The Efficacy of Triple Regimen in Newly Diagnosed AML Patients With FLT3 Mutation

The FMS tyrosine kinase 3 (FLT3) gene mutation occurs in 30% of newly diagnosed AML patients, leading to a higher relapse rate and mortality rate. In the past, multi-drug combination chemotherapy regimens had limited efficacy in newly diagnosed AML patients with FLT3 mutations, especially in those with FLT3-ITD. However, the FLT3 inhibitors greatly improved the survival of AML patients with FLT3 mutations. Although several studies have focused on the effectiveness of FLT3 inhibitor combination therapy for FLT3-mutated AML, further studies are needed to determine the optimal regimen and dosage. A triple regimen consisting of Gilteritinib, Venetoclax, and Azacitidine had shown good efficacy in unfit newly diagnosed FLT3-mutated AML patients. This clinical trial aims to determine the optimal dosage of the triple regimen and investigate its efficacy in newly diagnosed fit FLT3-mutated AML patients. Besides, this trial will provide evidence for treatment decisions based on measurable residual disease in patients with the triple regimen.

This stuay intends to conduct a multi-center, single-arm clinical study to explore the efficacy of the triple induction regimen consisting of Gilteritinib, Venetoclax, and Azacitidine in newly diagnosed FLT3 mutated AML patients who are suitable for intensive chemotherapy. The maximum dose of Gilteritinib that can be safely combined with Azacitidine and Venetoclax will be determined. Patients will receive 2 courses of a triple regimen therapy for induction and those who achieved complete remission will receive 3 courses of intermediate-dose cytarabine for consolidation. After consolidation therapy, dose-adjusted triple regimen therapy will be applied for 6 courses as maintenance treatment. Bone marrow morphology and minimal residual disease detected by flow cytometry and next-generation sequencing will be monitored during the treatment to provide evidence for treatment decisions. Response and survival of patients will be recorded to evaluate the efficacy of the triple regimen.

Eligibility Criteria:
Inclusion Criteria:

1. MDS/AML patients WHO meet AML and ICC definitions according to WHO (2022) or ICC standards (10%-20% of bone marrow naive cells) and have FLT3-TKD or ITD mutations detected by PCR or second-generation sequencing.
2. Age ≥15 years old, male or female.
3. The physical status assessment (ECOG-PS) of the Eastern Oncology Collaboration group was 0-2 points.
4. Pass the requirements of the following laboratory tests (performed within 7 days before treatment) :

1) Total bilirubin ≤ 1.5 times the upper limit of normal value (same age); 2) AST and ALT≤ 2.5 times the upper limit of normal value (same age); 3) Blood creatinine \< 2 times the upper limit of normal (same age); 4) Myocardial enzymes \< 2 times the upper limit of normal (same age); 5) Echocardiography (ECHO) was performed to determine the ejection fraction of the heart within the normal range.

Exclusion Criteria:

1. Acute promyelocytic leukemia with PML-RARA fusion gene
2. Acute myeloid leukemia with RUNX1-RUNX1T1 or CBFB-MYH11 fusion gene
3. Acute myeloid leukemia with BCR-ABL fusion gene
4. Have treated patients (those who have previously received induction chemotherapy but can receive hydroxyurea down-cell therapy).
5. Concurrent malignant tumors of other organs (those requiring treatment).
6. Active heart disease, defined as one or more of the following:

1) A history of uncontrolled or symptomatic angina; 2) Myocardial infarction less than 6 months after enrollment; 3) Have a history of arrhythmia requiring drug treatment or severe clinical symptoms; 4) Uncontrolled or symptomatic congestive heart failure (\> NYHA level 2); 5) The ejection fraction is lower than the lower limit of the normal range. 7. Serious infectious diseases (uncured tuberculosis, pulmonary aspergillosis). 8. Those who were not considered suitable for inclusion by the researchers.