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

Early T Acute Lymphoblastic Leukemia, Mixed Phenotype Acute Leukemia, T/Myeloid, Nos, T-Acute Lymphoblastic Leukemia

Adverse risk, newly diagnosed, induction therapy

The goal of this clinical trial is to evaluate the efficacy and safety of venetoclax combined with azacitidine in treating newly diagnosed early T-cell precursor (ETP)-like acute lymphoblastic leukemia (ALL), T-ALL with myeloid mutations, or T/myeloid mixed-phenotype acute leukemia (T/My-MPAL). Participant population: Patients aged ≥14 years diagnosed with ETP-like leukemia, T-ALL with myeloid mutations, or T/My-MPAL, regardless of sex/gender. The main question it aims to answer: Does venetoclax plus azacitidine achieve a significantly higher overall response rate (ORR: CR + CRi) compared to historical controls (54% vs. 90%) after two induction cycles? Comparison group: Researchers will compare ORR outcomes to historical data from conventional chemotherapy regimens to assess treatment superiority. Participants will: * Receive two 28-day cycles of venetoclax (oral, 100 mg D1, 200 mg D2, 400 mg D3-28) and azacitidine (75 mg/m²/day SC, D1-7). * Undergo serial bone marrow biopsies, blood tests, and imaging (e.g., PET-CT) for response assessment. * Follow dose adjustment protocols for toxicity management (e.g., neutropenia, thrombocytopenia).

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.

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