FLT3 Gene Mutation, AML
Conditions
Brief summary
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 triple regimen and investigate its efficacy in newly diagnosed fit FLT3-mutated AML patients.
Detailed description
This stuay intends to conduct a clinical study to explore the efficacy and safety of the triple induction regimen consisting of Gilteritinib, Venetoclax, and Azacitidine in newly diagnosed FLT3 mutated AML patients who are suitable for intensive chemotherapy. Patients will receive 2 courses of 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.
Interventions
DRUGVenetoclax
Venetoclax dose and schedule determined by arms and treatment phases
DRUGCytarabine
Consolidation therapy (3 courses): intermediate-dose cytarabine regimen :2g/m2 q12h d1-3, age \< 60 years;1g/m2 q12h d1-3, age ≥60 years. If NGS detected FLT3 mutation before consolidation chemotherapy, gilteritinib will be added during the consolidation course at d4-17.
DRUGGilteritinib
Gilteritinib 120mg schedule determined by arms or treatment phases
Azacitidine 75mg/m2/d schedule determined by treatment phases
Sponsors
Institute of Hematology & Blood Diseases Hospital, China
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
14 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free survival (EFS) | up to 2 years after the date of the last enrolled participants | The interval from the date of enrollment to the date of failed to achieve complete remission, the date of relapse, or the date of death, whichever occurred first. |
| Composite Complete remission (CRc) with negative MRD detected by flow cytometry. | up to 1 years after the date of the last enrolled participants | The ratio of CRc with negative MRD detected by flow cytometry after induction, consolidation, and maintenance therapy. |
| To determine the tolerated dose of triple regimens | up to 3 months after enrollment of the first participants | The dose of gilteritinib and venetoclax that can be safely combined with azacitidine |
| Composite Complete remission (CRc) rate | up to 3 months after the date of the last enrolled participants | The ratio of patients achieved CRc（CR/CRh/CRi) after induction therapy |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 30-day mortality | Within 30 days of the date of the last enrolled participants | Percentage of patients who died within 30 days from enrollment |
| 60-day mortality | Within 60 days of the date of the last enrolled participants | Percentage of patients who died within 60 days from enrollment |
| CRc with negative MRD detected by NGS (next-generation sequencing) | up to 1 years after the date of the last enrolled participants | The ratio of CRc with negative MRD detected by NGS after induction,consolidation, and maintenance therapy |
| overall survival | up to 2 years after the date of the last enrolled participants | The interval from the date of enrollment to the date of death or the date of last follow-up, , whichever occurred first. |
| Relapse free survival | up to 2 years after the date of the last enrolled participants | The interval from CR to the date of relapse, or the date of death, or the date of last follow-up, whichever occurred first. This outcome analyzes patients achieved CR in two courses of induction therapy. |
Countries
China
Contacts
CONTACTHui Wei, Doctor
PRINCIPAL_INVESTIGATORHui Wei, doctor
Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College
Outcome results
None listed