Gilteritinib Plus VA Followed By Consolidation Chemotherapy in Newly Diagnosed FLT3-ITD+ AML

Overview

This clinical trial aims to evaluate whether molecular MRD-guided chemotherapy can effectively treat FLT3-ITD mutated AML and potentially replace allogeneic hematopoietic stem cell transplantation. It primarily seeks to answer: * What is the complete remission rate after initial induction with Gilteritinib, Venetoclax, and Azacitidine? * What are the survival rates and safety of subsequent high-dose cytarabine consolidation after two cycles of this induction therapy? As a single-arm study, outcomes will be compared against historical data from standard treatments (including transplant) to assess if the new strategy is equally or more effective. Participants will: * Undergo three cycles of high-dose cytarabine consolidation after two cycles of induction therapy, contingent upon achieving deep FLT3-ITD molecular remission. * Start Gilteritinib maintenance therapy after consolidation if FLT3-ITD remains detectable, continuing until deep molecular remission is achieved again.

This single-center, phase II trial evaluates a novel, transplant-sparing strategy for fit patients with newly diagnosed intermediate-risk acute myeloid leukemia (AML) harboring FLT3-ITD mutations. The central hypothesis is that achieving deep molecular remission-as measured by a highly sensitive assay termed "DeepScan" (Levis et al., Blood 2022)-can identify a subset of patients who may attain long-term survival without allogeneic hematopoietic stem cell transplantation (allo-HSCT). The therapeutic strategy consists of a sequential three-phase approach: Induction: Initial therapy combines the FLT3 inhibitor gilteritinib with venetoclax and azacitidine (the GVA regimen). This synergistic approach targets leukemia through concurrent inhibition of FLT3 and BCL-2 pathways, aiming to achieve high rates of complete remission and deep molecular clearance. Consolidation: Patients who achieve deep FLT3-ITD negativity, as assessed by the "DeepScan" minimal residual disease (MRD) assay after induction therapy, will proceed to consolidation with high-dose cytarabine (2 g/m² twice daily for 3 days) for three cycles, concurrently with gilteritinib. Maintenance: Patients maintaining deep FLT3-ITD negativity will receive gilteritinib monotherapy at 120 mg daily for 3 months. Those with detectable mutations will be withdrawn from the study. A key innovation of this trial is the implementation of "DeepScan," a next-generation sequencing-based assay co-developed with Professor Levis's team. This method detects FLT3-ITD mutations with a sensitivity of up to 10-⁶, surpassing conventional MRD monitoring techniques. It is designed to accurately define a state of deep molecular remission, which serves as the primary biomarker for directing patients toward a transplant-free pathway. This study challenges the current standard of care, in which allo-HSCT is frequently recommended. By prospectively assessing whether deep molecular responses-induced and maintained through this targeted and chemotherapy-inclusive regimen-can lead to durable survival, the trial aims to provide evidence for a paradigm shift in the treatment of FLT3-ITD-mutated AML, potentially offering a transplant-free alternative for selected patients.