Intermediate-dose HAD Regimen for CEBPA Double-mutated AML

Official title

A Multicenter, Randomized, Controlled Clinical Trial of Intermediate-dose HAD Regimen for CEBPA Double-mutated Acute Myeloid Leukemia

Overview

AML is highly heterogeneous in pathogenesis, and CEBPA double-mutated (CEBPAdm) AML is a common type of leukemia in China. Currently, no targeted therapies for CEBPAdm, and chemotherapy and transplantation are still the treatment options for CEBPA double-mutated AML. At present, the "3+7" treatment induction regimen of cytarabine combined with anthracyclines is still the first-line recommended regimen. In our retrospective study, the intermediate dose HAD regimen produced a 3-year RFS of 84.7% and a 3-year OS of 92.8% in CEBPAdm AML. Therefore, this project intends to confirm the efficacy of intermediate-dose HAD in the treatment of CEBPA double-mutated AML is superior to the conventional treatment regimen through the multi-center RCT study.

Detailed description

This is a prospective, randomized, controlled clinical trial of patients diagnosed with CEBPA double-mutated AML. Patients who meet the inclusion criteria are randomly assigned to receive the intermediate-dose HAD regimen or the conventional 3+7 induction regimen (IA or DA), respectively. When patients reach complete remission (CR) after the induction therapy, 3 courses of the high-dose cytarabine regimen (3g/m2 q12h, 3 days) are used. Hematopoietic stem cell transplantation is recommended for patients with persistent MRD positive after treatment. When patients do not achieve CR after the induction therapy, reinduction therapy with IAC (IDA 10mg/ m2 for 3 days, cytarabine 100mg/m2 for 7 days, cyclophosphamide 350mg/m2 d2, d5) regimen is used. Patients who still do not achieve CR after reinduction therapy will be removed from the group.

Interventions

• Drug HAD
  Induction therapy:Homoharringtonine: 2mg/㎡/d, days 1-7 Cytarabine: (Ara-c 100mg/㎡/d, day 1-4; 1g/㎡ /q12h, day 5-7), Daunorubicin: (DNR 40mg/㎡/d, day 1-3). Reinduction therapy: Idarubicin (IDA) 10mg/㎡ for d1-3 , Ara-c 100mg/㎡ d1-7 , Cyclophosphamide (CTX350mg/㎡ d2, d5) . Patients who did not achieve CR after reinduction therapy were removed from the group. After achieving CR, they received high-dose cytarabine (3g/m2 q12h, 3 days) regimen for consolidation for 3 courses. Hematopoietic stem cel
• Drug Daunorubicin+Cytarabine
  Cytarabine: (Ara-c 100mg/㎡/d, day 1-7), Daunorubicin: (DNR 60mg/㎡/d, day 1-3) or idarubicin (IDA 12mg/㎡/d, day 1-3). Treatment did not achieve CR, and reinduction of IAC regimen was given. Reinduction therapy: Idarubicin (IDA) 10mg/㎡ ,d1-3, Ara-c 100mg/㎡ d1-7 , Cyclophosphamide (CTX350mg/㎡ d2, d5). Patients who did not achieve CR after reinduction therapy were removed from the group. After achieving CR, they received high-dose cytarabine (3g/m2 q12h, 3 days) regimen for consolidation for 3 c

Primary outcome measures

• Event-free survival (EFS) [Time frame: up to 2 years after the date of the last enrolled participants]

Secondary outcome measures (8)

• Complete response rate (CR) [Time frame: Six weeks after induction therapy]
• 30-day mortality [Time frame: Within 30 days of randomization]
• overall survival [Time frame: up to 2 years after the date of the last enrolled participants]
• Event-free survival censored at hematopoietic stem cell transplantation [Time frame: up to 2 years after the date of the last enrolled participants]
• Relapse free survival censored at hematopoietic stem cell transplantation [Time frame: up to 2 years after the date of the last enrolled participants]
• overall survival censored at hematopoietic stem cell transplantation [Time frame: up to 2 years after the date of the last enrolled participants]
• 60-day mortality [Time frame: Within 60 days of randomization]
• Relapse free survival(RFS) [Time frame: up to 2 years after the date of the last enrolled participants]

Eligibility criteria

Inclusion criteria

• AML diagnosed according to WHO-2022 classification with recurrent CEBPA mutations and containing mutation in the bZIP domain.
• Older than 14 years old and younger than 55 years old
• Male or female.
• The Eastern Cooperative Oncology Group Performance Status (ECOG-PS) of AML patients were 0-2 points.
• Meet the following laboratory tests (performed within 7 days prior to treatment) 1) Total bilirubin ≤ 1.5 times of the upper limit of normal value (same age); 2) AST and ALT≤ 2.5 times of the upper limit of normal value (same age); 3) Blood creatinine < 2 times of the upper limit of normal value (same age); 4) Myocardial enzymes < 2 times of the upper limit of normal value (same age); 5) Echocardiography (ECHO) was performed to determine the ejection fraction of the heart within the normal range.

Exclusion criteria

• Patients who have previously received induction chemotherapy, regardless of efficacy.
• Simultaneously suffering from malignant tumors of other organs and requiring treatment).
• Pregnant or lactating women. Male or female patients participating in the trial must take contraceptive measures during the trial treatment period.
• Active heart disease, defined as one or more of the following:1) Have a history of uncontrolled or symptomatic angina pectoris;2) Myocardial infarction less than 6 months prior to enrollment in the study;3) A history of arrhythmia requiring medication treatment or severe clinical symptoms;4) Uncontrolled or symptomatic congestive heart failure (> NYHA grade 2);5) The ejection fraction is below the lower limit of the normal range.
• Serious infectious diseases (uncured tuberculosis, pulmonary aspergillosis).
• Those who were not considered suitable for inclusion by the researchers.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Blood Hospital — Tianjin

Publications

• Wei H, Wang Y, Zhou C, Lin D, Liu B, Liu K, Qiu S, Gong B, Li Y, Zhang G, Wei S, Gong X, Liu Y, Zhao X, Gu R, Mi Y, Wang J. Distinct genetic alteration profiles of acute myeloid leukemia between Caucasian and Eastern Asian population. J Hematol Oncol. 2018 Feb 10;11(1):18. doi: 10.1186/s13045-018-0566-8. PMID 29427994
• Wei H, Zhou C, Liu B, Lin D, Li Y, Wei S, Gong B, Zhang G, Liu K, Gong X, Fang Q, Liu Y, Qiu S, Gu R, Song Z, Chen J, Yang M, Zhang J, Jin J, Wang Y, Mi Y, Wang J. The prognostic factors in acute myeloid leukaemia with double-mutated CCAAT/enhancer-binding protein alpha (CEBPAdm). Br J Haematol. 2022 May;197(4):442-451. doi: 10.1111/bjh.18113. Epub 2022 Mar 10. PMID 35274287
• Wei H, Wang Y, Gale RP, Lin D, Zhou C, Liu B, Qiu S, Gu R, Li Y, Zhao X, Wei S, Gong B, Liu K, Gong X, Liu Y, Zhang G, Song Z, Wang Y, Li W, Mi Y, Wang J. Randomized Trial of Intermediate-dose Cytarabine in Induction and Consolidation Therapy in Adults with Acute Myeloid Leukemia. Clin Cancer Res. 2020 Jul 1;26(13):3154-3161. doi: 10.1158/1078-0432.CCR-19-3433. Epub 2020 Feb 6. PMID 32029439

Identifiers

NCT: NCT06529250 · IIT2023005

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗