Study on the efficacy and safety of HDAC inhibitor combined with venetoclax and azacitidine in the treatment of adult T-ALL

Abstract Background Acute T-ALL leukemia (T-ALL) is prone to primary drug resistance, induction failure, central infiltration, early recurrence, etc. At present, traditional chemotherapy schemes have low remission rate, high recurrence rate and high incidence of adverse reactions, and the overall prognosis of adult T-ALL patients is poor and the long-term survival rate is low. Objective A combined scheme targeting epigenetic pathway (DNA methyltransferase inhibitor azacytidine+histone deacetylase inhibitor) and apoptosis pathway inhibitor (Bcl-2 inhibitor Venetoclax) were used to treat T-ALL patients through multi-target synergy. To evaluate the efficacy and safety of HDAC inhibitor combined with venetoclax and azacytidine in adult T-ALL patients. Methods This study is an exploratory, single-center, single-arm study. Twelve patients with T-ALL admitted to the Department of Hematology of Sichuan Provincial People's Hospital from June 2023 to January 2025 were selected as the research objects. And the baseline data (clinical characteristics and molecular genetic characteristics) were collected. All the patients were treated with HDAC inhibitor, azacytidine, venetoclax and dexamethasone for half a month, and the curative effect was evaluated after one or two courses. Follow-up of patients through outpatient service, in-patient review, telephone consultation or medical record inquiry. Patients were divided into ETP group and non-ETP group according to their leukemia types. The complete remission (CR) rate, total response rate (ORR), minimal residual disease (MRD) negative rate, overall survival rate (OS) and event-free survival rate (EFS) were recorded and analyzed between subgroups. Kaplan-Meier method was used to draw the survival curve of patients for survival analysis, and Log-rank test was used to compare the survival curves. Univariate Cox regression analysis was used to explore the prognostic factors of T-ALL patients. Adverse events were evaluated according to NCI-CTCAE version 5.0, the general terminology standard for adverse events. Results After one course of treatment, the ORR (CR+CRi) was 83.3% (10/12) in 12 patients, including 5 cases of CR (41.7%) and 2 cases of MRD negative (16.7%). After two courses of treatment, ORR (CR+CRi) was 91.7% (11/12) and MRD was negative in 8 cases (66.7%). Seven patients were successfully grafted with bone marrow after two or three courses of chemotherapy, and all the patients survived after transplantation. Three patients died because of self-withdrawal. The median follow-up time was 6.5 (2.0,22.0) months, and the median OS and EFS were not reached. There was no significant difference in clinical efficacy between ETP group and non-ETP group. The cumulative survival rate between ETP group and non-ETP group was significantly different (P=0.028), and the prognosis of patients in ETP group was poor. The prognosis of transplant recipients was significantly better than that of non-transplant recipients (P=0.011). The prognosis with negative CR and MRD after the second course of treatment is better (P=0.033). All patients had at least one adverse event, and the most commonly reported ≥3 grade hematological adverse events included neutropenia (50%), thrombocytopenia (41.7%) and anemia (25%). The incidence of liver function damage and kidney function damage is small, which are 16.7% and 8.3% respectively. The main gastrointestinal adverse events were nausea and vomiting (83.3%). A total of 5 patients developed pneumonia (41.7%), among which 1 patient in ETP group developed ≥3 grade pneumonia and ≥3 grade sepsis; no adverse events of cardiovascular system were reported. Conclusion HDAC inhibitor combined with venetoclax and azacytidine is an effective induction therapy for adult T-ALL patients, which can achieve higher and deeper remission, and has good safety and tolerance, which can strive for the greatest opportunity for further allo-HSCT. It is worthy of further large sample study.