Objective In recent years, the combination of venetoclax with azacitidine (VenAza) has established itself as the standard first-line treatment for elderly, unfit patients with acute myeloid leukemia (AML), markedly improving treatment response rates. However, among newly diagnosed elderly AML patients receiving initial induction therapy with the VenAza regimen, a notable divergence in outcomes has been observed: some achieve complete remission (CR, defined as bone marrow blasts < 5%, absence of peripheral blood blasts and extramedullary lesions, neutrophils ≥ 1×10⁹/L, and platelets ≥ 100×10⁹/L), while others attain CR with incomplete hematologic recovery (CRi, characterized by bone marrow blasts < 5%, resolution of peripheral blood blasts and extramedullary lesions, but with neutrophils < 1×10⁹/L or platelets < 100×10⁹/L). To date, the underlying reasons for these differential treatment responses remain poorly understood. Therefore, this retrospective study was conducted to explore the potential factors associated with treatment outcomes in newly diagnosed elderly AML patients receiving first-line VenAza therapy, in order to provide a reference for clinical treatment and prognosis evaluation.

Methods This retrospective study enrolled 48 newly diagnosed elderly patients with AML who received first-line VenAza therapy at a single institution. The treatment regimen comprised a subcutaneous injection of azacitidine at a dose of 75 mg/(m²·d) administered on days 1 through 7, in combination with oral venetoclax. Venetoclax was initiated at 100 mg on day 1, escalated to 200 mg on day 2, and maintained at a dosage of 400 mg per day from day 3 to day 28. The complete chemotherapy regimen was repeated in cycles of 28 days. The baseline characteristics were collected, including gender, age, baseline blood cell counts, AML subtype (according to WHO classification), risk stratification (according to the European Leukemia Net risk stratification), and genetic mutations. The patients were stratified into subgroups based on treatment outcomes: specifically, a CR/CRi group versus a non-CR/CRi group, and further into a CR group versus a CRi group.

Results After one course of VenAza treatment, 23 patients (47.9%) achieved CR, and 8 patients (16.7%) attained CRi. The CR/CRi rate in the TET2 gene mutation subgroup was significantly higher than that in the subgroup without TET2 gene mutations (100% vs. 56.4%, χ² = 5.18, RR=1.77, 95%CI: 1.18- 2.66, p = 0.032). The positivity rate for BCOR gene mutations was significantly higher in the CRi group compared to the CR group (37.5% vs. 4.3%, RR=8.625, 95% CI: 1.04- 71.53, p = 0.043). Furthermore, the DNMT3A mutation positivity rate was also higher in the CRi group than in the CR group (75% vs. 34.7%, RR=2.16, 95%CI: 0.99- 4.71, p = 0.069); although this difference did not reach statistical significance, a notable increasing trend in risk was observed.

Conclusion The VenAza regimen demonstrates definitive efficacy in newly diagnosed elderly AML patients. Elderly patients newly diagnosed with AML who carry the TET2 mutation are more likely to achieve remission following treatment with the VenAza regimen. Furthermore, BCOR gene mutations were significantly enriched in the CRi group compared to in the CR group, indicating that BCOR dysfunction may underlie the molecular pathogenesis of CRi. Meanwhile, DNMT3A mutations exhibited a certain degree of enrichment in the CRi group, further validation in a larger cohort is required.

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2025
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