Venetoclax in combination with a pediatric-inspired regimen for the treatment of newly diagnosed adults with Philadelphia chromosome-negative acute lymphoblastic leukemia.

BCL-2 protein overexpression, common in B-cell acute lymphoblastic leukemia (B-ALL), including the Philadelphia chromosome (Ph)-like subtype, mediates leukemic cell survival. We treated 24 patients with 14 days of BCL-2 inhibitor, venetoclax, 400 mg daily (dose level 1) during induction and consolidation cycles combined with the CALGB 10403 regimen in newly diagnosed adults with Ph-negative B-ALL. Median age was 31 years (range: 18-53), 92% were Hispanic, and 12 (50%) patients had Ph-like ALL. No dose-limiting toxicity occurred in the phase 1 part. Median times to neutrophil and platelet count recovery were 20 and 21 days from start of induction, respectively. The most common grade ≥3 treatment-related adverse events were leukopenia (96%), neutropenia (83%), anemia (83%), thrombocytopenia (79%), lymphopenia (71%), hyperbilirubinemia (38%), and elevated ALT (33%). One patient with non-Ph-like ALL died from asparaginase-associated pancreatitis, and 23 (96%) patients achieved complete remission (CR) or CR with incomplete count recovery (CRi) following induction with or without extended induction phase. Of the 22 patients who started consolidation, 20 (91%) achieved negative minimal residual disease status (MRD-) (<0.01%) CR/CRi by flow cytometry. Of 12 patients with Ph-like B-ALL, 11 achieved MRDstatus post consolidation, with only one patient having persistent MRD at 0.01%. At diagnosis, Ph-like B-ALL cases had a trend toward a greater BCL-2-dependency compared to non-Ph-like (P=0.06). The addition of venetoclax to a pediatric-inspired regimen was safe in adults with B-ALL, leading to encouraging MRD- rate post consolidation in high-risk B-ALL, including the Ph-like subtype (clinicaltrials.gov 05157971).