A New Treatment of Newly Diagnosed KIT Mutation CBF-Acute Myeloid Leukemia

Avapritinib Combined With Standard Therapy for the Treatment of Newly Diagnosed KIT Mutation Acute Myeloid Leukemia With t(8;21)(q22;q22.1); Inv(16)(p13.1q22) or t(16;16)(p13.1;q22): a Prospective, Multi-center, Single-arm, Two-cohorts Study

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?

The prognosis of CBF-AML patients with KIT mutation remains relatively poor. CBF-AML is a heterogeneous disease in which many altered molecular pathways could contribute to the prognosis of the disease. Thus, curative approaches have been based on standard and high-dose cytarabine regimens using high-dose chemotherapy. However, the high rate of relapses in these patients should stimulate the development of new regimens. In recent years, there has been a series of new drugs under development that allow the design of combination therapies in this population. These drugs have an acceptable toxicity profile and are able to improve the CR rate in this population. In this way, the standard therapy and a small molecular targeted agent (Avapritinib) could produce a powerful antileukemic effect, preventing the adaptive escape mechanisms of leukemic cells. The investigators have designed a phase I-II trial based on the combination of a three-drug regimen (IA: standard-dose cytarabine + darubicin) or (VA: Azacitidine + Venetoclax) combined with avapritinib, which in this population could be well tolerated by a sequential type administration. The first objective is to achieve rapid control of the disease and the recommended dose for Phase II, using two different schemes, one based on IA and the other on VA, by dose escalation in Phase I of the trial. The second goal is to prevent relapse through a consolidation and maintenance schedule. Phase II will study the efficacy and safety of the recommended dose for Phase II.

Inclusion Criteria:

• 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
• Life expectancy >12 weeks Group A: ≥18 and <65 years with ECOG 0-1; Group B: ≥65 years or ≥18 and <65 years with comorbidities (ECOG ≥2, cardiac disease, creatinine clearance 30-50ml/min, or mild hepatic impairment)
• Adequate organ function: bilirubin ≤2×ULN, ALT/AST ≤3×ULN (≤5×ULN if leukemic infiltration), creatinine clearance ≥30ml/min, left ventricular ejection fraction >45%

Exclusion Criteria:

• 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
• Significant organ dysfunction: myocardial infarction, chronic heart failure, decompensated liver dysfunction, renal failure
• Pregnancy or breastfeeding