Venetoclax plus Inotuzumab Ozogamicin for Relapsed and Refractory Acute Lymphoblastic Leukemia.

In relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL), responses to the CD22 antibody-drug conjugate inotuzumab ozogamicin (INO) are frequent but short-lived. Based on preclinical evidence of synergy, we conducted a phase 1 trial of the BCL-2 inhibitor venetoclax (VEN) plus standard-dose INO for adults with R/R CD22+ ALL/LBL. Twenty-three patients enrolled (15 ALL, 8 LBL): three at dose level 1 (DL1; VEN 200 mg/day), six at DL2 (VEN 400 mg/day), and fourteen in an expansion cohort (VEN 400 mg/day). The recommended dose was VEN 400 mg/day for 21 days per cycle. No dose-limiting toxicities or early mortality occurred. Patients received a median of 2 cycles (range 1-5). The most common grade ³3 adverse events were thrombocytopenia (43.5%) and neutropenia (39.1%). Four patients (17.4%) developed sinusoidal obstructive syndrome. Of 22 evaluable patients, 21 (95.5%) achieved complete remission, including 19 after one cycle. Measurable residual disease (MRD) cleared in 16/18 (88.9%) by flow cytometry (<10-4) and 14/19 (73.7%) by next-generation sequencing (<10-6). Fourteen (63.6%) patients proceeded to HSCT. With a median follow-up of 25.3 months (95% CI 19.0-32.4), two-year disease-free (DFS) and overall survival (OS) were 48% (95% CI 24-72%); median DFS was 22.1 months (95% CI 10.4-NA), and median OS was not reached. MRD-positivity was associated with lower baseline BCL-2 dependence. Correlates of progression included acquired MCL-1 dependence, CD22 antigen escape, drug efflux gene ABCB1 expression, and oncogenic mutations. In summary, VEN+INO is safe and effective for R/R B-ALL/LBL, producing frequent and durable MRD-negative remissions. NCT05016947.