Efficacy and Safety of Gilteritinib-Based Therapy Combinated with Allo-HSCT in Relapsed or Refractory Acute Myeloid Leukemia Patients with Positive FLT3-ITD Mutation

Introduction In patients with relapsed or refractory acute myeloid leukemia (R/R AML), FMS-like tyrosine kinase 3 (FLT3) gene mutation portends a poorer prognosis and survival. Gilteritinib, as a novel type I inhibitor, is a kind of highly selective and potent FLT3 inhibitor. It has been recommended by NCCN and ESMO guidelines for the treatment of R/R AML patients with FLT3 gene mutation. The objective of this study is to evaluate the safety and efficacy of gilteritinib-based therapy combinated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) for R/R AML patients with positive FLT3-ITD mutation, and assess the impact of gilteritinib maintenance therapy on the prognosis of patients after allo-HSCT.

Methods The clinical data of 23 patients treated at the First Affiliated Hospital of Soochow University from August 2019 to January 2023, were retrospectively analyzed. We applied gilteritinib-based therapy combinated with allo-HSCT and gilteritinib maintenance after allo-HSCT. All patients received oral gilteritinib at a dose of 120mg/day, and 14 patients of them continued oral gilteritinib at a dose of 40-80 mg/day after allo-HSCT as maintenance therapy. Combination scheme including gilteritinib + venetoclax (Ven) ± azacitidine (AZA)/decitabine (DAC) (n=18), gilteritinib + Ven + DAC + Cladribine (n=1), gilteritinib + IA (idarubicin, cytarabine) (n=1) and gilteritinib + AZA + lower-dose HAAG regime (homoharringtonine, cytarabine, aclarubicin, G-CSF) (n=3). The analysis included an assessment of the composite complete remission rate (CRc), overall survival (OS), disease-free survival (DFS), and adverse events.

Results A total of 23 FLT3-ITD+ R/R AML patients were enrolled, including 12 males and 11 females, with a median age of 37 (range, 18-65) years. Eighteen cases were refractory and 5 cases were relapsed. The curative effect evaluation conducted between 14 and 21 days showed that the complete remission (CR) rate was 30.4%, the rate of CR with hematology incomplete recovery (CRi) was 56.5%, and the partial response (PR) rate was 4.3%. The CRc was 87.0%, and the minimal residual disease (MRD) negativity rate was 73.9%. The 12-month and 24-month cumulative OS rate for all patients was 91% and 79%. The median OS was not determined. The median follow-up time was 21.4 months (95% CI, 15.3-27.4).

Among the patients who responded to treatment, the 12-month and 24-month cumulative DFS rate was 91% and 78%. The median DFS time was not determined. The median OS of patients with or without gilteritinib maintenance therapy after allo-HSCT was not determined, but the OS of patients with gilteritinib maintenance therapy after allo-HSCT was longer than that of patients without gilteritinib maintenance therapy after allo-HSCT (P = 0.017). The FLT3-ITD mutation clearance rate in this study was 43.5%, and the median OS of patients with FLT3-ITD mutation clearance was significantly longer than the median OS of patients without FLT3-ITD mutation clearance (P = 0.033). The most common grade 3 and above hematological adverse events of gilteritinib-based combination therapy included leukopenia (n=17), neutropenia (n=17), febrile neutropenia (n=14), thrombocytopenia (n=15), and anemia (n=12). Gilteritinib dose was reduced to 80mg/day in 8 patients with agranulocytosis, while 5 of them stopped medication because of the occurrence of severe neutropenia (ANC < 0.5×10⁹/L) combined with severe infections or serious adverse reactions. One patient developed differentiation syndrome during oral gilteritinib maintenance therapy after allo-HSCT, but his condition improved after treatment.

Conclusions The gilteritinib-based combination therapy demonstrates a high composite complete remission rate, MRD negativity rate, and long patients' survival in treating R/R AML patients with positive FLT3-ITD mutation. Furthermore, the clearance rate of FLT3-ITD mutation is notably high. Additionally, gilteritinib maintenance therapy after allo-HSCT has demonstrated a significant enhancement in patients' survival. It is crucial to closely monitor and manage any adverse events that may occur during treatment.

No relevant conflicts of interest to declare.