Response to venetoclax-containing regimens in patients with relapsed/refractory (R/R) T-cell acute lymphoblastic leukemia (T-ALL) and lymphoblastic lymphoma (T-LBL).

e18528 Background: Patients (pts) with R/R T-ALL/LBL have poor outcomes with limited approved therapies available to them. Early-phase studies of venetoclax (ven)-based regimens in R/R T-ALL/LBL have shown promising efficacy (Short et al, Blood Adv 2024; Pullarkat et al, Cancer Discov 2021; Cao et al, Lancet Haematol 2025). Given these data, we aimed to characterize the outcomes of pts with R/R T-ALL/LBL treated with ven-based regimens at our institution. Methods: A retrospective review of 19 pts with R/R T-cell disease (13 ALL, 6 LBL) treated with ven-based regimens at the University of Chicago was performed. Five pts had Early T-cell Precursor (ETP) phenotype. Molecular risk stratification was applied using Simonin et al, Blood 2024. The most recent molecular data prior to ven treatment were utilized if available. Response was assessed via European LeukemiaNet (ELN) 2024 criteria. Overall survival (OS) was estimated using the Kaplan-Meier method. Results: The median age at diagnosis was 34.9 years (range 19-74), and 74% of pts were male. In pts with molecular data (n=16), 75% had adverse-risk mutations, while 25% had favorable-risk mutations. The pts were heavily pre-treated prior to ven-based therapy for R/R disease, with 68% receiving ≥ 3 lines of therapy and 42% previously receiving an allogeneic hematopoietic stem cell transplant (allo-HCT). The ven-based regimens utilized are summarized in Table 1. The most common regimens were ven + hypomethylating agent (36.9%), ven + chemotherapy (15.8%), and ven + navitoclax (15.8%). In response to ven-based regimens, 10.5% had a complete remission (CR), 21% had a CR with incomplete count recovery (CRi), 5% had a partial response (PR), and 63.5% had no response or were not evaluable. The CR/CRi rate was 41.6% in those with prior nelarabine exposure (n=12), 0% in those with prior ven exposure (n=3), 31% in those with prior asparaginase exposure (n=13), and 50% in those with prior allo-HCT (n=8). Of the 5 ETP pts, 2 (40%) achieved CR/CRi. Median OS from the time of ven was 6.3 months, 95% CI (3.1 – N/A); 21% of pts proceeded to allo-HCT after ven-based therapy. At the time of data cut-off, 4 patients were alive. Conclusions: In this cohort of R/R T-ALL/LBL patients, responses to ven-based regimens were modest compared to recently reported prospective trials. Especially given the investigation of venetoclax-based therapies in the frontline treatment of T-ALL/LBL, additional novel therapeutic approaches will need to be explored in the R/R setting. Ven-based regimens utilized for R/R T-ALL/LBL (n = 19). Ven monotherapy 2 (10.5%) Ven + hypomethylating agent 7 (36.9%) Ven + chemotherapy 3 (15.8%) Ven + nelarabine 2 (10.5%) Ven + targeted agent 2 (10.5%) Ven + navitoclax 3 (15.8%)