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

A Single-Center, Prospective, Single-Arm Phase II Clinical Study of Consolidation With High-Dose Cytarabine Following Deep Molecular Remission Induced by Gilteritinib Plus VA Regimen in Newly Diagnosed Intermediate-Risk Fit AML Patients With FLT3-ITD Mutation

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.

Inclusion Criteria:

• Each subject (or their legal representative) must sign an informed consent form (ICF) before any specific study procedures or tests, indicating that he/she understands the purpose and procedures of the study and is willing to participate.
• Age ≥ 18 years or reaching the legal minimum adult age (whichever is greater) and ≤ 60 years (at screening);
• Newly diagnosed acute myeloid leukemia with FLT3-ITD mutation according to the European LeukemiaNet (ELN) 2022 diagnostic criteria (no VAF requirement), with no low-risk or high-risk genetic features as defined by ELN 2022.
• ECOG performance status ≤ 2. Biochemical indicators must be within the following limits within 21 days before randomization and at baseline: ALT and AST ≤ 3× upper limit of normal (ULN); total bilirubin ≤ 3× ULN; serum creatinine ≤ 2× ULN or CrCl ≥ 40 mL/min. LVEF determined by echocardiography is within the normal range (LVEF > 50%).

Exclusion Criteria:

• Diagnosed with acute promyelocytic leukemia (APL), BCR-ABL positive acute myeloid leukemia, or AML secondary to previous chemotherapy or radiotherapy.
• History of other malignancies, except for adequately treated non-malignant skin melanoma, cured in situ tumors, or other solid tumors that have been treated and have had no evidence of disease for at least 2 years.
• Assessed as unfit for intensive chemotherapy based on the following criteria: ECOG performance status ≥ 2 at screening; severe cardiac diseases (e.g., congestive heart failure requiring treatment, ejection fraction ≤ 50%, or chronic stable angina); severe pulmonary diseases (e.g., DLCO ≤ 65% or FEV1 ≤ 65%); creatinine clearance < 45 ml/min (calculated by Cockcroft-Gault equation), liver disease with total bilirubin > 1.5 times the normal upper limit (ULN); any other comorbidities deemed incompatible with intensive chemotherapy by the attending physician.
• Uncontrolled fungal, bacterial, or viral infections.
• Known active clinically relevant liver disease (e.g., active hepatitis B or C); known history of HIV infection (participants should undergo HIV testing before randomization).
• History of allergy to any excipients in gilteritinib tablets.
• Pregnant or breastfeeding women.
• Other conditions deemed unsuitable for this study by the investigator.