Efficacy of the triplet therapy with venetoclax, azacitidine and gilteritinib for the treatment of FLT3-ITD mutated AML patients with refractory/relapsed disease or persistent minimal residual disease bridging to allogeneic hematopoietic stem cell transplantation

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Abstract Background Patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) with FLT3-Internal Tandem Duplication (ITD) mutation have a poor prognosis and high risk of relapse.Triplet therapy with venetoclax (VEN), azacitidine (AZA) and gilteritinib is effective and significantly improves response rates and survival outcomes in this high-risk patient population. Aims We aimed to evaluate the efficacy and safety of the triplet regimen including VEN, AZA and gilteritinib in FLT3-ITD mutated AML patients with R/R disease or persistent minimal residual disease (MRD), as a bridge to allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods We analyzed 48 FLT3-ITD mutated AML patients in a retrospective cohort study. Patients with R/R disease or persistent MRD received triplet therapy (VEN, AZA and gilteritinib) and bridged to allo-HSCT between August 2021 and June 2024. Bone marrow aspirates were obtained, cytogenetic and molecular characteristics were collected at the time of diagnosis. HLA-haploidentical donor transplants were performed if no HLA matched sibling or unrelated donor was available. Patients received myeloablative conditioning regimens followed by post-transplant gilteritinib maintenance therapy. The therapeutic process and clinical outcomes were retrospectively analyzed. Results 48 adult patients were enrolled in this study, 27 (56.2%) were female and 21 (43.8%) were male. The median age was 41 (range 15-61). Based on prognostic stratification defined by the 2022 European LeukemiaNet (ELN) guidelines, 38 (79.2%) patients were categorized in the Intermediate-risk group and 10 (20.8%) were categorized in the adverse-risk group at diagnosis. At the time of enrollment, 38 (79.2%) patients had R/R disease, of whom 36 cases failed to achieve remission with prior chemotherapy and two cases attained complete remission with MRD positivity. The remaining 10 patients (20.8%) were in CR1 but were detected with persistent positive MRD during chemotherapy. After one cycle of triplet therapy (VEN, AZA and gilteritinib), 39 (81.3%) patients reached CR/CRi (16 were MRD negative and 23 were MRD positive). The remaining 9 (18.7%) patients showed no treatment response and proceeded to transplantation with active disease. No treatment-related mortality (TRM) was observed. Patients received myeloablative conditioning with a modified Bu/Cy/Cla/Ara-c (busulfan/cyclophosphamide/cladribine/cytarabine) or MCBC (melphalan/cladribine/busulfan/cyclophosphamide) preparative regimen. All patients engrafted successfully, with hematopoietic recovery within 60 days of transplantation. Gilteritinib maintenance therapy started between day +30 to latest day +90 after allo-HSCT. At the time of this analysis, 40 (83.3%) patients remained alive, while disease relapse had occurred in 9 patients (18.8%). The median follow-up of alive patients was 16.6 months (11-43.2). The 1-year overall survival (OS) and relapse-free survival (RFS) were 83.3% (95% CI 72.7-93.9%) and 75.0% (95% CI 62.7-87.3%), respectively. The leading causes of death were leukemia relapse (n=4), followed by grade IV aGVHD (n=3) and severe infection (n=1). The 1-year incidences of relapse and non-relapse mortality (NRM) were 14.6% (95% CI 6.3-26.1%) and 10.4% (95% CI 3.8-21.0%) , respectively. 19 (39.6%) patients experienced aGVHD and 15 (31.3%) experienced cGVHD. Conclusion The triplet therapy of VEN, AZA and gilteritinib resulted in high rates of CR/CRi and enhanced the feasibility of HSCT in FLT3-ITD mutated AML patients with R/R disease or persistent MRD. Sequential allo-HSCT followed by gilteritinib maintenance therapy may significantly improve the long-term prognosis in this high-risk group of patients.

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