INTRODUCTION Mutations in splicing factor (SF) genes SRSF2, U2AF1, SF3B1, and ZRSR2 are now considered adverse risk in the European Leukemia Net 2022 acute myeloid leukemia (AML) risk stratification. In recent years, Venetoclax (VEN) combined with intensive chemotherapy(IC) has significantly improved the complete remission (CR) rate and MRD(-) rate in newly diagnosed AML patients, but the efficacy in patients with SFmut is still unclear, in order to further investigate the efficacy of VEN combined with IC for SFmut AML patients.Herein, we reported the data of 20 patients with SFmut AML who received 7-day VEN combined with IC (DA, HAA, or HAD) as induction therapy. To further elucidate the efficacy and safety of VEN combined with IC for AML in SFmut groups.

METHODS The patients included in this study were derived from two clinical trials (VEN+DA: ChiCTR2200061524; VEN+HAA: ChiNCT05893472) and one retrospective study (VEN+HAD). All induction regimens include a 7-day oral administration of VEN, in combination with either DA (DNR 60 mg/m²/day d2-3, and Ara-c 100 mg/m²/q12h d2-7), HAA (HHT at 2.5mg/m2/day d3-7, Ara-c 100 mg/m²/day d3-7, and Acla 20mg/day d3-7), or HAD regimen (HHT at 2mg/m2/day d2-6, DNR 45 mg/m²/day d 4-5, and 100 mg/m²/day d2-6).

After achieving CR, allogeneic hematopoietic stem-cell transplantation (allo-HSCT) were recommended according to ELN guidelines (2022). Patients who could not proceed allo-HSCT received consolidation and maintenance therapy.

The primary objective of this study was to assess the effectiveness and safety of a 7-day VEN-based induction therapy in patients with SFmut AML. The secondary objectives were to evaluate overall survival (OS) and event-free survival (EFS).

RESULTS Between January 2022 and June 2024, a total of 259 de novo AML patients were enrolled, including 20 patients with splicing factor genes mutations, all using VEN combined with IC as induction therapy. We further analyzed the profile of SFmut and found that the mutation frequency was 35.0% for SRSF2, 50.0% for U2AF1 and 15.0% for SF3B1. Among SFmut patients, 8 patients underwent treatment with VEN+DA, 7 patients received VEN+HAA, and 5 patients were treated with VEN+HAD. The cCR(CR+CRi) rate in the entire cohort was 90.3%(CR 232/259，CRi 2/259), and the MRD(-) rate was 92.3% by flow cytometry. The cCR(CR+CRi) rate in the SFmut patients and the SFwt patients was 60.0%(CR 12/20，CRi 0/20) and 92.9%(CR 220/239，CRi 2/239) , and the MRD(-) rate was 55.0% and 81.2% by flow cytometry（cCR(CR+CRi) rate: p＜0.001; MRD(-) rate: p=0.018）. The most frequent adverse effects were neutropenia (100%), thrombocytopenia (100%) and pneumonia (56.8%). The median recovery time for neutrophils and platelets were 14(range:5-52) and 13(range:4-63) days, respectively. In the SFmut cohort, The most frequent adverse effects were neutropenia (100%), thrombocytopenia (100%) and pneumonia (75.0%).The median recovery time for neutrophils and platelets were 16(range:8-52) and 15(range:10-63) days, respectively.

Until April,30, 2025, with a median follow-up of 18(0.5-39) months, 24.3% of patients underwent allo-HSCT (15.5% in VEN+DA, 26.2% in VEN+HAA, and 47.2

% in VEN+HAD, p＜0.001). In the SFmut cohort, 40.0% of patients underwent allo-HSCT. The median OS and EFS were not reached. The estimated 24-month OS and EFS were 74.0% (95% CI: 68.1-79.9%) and 70.8% (95% CI: 64.7-76.9%) in the entire cohort, 43.8% (95% CI: 21.5-66.1%) and 36.5% (95% CI: 13.8-59.2%) in the SFmut group, and 76.8% (95% CI: 70.9-82.7%) and 74.9% (95% CI: 69.2-80.6%) in the SFwt group, respectively(OS: p＜0.001; EFS: p＜0.001).

Conclusion 7-day VEN combined with intensive chemotherapy is an effective and safe induction therapy for newly diagnosed AML patients. But，compared with SFwt patients, SFmut patients had significantly lower MRD (-) rate levels and cCR rates after induction therapy.

【Keywords】Venetoclax; Chemotherapy; AML; Splicing Factor Gene Mutations;

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2025
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