Adult T-cell acute lymphoblastic leukemia (T-ALL) is often associated with primary resistance, induction failure, central nervous system infiltration, and early relapse. Traditional chemotherapy regimens have shown low remission rates, high recurrence rates, and high incidence of adverse events, leading to poor overall prognosis and low long-term survival rates for adult T-ALL patients.

To evaluate the efficacy and safety of a targeted epigenetic pathway regimen [DNA methyltransferase inhibitor azacitidine + histone deacetylase (HDAC) inhibitor)] combined with an apoptosis pathway inhibitor, venetoclax, in treating T-ALL patients through multi-target synergistic effects.

This exploratory, single-center, single-arm study included 12 T-ALL patients admitted to the Hematology Department of Sichuan Provincial People's Hospital from June 2023 to January 2025. Baseline data (clinical features and molecular genetic characteristics) were collected. All patients received a combination therapy of HDAC inhibitors, azacitidine, venetoclax, and dexamethasone, with each cycle lasting half a month. Efficacy was assessed after 1-2 cycles of treatment. Follow-up was conducted via outpatient review, inpatient review, telephone follow-up, or medical record system follow-up. Patients were categorized into early T-cell precursor ALL (ETP) and non-early T-cell precursor ALL (non-ETP) groups, recording complete response (CR) rate, overall response rate (ORR), minimal residual disease (MRD) negativity rate, overall survival (OS), and event-free survival (EFS). Subgroup analyses were performed using Kaplan-Meier curves and Log-rank tests for survival comparison and univariate Cox regression analysis for prognostic factors exploration. Adverse events were also recorded.

After one cycle of treatment, ORR among 12 patients was 83.3% (10/12), with CR in 5 cases (41.7%). After two cycles, ORR increased to 91.7% (11/12), and MRD negativity rose to 8 cases (66.7%). Seven patients successfully bridged to bone marrow transplantation post 2-3 cycles of chemotherapy, all currently surviving. Three deaths occurred due to self-discontinuation of medication. The median follow-up time was 6.5 months, without reaching median OS or EFS. There was no significant difference in clinical outcomes between ETP and non-ETP groups (P>0.05). However, ETP group showed worse prognosis compared to non-ETP (χ²=4.830, P=0.028), while transplanted patients had better prognosis than non-transplanted ones (χ²=6.545, P=0.011). Moreover, CR patients post two cycles had better prognosis than those not achieving CR (χ²=4.571, P=0.033), as did MRD negative patients versus MRD positive ones (χ²=4.571, P=0.033). Univariate Cox regression analysis indicated that gender, age, T-ALL subtype, number of mutated genes, chromosomal karyotype, efficacy, MRD status, and transplantation were not significant predictors of OS (P>0.05). All patients experienced at least one adverse event, with common grade ≥3 hematological adverse events including neutropenia (50.0%), thrombocytopenia (41.7%), and anemia (25.0%). Hepatotoxicity and nephrotoxicity were less frequent at 16.7% and 8.3%, respectively. Gastrointestinal adverse events primarily consisted of nausea and vomiting (83.3%), with pneumonia occurring in 5 patients (41.7%).

The combination of HDAC inhibitors, venetoclax, and azacitidine represents an effective induction therapy strategy for adult T-ALL, achieving higher and deeper remissions with acceptable safety profiles, making it a promising approach worthy of further investigation in larger studies.