The goal of this clinical trial is to learn if avapritinib combined with standard induction therapy works to treat newly diagnosed adult acute myeloid leukemia (AML) patients with KIT mutations and t(8;21)(q22;q22.1); inv(16)(p13.1q22) or t(16;16)(p13.1;q22). It will also investigate the safety and tolerability of this combination therapy. The main questions it aims to answer are:
To determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of avapritinib combined with chemotherapy by Dose-limiting toxicity (DLT).
Does this combination therapy improve the rates of minimal residual disease (MRD) negativity and long-term survival outcomes?
Age ≥18 years, both genders
Diagnosis of acute myeloid leukemia according to WHO 2022 criteria
Treatment-naive patients (hydroxyurea or low-dose cytarabine <0.5g cumulative dose allowed)
Bone marrow detection of KIT mutations with concurrent t(8;21)(q22;q22.1) or RUNX1::RUNX1T1 fusion gene; or inv(16)(p13.1q22) or t(16;16)(p13.1;q22) or CBFβ::MYH11 fusion gene
Known hypersensitivity to KIT inhibitors, cytarabine, idarubicin, venetoclax, azacitidine or similar agents
Concurrent use of other KIT inhibitors (dasatinib, sorafenib, gilteritinib, midostaurin)
Intracranial hemorrhage on imaging or unresolved prior intracranial bleeding
Active uncontrolled infection
Single group
Group A (FIT): Avapritinib + IA regimen
DrugCytarabine 100mg/m² days 1-7 Idarubicin 12mg/m² days 1-3 Avapritinib orally on days 8-21 (28-day cycle)
Group B (UNFIT): Avapritinib + VA regimen
DrugVenetoclax 100mg day 1, 200mg day 2, 400mg days 3-28 Azacitidine 75mg/m² days 1-7 Avapritinib orally on days 8-21 (28-day cycle)
Phase I: Recommended phase 2 dose (RP2D)
Recommended phase 2 dose (RP2D) of IA-based and VA-based combination with avapritinib schedules
Phase II: MRD (Measure residual disease) negativity rate
MRD negativity rate - proportion of patients achieving ≥3-log reduction in RUNX1::RUNX1T1 or CBFβ::MYH11 fusion gene levels by qPCR between the 1st and 2nd consolidation courses.
Overall survival (OS)
Overall survival will be defined as the number of days from the start of treatment to the date of death. Subjects that have not died will be censored at the last known date to be alive. To estimate 1, 2 and 3 years progression-free survival.
Composite complete remission rate (CRc)
Composite complete remission rate (CRc) after one cycle of induction therapy
Adverse Event
Safety profile: incidence of grade 3-4 clinical adverse events and laboratory abnormalities
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