This multi-institutional study retrospectively reviewed patients with ND-AML/mixed-phenotype AML (MPAL) who received HMA + VEN as maintenance therapy after achieving CR or complete remission with incomplete count recovery (CRi) post IC, between 2017 and 2025. Patients who received up to 2 cycles of intermediate- or high-dose cytarabine-based consolidation before HMA + VEN, and patients who received concomitant FLT3 or IDH1/2 inhibitors were also included. We investigated the reason for switching to low-intensity therapy, conversion to negative measurable residual disease (MRD-CR), receipt of HSCT, acute/chronic graft versus host disease (GVHD), overall survival (OS), and RFS. OS and RFS after initiation of consolidation/maintenance treatment were evaluated using Kaplan-Meier estimates for the entire cohort and stratified by transplant status.

Results

We identified 25 patients with ND-AML who received HMA + VEN therapy after IC and CR/CRi. Median age at diagnosis was 62 years (range 53-69) - 68% were male. By ELN-2022, 58% of patients were adverse risk. Five patients (21%) had complex cytogenetics, 2 (8%) had core-binding factor AML, 3 (12%) had secondary AML and 1 (4%) had MPAL. Three (12.5%) had TP53 mutations (3/24 evaluable NGS), 6 (25%) had FLT3 mutations (4 ITD), 2 (8%) had IDH1 mutations, and 5 had IDH2 mutations (21%). No patients had therapy-related AML. The median number of HMA + VEN maintenance cycles was 1 cycle (range 1-9). The most common reasons for switching to HMA + VEN were post-induction MRD positivity (36%) and decline in performance and/or induction treatment toxicities (32%). Five patients (20%) received a FLT3 inhibitor with HMA and VEN (3 quizartinib, 2 gilteritinib), and 1 patient (4%) received an IDH-2 inhibitor (enasidenib).

Eighteen patients had disease assessments during consolidation. Of the 5 MRD+ patients, with disease assessments after maintenance, all converted to MRD-CR after a median of 1 cycle. Eighteen patients (72%) proceeded to HSCT, of whom 41% had acute GVHD (1 patient with grade 3/4 gastrointestinal GVHD), and 31% had chronic GVHD. At a median follow-up of 12.0 months, median OS was 37.7 months (95% CI 19.3-NR (not reached)) for the entire cohort, NR (95% CI 37.8-NR) for patients who proceeded to HSCT, and 19.3 months (95% CI 11.2-NR) for patients who did not proceed to HSCT. Median RFS was NR (95% CI 22.7-NR) for the whole cohort, NR (95% CI 22.7-NR) for patients who proceeded to HSCT, and 11.2 months (95% CI 5.7-NR) for patients who did not proceed to HSCT. The 2-year OS and RFS for the whole cohort were 68% (95% CI 0.48-0.97) and 67% (95% CI 0.48-0.95), respectively. There were no treatment-related mortalities for patients receiving HMA + VEN.

Conclusion

In this cohort of patients with ND-AML, HMA + VEN showed promise as a safe and efficacious maintenance strategy following induction with IC, particularly as a bridge to allogeneic HSCT. Our population was relatively young, had a low proportion of secondary or therapy-related AML, included CBF AML, and a proportion received triplet therapy. Many patients were able to proceed to HSCT, supporting the utility of this low-intensity regimen in maintaining remission for patients who may not tolerate immediate further intensive therapy, and reducing pre-transplant morbidity. These findings must be interpreted in the context of several limitations: a relatively small sample size, a median of one maintenance cycle, and the absence of scheduled repeat disease assessments. Larger, prospective studies are needed to confirm these observations and better define the role of HMA + VEN in this setting.

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2025
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