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Patients failing to achieve at least partial remission (PR) after Cycle 1 will be withdrawn from the study.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.

Inclusion criteria

• No gender restrictions
• Age ≥ 14 years
• Confirmed diagnosis of one of the following:

ETP-like leukemia (CD7⁺, CD1a-, CD8-, with CD5 expression stratified as ETP-ALL ≤75% or Near-ETP-ALL >75%) T-cell acute lymphoblastic leukemia (T-ALL) with myeloid mutations (including FLT3, DNMT3A, STAG2, IDH1/2, RUNX1, EZH2, WT1, ASXL1/2, SF3B1, TET2, BCOR, BCORL1, and MLL-PTD) T/myeloid mixed phenotype acute leukemia (T/My-MPAL) (with concurrent T-lineage and myeloid markers, e.g., cCD3⁺/mCD3⁺, CD7⁺, MPO⁺)

• Newly diagnosed patients without prior induction therapy Limited prior therapy allowed: hydroxyurea, dexamethasone, or low-dose cytarabine/venetoclax (cumulative dose <0.5g), and leukocytapheresis
• Expected survival time ≥ 3 months
• Liver function: total bilirubin ≤ 2× ULN; ALT/AST ≤ 3× ULN (or ≤ 5× ULN if liver infiltration by leukemia is present) ; Renal function: endogenous creatinine clearance ≥ 30 ml/min; Cardiac function: left ventricular ejection fraction > 45%
• Demonstrated capacity to understand the study and willingness to provide informed consent

Exclusion criteria

• Presence of recurrent genetic abnormalities such as t(8;21), t(15;17), inv(16)/t(16;16) leukemia
• Prior hypersensitivity to study drugs or compounds of similar chemical structure
• Active uncontrolled infections as determined by the investigator
• Active bleeding
• Recent history (within 1 year) of thrombosis, embolism, or cerebral hemorrhage
• Pregnancy, breastfeeding, or unwillingness to use contraception in women of childbearing potential
• Drug addiction or chronic alcoholism that could interfere with trial evaluation
• Psychiatric disorders or other conditions that would prevent obtaining informed consent or compliance with trial requirements
• Any condition deemed unsuitable for trial participation by the investigator