Vennetoclax combined with decitabine, cytarabine, aclacinomycin and granulocyte colony-stimulating factor as induction regimen achieved high response rate in newly diagnosed adverse risk Acute Myeloid Leukemia Free

Background With the identification of increasing molecular markers, acute myeloid leukemia (AML) patients in the adverse risk group constitute a growing proportion of the overall AML population according to the 2022 European LeukemiaNet genetic risk stratification. However, these patients who received intensive chemotherapy (IC) had lower complete remission (CR) rate and more dismal outcomes than those in favorable and intermediate risk groups. Therefore, new induction regimens are urgently needed to improve remission rates in the adverse risk group.

Method This prospective, single-armed, multi-center cohort study (ChiCTR2400083301) was conducted in newly diagnosed AML adults in adverse risk group, who were eligible for intensive chemotherapy. We intenteded to enrolled 38 patients (pts) who would receive venetoclax (VEN) combined with decitabine (DEC), cytarabine (Ara-C), aclacinomycin (Acla) and granulocyte colony-stimulating factor (G-CSF) (DCAG). VEN was orally taken 100mg on day 1,200mg on day 2 and 400mg on days 3 to 12. The details of DCAG were as follows: DEC 20mg/m² on day 1 to 5, Ara-C 10mg/m² q12h on day 6 to 12, Acla 10mg on day 6 to 10, and G-CSF 5ug/kg on day 6 to 12, which was adjusted according to the white blood cell count. The primary endpoint was response rate.

Results: Between October 2023 to April 2025, 40 patients (pts) were enrolled in this study. The median follow-up time was 6 (2.4-20.8) months.

The median age was 54 (21-72) years, in which 72.5% (29/40) pts were less than 60 years, and 57.5% (23/40) pts were male. There were 12.5% (5/40) pts with preceding hematological disease, and 5% (2/40) pts with malignant tumor treatment. In total, 47.5% (19/40) pts had myelodysplasia-related (MR) gene mutation, 22.5% (9/40) pts with KMT2A-rearranged, 12.5% (5/40) pts with mutated TP53and complex karyotype (CK), 7.5% (3/40) pts with CK, 5.0% (2/40) with DEK::NUP214,1 pts with NUP98::TOP1, and 1 pts with t (3;3). After one cycle of induction, overall response was 80.0% (32/40). CR/CR with incomplete blood count recovery (CRi) rate was 70.0% (28/40). Partial remission (PR) rate was 7.5% (3/40)，and 1 pts achieved morphologic leukemia free state (MLFS). None of them died during the induction. The median time of achieving response was 1.5 (0.7-3.2) months. The response rate in MR gene mutation group was 94.7% (18/19), including 1 pts achieved PR and 1 pts MLFS. In KMT2A-rearranged group, 55.6% (5/9) pts and 22.2%(2/9) pts achieved CR/CRi and PR. Three (60%) of 5 pts with mutated TP53 and CK achieved CR. Four (57.1%) out of the left 7 pts achieved CR. Measurable residual disease (MRD) of multi-parameter flow cytometry (MFC) in 50.0% (16/32) pts achieved negativity. No response (NR) rate was 20% (8/40). After 5.1(3.2-7.0) months, 18.8% (6/32) pts relapsed. Six (15%) pts died. In total, 60.0% (24/40) pts underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Among them, 87.5% (21/24) pts were allo-HSCT after the first response, and 3 with salvaged allo-HSCT. The median time from receiving response to allo-HSCT was 2.9 (1.9-6.3) months.

Both of the median relapse free survival (RFS) and overall survival (OS) did not reach, with estimated 1-year RFS rate of 66.6% (95%CI, 45.6-87.6), and OS rate of 80.6% (95%CI, 65.7-95.5) respectively. Patients who underwent allo-HSCT had higher RFS rate (estimated 1-year, 38.6% vs. 78.0%, p=0.022) and OS (estimated 1-year, 46.8% vs. 95.7%，p=0.002). In MR gene mutation group, 63.2% (12/19) pts received allo-HSCT and estimated 1-year RFS and OS compared with chemotherapy were 55.6% vs.88.9%(p=0.090%) and 100% vs.71.4% (p=0.054) respectively. In 5 pts with mutated TP53 and CK, 2 pts underwent allo-HSCT is still alive at 13.9 and 16.1 months, 2 pts with NR were lost at 2.5 and 4.7 months, and 1 pts with CR is preparing for allo-HSCT with a OS of 4.0 months without relapse.

Conclusion VEN combined with DCAG regimen was effective and well-tolerated in newly diagnosed adverse risk AML when used as induction therapy, which could provide more opportunity to adverse risk AML pts in remission with allo-HSCT to improve survival.