Acute Myeloid Leukemia (AML)
Conditions
Keywords
Acute myeloid leukemia, venetoclax, gilteritinib, D5-PBCR, Risk-stratified
Brief summary
This study aims to investigate the safety and efficacy of drug X in combination with intensive chemotherapy in subjects with newly diagnosed AML (excluding APL and CBF-AML). X drugs included BCL-2 inhibitor venetoclax and FLT3 inhibitor Gilteritinib. Subjects will receive standard intensive chemotherapy during induction and consolidation. Early induction response will be evaluated according to the results of peripheral blood blast clearance rate on the fifth day after induction therapy (D5-PBCR). Venetoclax will be added in D5-PBCR positive subjects. For subjects with FLT3 mutations, Gilteritinib will be combined. Subjects will be stratified based on the genetic risk classification of 2022 European LeukemiaNet recommendations (ELN risk) and MRD status to receive specific consolidation therapy after the induction therapy.
Detailed description
Young patients with naïve AML (excluding APL and CBF-AML) were included in this study. 218 subjects who meet the eligibility criteria will receive the standard 3+7 intensive chemotherapy induction, containing cytarabine and idarubicin. On the basis of the IA induction regimen, the early chemotherapy response was evaluated according to the results of peripheral blood blast clearance rate on the fifth day after induction therapy (D5-PBCR). For D5-PBCR-positive patients, venetoclax will be added to conventional chemotherapy. For patients with FLT3 mutations, gilteritinib will be combined. Subjects who achieve a composite complete remission (CRc) after induction therapy will receive further consolidation therapy, which regimen will be decided based on the ELN risk at diagnosis and MRD status detected by MFC and gene quantification after induction therapy. The purpose of the study is to determine whether the addition of drug X to the standard induction regimen improves efficacy in the treatment of naïve AML. Primary objective: To evaluate whether intensive IA combined with targeted drug (drug X) regimens can improve the composite response rate (CRc) after 1 course of induction therapy in newly diagnosed young AML patients Secondary Objective: To evaluate whether intensive chemotherapy combined with drug X during induction and consolidation can improve overall response rates, overall survival, and event-free survival in newly diagnosed young AML patients Safety indicators: incidence of adverse reactions during treatment, recovery time of neutrophils and platelets
Interventions
DRUGD5-PBCR(-) IA arm
Induction: IA Drug: idarubicin, intravenously, 10 mg/m\^2 on D1-3 Drug: cytarabine, intravenously, 100 mg/m\^2 on D1-7 Consolidation: Subjects who achieve composite complete remission (CRc) proceed with consolidation therapy. In consolidation therapy phase, subjects in the group with favorable/intermediate risk and MRD negetive, will receive cytarabine intravenously at 2g/m\^2/q12h\*6 doses. Subjects in the group with adverse risk or MRD positive will receive cytarabine intravenously at 2g/m\^2/q12h\*6 doses together with venetoclax 400mg on D4-10. Dose ramp-up of venetoclax is not required. After two cycles of consolidation, a multi-disciplinary team will discuss whether the patient need allogeneic hematopoietic stem-cell transplant (allo-HSCT) according to ELN risk stratification and MRD status.
DRUGD5-PBCR(+) IA+Venetoclax arm
Induction: IA+Ven Drug: idarubicin, intravenously, 10 mg/m\^2, on D1-3, Drug: cytarabine, intravenously, 100 mg/m\^2 on D1-7 For D5-PBCR (+) patients, Venetoclax will be combined. Drug: Venetoclax. Orally once daily, on D6-14. A 3-day dose ramp-up is required for the first induction (100mg D6, 200mg D7, 400mg D8-14) If a second induction is needed, the dose of IA is the same as the first cycle, and dose ramp-up of venetoclax is not required. Consolidation: Subjects who achieve composite complete remission (CRc) proceed with consolidation therapy. In consolidation therapy phase, subjects in the group will receive cytarabine intravenously at 2g/m\^2/q12h\*6 doses together with venetoclax 400mg on D4-10. Dose ramp-up of venetoclax is not required. After two cycles of consolidation, a multi-disciplinary team will discuss whether the patient need allogeneic hematopoietic stem-cell transplant (allo-HSCT) according to ELN risk stratification and MRD status.
Sponsors
Ruijin Hospital
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Subjects receive IA regimen as the initial induction. On day five of induction, D5-PBCR will be tested according to protocol. Patients will be assigned to different arms according to the result of D5-PBCR. For FLT3 mutate patients, a combination of gilteritinib will be recommended in this study. Induction and consolidation phase: gilteritinib 80mg on D8-14.
Eligibility
Sex/Gender
ALL
Age
18 Years to 59 Years
Healthy volunteers
No
Inclusion criteria
1. Bone marrow morphology and immunology confirmed newly diagnosed AML patients (according to 2022 ICC criteria) 2. Exclude patients with APL and CBF-AML (according to fusion genes and chromosomes) 3. Performance status score 0-2 (ECOG score) 4. Age 18\ 59 years old 5. Liver and kidney function: blood bilirubin ≤ 35 μmol/L, AST/ALT below 2 times the upper limit of normal, creatinine ≤ 150 μmol/L 6. Normal cardiac function (EF ≥50%) 7. Obtained informed consent signed by the patient or family member
Exclusion criteria
1. FAB classification is M3, or confirmed APL at the molecular level 2. CBF-AML 3. Patients who have already been treated 4. Comfirmed central nervous system leukemia 5. Allergy to any of the drugs involved in the protocol 6. Medical condition or organ system dysfunction that precludes the inability to swallow capsules or tablets, or has a disease that significantly affects gastrointestinal function and/or inhibits small bowel absorption (including malabsorption syndrome, small bowel resection, or poorly controlled inflammatory bowel disease) 7. Cardiac function and disease consistent with one of the following: a) long QTc syndrome or QTc interval \>480 ms; b) second- or third-degree atrioventricular block; Severe, uncontrolled cardiac arrhythmias requiring medication; c) United States New York College of Cardiology Grade ≥ III; d) Ventricular ejection fraction (LVEF) less than 50%; e) History of myocardial infarction, unstable angina, severe unstable ventricular arrhythmia or any other arrhythmia requiring treatment, history of clinically severe pericardial disease, or ECG evidence of acute ischemic or active conduction abnormalities within 6 months prior to recruitment 8. Previous or present concomitant malignancies (except for basal cell carcinoma of the skin that have been effectively controlled as non-melanoma, carcinoma in situ of the breast/cervix, and other malignancies that have not been effectively controlled for more than 6 months, and patients who have been receiving long-term non-chemotherapy treatments such as hormonal therapy) 9. Significant abnormalities in liver and kidney function (serum bilirubin, aspartate aminotransferase, alanine aminotransferase or serum creatinine more than 2 times the upper limit of normal reference values; Excluded from AML-related as judged by the investigator) 10. Patients who have previously used other drugs for the treatment of AML (except hydroxyurea and cytarabine for cell count control), including but not limited to BCL2, FLT3, IDH1, IDH2 inhibitors, or other drugs in clinical trials 11. Coagulopathy not associated with AML 12. HIV infection, syphilis infection, HCV infection, active HBV infection (HBsAg positive, or HBsAg negative but HBcAb positive with HBV DNA \> 1.0 ×ULN) 13. Other uncontrolled active infection (as judged by the investigator) 14. Pregnant or lactating women 15. Inability to understand or follow the study protocol 16. Participation in other relevant clinical studies within 30 days (except diagnostic clinical studies) 17. Patients who in the opinion of the investigator, are not suitable to participate in this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite complete remission rate | At the end of cycle one (up to 42 days from the start of cycle 1） | Complete remission/complete remission with partial hematological recovery/complete remission with incomplete hematological recovery |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Total composite complete remission rate | At the end of induction cycle 2 (up to 42 days from the start of cycle 2) | Complete remission/complete remission with partial hematological recovery/complete remission with incomplete hematological recovery |
| OS | 2-year | overall survival rate |
| EFS | 2-year | event free survival rate |
| AE | Throughout the entire study period, an average of 1 year | Adverse Events (AEs), Serious Adverse Events (SAEs) Based on NCI-CTCAE 5.0 Assessment |
| Recovery time for neutrophils and platelets | During induction cycle one (up to 42 days from the start of cycle 1) | The time from the first day of induction therapy to the recovery of neutrophils to a count greater than 0.5\*10\^9/L and platelets to greater than 20\*10\^9/L |
Other
| Measure | Time frame | Description |
|---|---|---|
| The complete remission rate of MRD negative | at the end of induction (up to 42 days from the start of induction cycle 2) and consolidation stage (after two cycles of consolidation, up to 42 days from the start of consolidation cycle 2) | The complete remission rate of MRD negative |
| biomarkers of apoptosis | Throughout the entire study period, an average of 1 year | Level of apoptosis biomarkers such as BCL-2, BCL-xL and MCL-1 |
Countries
China
Contacts
Primary ContactYunxiang Zhang
Backup ContactHongming Zhu
Outcome results
None listed