Venetoclax-based treatment in adult relapsed/refractory acute lymphoblastic leukemia and lymphoblastic lymphoma: a single-center real-world experience

Aims: Relapsed/refractory (R/R) acute lymphoblastic leukemia and lymphoblastic lymphoma (ALL/LBL) remain clinically challenging entities with limited effective salvage options, particularly in T-cell and early T-cell precursor (ETP) subtypes. Venetoclax has shown encouraging activity in preclinical and early clinical studies; however, real-world data are still scarce. This study aimed to evaluate venetoclax-based regimens in adult patients with R/R ALL/LBL treated at a single-center. Methods: This retrospective analysis included 13 adults with R/R ALL/LBL who received venetoclax-based therapy between 2019 and 2025. Clinical characteristics, prior treatments, cytogenetics, venetoclax dosing schedules, treatment combinations, response rates and survival outcomes were extracted from institutional records. Responses were assessed using bone marrow evaluation, multiparameter flow cytometry for measurable residual disease (MRD) and PET-CT for extramedullary disease. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier analysis. Results: The median age was 30 years, and most patients had T-ALL/LBL (61.5%), including two with ETP-ALL/LBL. Patients were heavily pretreated (median 3 prior lines); 38.5% had relapsed after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Venetoclax was administered with various backbones, most commonly FLAG (46.2%) or nelarabine/asparaginase (23.1%). Venetoclax treatment duration ranged from 7–28 days per cycle, with shorter schedules frequently used in individualized regimens. The overall CR/CRi rate was 84.6%, including 38.5% MRD-negative CR. Complete metabolic response (CMR) was achieved in 3 patients with extramedullary disease. Both patients with ETP-ALL/LBL achieved deep responses (CMR or MRD negative CR), aligning with the biological venetoclax sensitivity of this subtype. Following venetoclax-based therapy, 7 patients (53.8%) proceeded to allo-HSCT. Median OS was 7 months and median PFS was 5 months, comparable to previously published real-world series. Toxicities were manageable; although Grade ≥3 cytopenias were universal, prolonged cytopenias were infrequent with 7-14-day venetoclax courses. Infectious complications included febrile neutropenia (84.6%), mucormycosis (7.7%) and invasive aspergillosis (7.7%). No patient discontinued therapy due to toxicity. Conclusion: Venetoclax-based regimens demonstrated substantial activity in a young, heavily pretreated R/R ALL/LBL population, yielding high CR/CRi rates, MRD-negative remissions and successful transition to allo-HSCT in over half of patients. Efficacy in the ETP-ALL/LBL subgroup and manageable toxicity with shorter venetoclax schedules highlight the practicality of individualized real-world use. These findings support venetoclax-based combinations as a promising salvage and bridging strategy in R/R ALL/LBL, warranting further prospective evaluation.