Venetoclax + Azacytidine for Newly Diagnosed ETP-like ALL and T-ALL With Myeloid Mutations

This study addresses the unmet need for effective therapies in high-risk T-ALL subtypes, including ETP-like leukemia and T/My-MPAL, which exhibit myeloid-like genetic profiles (e.g., FLT3, DNMT3A, RUNX1 mutations) and poor outcomes under conventional chemotherapy (5-year OS \<40%). Preclinical and pilot clinical data demonstrate that venetoclax, a BCL-2 inhibitor, synergizes with azacitidine, a hypomethylating agent, to induce apoptosis in leukemia stem cells by targeting oxidative phosphorylation and epigenetic dysregulation. Building on a pilot study, this Phase II trial employs a single-arm design to validate efficacy in a larger cohort. Patients receive two induction cycles of venetoclax (oral, 100 mg D1, 200 mg D2, 400 mg D3-28) and azacitidine (75 mg/m² SC D1-7), with response assessed via bone marrow morphology, flow cytometry, and molecular testing (Days 22-35). Early Efficacy Evaluation: After the first induction cycle (Days 22-35), response is assessed via bone marrow morphology, flow cytometry, and molecular profiling. Stopping Criteria: Patients failing to achieve at least partial remission (PR) after Cycle 1 will be withdrawn from the study. Patients failing to achieve CR or CRi at the end of Cycle 2 will also discontinue study treatment. Consolidation strategies include allo-HSCT or high dose cytarabine (HiDAC) for fit patients or maintenance therapy for unfit individuals. Rigorous safety monitoring follows NCI-CTCAE v5.0 criteria, with dose adjustments for hematologic/non-hematologic toxicities. Statistical analysis includes intent-to-treat and per-protocol populations, with ORR analyzed via exact binomial tests and survival endpoints via Kaplan-Meier/Cox regression. The study integrates translational biomarkers (e.g., BCL-2 expression, mutational profiling) to identify predictors of response, aiming to establish a novel, mechanism-driven regimen for these aggressive leukemias.