Real-world effectiveness and safety of gilteritinib plus venetoclax and azacitidine in FLT3 mutated acute myeloid leukemia

Abstract Purpose: Gilteritinib plus venetoclax and azacitidine (GVA) therapy has achieved promising efficacy in older/unfit patients with FLT3-mutated acute myeloid leukemia (AML). However, evidence on this low-intensity therapy in newly diagnosed (ND) patients, especially in young/fit patients with AML are lacking. We conducted a retrospective observational study in both ND or relapsed/refractory (R/R) FLT3-mutated AML to fully investigate the efficacy and safety of GVA therapy. Patients and Methods: The ND cohort including 38 patients treated with GVA therapy. For R/R cohort, 29 patients with induction failure were also included, which defined as treatment failure after one cycle of standard dose anthracycline containing induction therapy or other induction therapy considered the optimum choice per investigator assessment. And the remaining 30 patients in R/R cohort were relapsed or refractory after two courses of induction treatment, which defined as standard relapse/refractory (S-R/R) for discrimination. Gilteritinib was given at a dose of 80 or 120mg/day orally, from day (d) 1 to d28. Azacitidine was administrated at a dose of 75 mg/m2/day subcutaneously d1-7. Venetoclax was given by oral administration at a dose of 100mg d1, 200mg d2, 400mg d3-28. Patients prior exposed to venetoclax was given at a dose of 400mg d1-28, dose adjustments were implemented based on drug interactions, particularly with azole antifungal prophylaxis. In the ND cohort, 12 patients received gilteritinib plus cytarabine and anthracyclines based intensive chemotherapy (G+IC) were regarded as control group. Response assessments were performed using 2022 ELN criteria, composite complete remission (CRc) was defined as CR or CR with incomplete hematologic recovery (CRi). Minimal residual disease (MRD) was assessed using multiparameter flow cytometry (MFC-MRD) and quantitative polymerase chain reaction (Molecular-MRD, Mol-MRD). Results: The retrospective study collected data from consecutive patients diagnosed between January 2021 and March 2025 with FLT3-mutated AML from 8 clinical centers in China. In ND cohort, following the first cycle of induction therapy, CRc rate was 84.2% (32/38) in the GVA group versus 75.0% (9/12) in the G+IC group, MFC-MRD and Mol-MRD was 93.8% (30/32) and 74.1% (20/27) versus 88.9% (8/9) and 71.4% (5/7) in two groups, respectively. CRc and MRD analyses revealed no statistically significant differences between two groups. As for patients achieved CRc after induction therapy, the median time to neutrophil recovery≥0.5×109/L in GVA and G+IC groups was 29.0 versus 30.0 days, and the median time to platelet recovery≥50×109/L among patients in GVA and G+IC groups was 27.0 versus 26.0 days. After a median follow-up of 19.5 months, median overall survival (OS) and event-free survival (EFS) was not reached in both groups with no significant differences. All the patients in both groups developed grade III/IV cytopenia, no significant differences observed between two groups on hematologic or non-hematologic toxicity. In R/R cohort, following GVA therapy, the CRc rate in induction failure and S-R/R group was 93.1% versus 43.3%, respectively, the MFC-MRD and Mol-MRD was 88.9% and 83.3% in induction failure group, versus 84.6% and 100.0% in S-R/R group. With a median follow-up of 12.8 months, the median OS and EFS was not reached in induction failure group, versus 15.4 months and 2.9 months in the S-R/R group, patients in the induction failure group achieved higher CRc rate and longer OS and EFS than that in S-R/R group. And the CRc rate and survival was no significant difference between ND group and the induction failure group. After GVA therapy, patients benefited from allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, whether allo-HSCT received or not, no significant difference on median OS was observed if patients continue with gilteritinib maintenance therapy, which means gilteritinib maintenance therapy may be a promising and alternative option instead of allo-HSCT. Conclusions:These real-world data indicated GVA is an efficient treatment for these FLT3 mutated AML patients, not only limited to older/unfit or R/R patients.