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.
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%).
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.
Single group
GVA + HDAC Consolidation & Gilteritinib Maintenance
DrugPhase I. Induction Therapy (2 cycles): Gilteritinib plus 80 mg, orally (po), once daily (qd), continuously from Day 1 of Cycle 1 until the end of Induction.Venetoclax + Azacitidine (VA Regimen): Azacitidine: 75 mg/m², intravenously (iv) or subcutaneously (sc), once daily on Days 1-7 of each 28-day cycle.Venetoclax: Cycle 1: Dose ramp-up: 100 mg po on Day 1, 200 mg po on Day 2, then 400 mg po once daily from Day 3 to Day 28.Subsequent Cycles: 400 mg po once daily on Days 1-28 of each 28-day cycle. Phase II. Consolidation Therapy (3 cycles): High-Dose Cytarabine (HiDAC): 3.0 g/m², intravenously (iv), over 3 hours, every 12 hours (q12h) on Days 1, 3, and 5 (total of 6 doses per cycle)；Gilteritinib: Dose increased to 120 mg, orally (po), once daily (qd), from day8 to day21. The interval of each cycle is 30 days. Phase III. Maintenance Therapy: Gilteritinib: 120 mg, orally (po), once daily (qd), continuously for up to 3 months.
Composite Complete Remission (CRc) Rate after 2 induction cycles
CRc is defined as the proportion of participants achieving CR or CRi based on 2022 ELN criteria. CR: Bone marrow blasts \<5%, ANC ≥1.0 x 10⁹/L, platelets ≥100 x 10⁹/L, no extramedullary disease, and transfusion independence. CRi: Bone marrow blasts \<5%, no extramedullary disease, and insufficient hematologic recovery to qualify for CR.
MRD Negativity Rate
The proportion of participants who achieve CRc and subsequently achieve Measurable Residual Disease (MRD) negativity, defined as \< 0.1% by multiparameter flow cytometry.
Deep Molecular Negativity Rate (for FLT3-ITD)
The proportion of participants who achieve deep molecular negative, defined as \< 0.0001% (10\^-6) via the DeepScan molecular assay, to the patients who achieved CRc
Overall Survival (OS)
Time from enrollment to death from any cause, whichever came first (censored at last follow-up for survivors)
Leukemia-Free Survival (LFS)
Time from first composed complete remission to relapse or death, whichever occurred first
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