Comparing the efficacy and safety of the ABC-14 regimen (azacitidine, venetoclax, and chidamide) with traditional "3 + 7" intensive induction regimen or AB-14 regimen (venetoclax combined with azacitidine) in newly diagnosed AML: study protocol for a prospective, multicenter, randomized, open-label clinical trial.

[BACKGROUND] Induction therapy is the first critical step in the overall treatment of Acute myeloid leukemia (AML). The "3 + 7" regimen remains the backbone treatment for newly diagnosed AML patients suitable for intense chemotherapy (IC). However, its efficacy, toxicity, high complications management costs, and prolonged hospitalizations necessitate optimization. The azacitidine-venetoclax (AB) regimen is recommended for elderly or IC-ineligible AML patients, but its efficacy and safety remain suboptimal regarding early mortality and specific leukemia subtypes (e.g., M5, RUNX1-, FLT3-ITD-, TP53-mutated AML, or cases with high MCL-1 expression). Chidamide, a novel oral histone deacetylase inhibitor, counteracts venetoclax-induced MCL-1 upregulation and synergizes with azacitidine-venetoclax to induce AML cell apoptosis. Whether the Azacitidine, Venetoclax, and Chidamide (ABC) regimen can match the "3 + 7" or AB regimen in newly diagnosed AML induction therapy warrants investigation.

[METHODS] Newly diagnosed AML patients will be stratified by IC suitability into unfit-AML and fit-AML. Unfit-AML patients will be randomized to receive ABC-14 or AB-14 regimens. Fit-AML patients will be randomized to receive ABC-14 or "3 + 7" regimens. The primary endpoint is composite complete response rate (CRc). Secondary endpoints include the measurable residual disease (MRD) negative rate, duration of remission (DoR), 1-year Relapsed-free survival (RFS) rate, 1-year overall survival (OS) rate. Exploratory endpoints include the genetic characteristics spectrum of the ABC-14 group, hospital stay duration, treatment costs, blood product transfusion volume, quality of life, and apoptotic index.

[DISCUSSION] This study aims to demonstrate that ABC-14 regimen is non-inferior to "3 + 7" regimen in newly diagnosed AML induction therapy while overcoming AB resistance and reducing toxicity associated with "3 + 7". It seeks to provide a broadly applicable alternative induction strategy for AML.

[TRIAL REGISTRATION] ClinicalTrials.gov NCT06451861, Registered on June 11, 2024. https://clinicaltrials.gov/study/NCT06451861 .