Venetoclax Combined With Chemotherapy in Pediatric and Adolescent/Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

Background: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and although many patients respond to induction therapy, those who relapse or have refractory disease face a poor prognosis. Venetoclax has promising preclinical and clinical activity in ALL. Here, we report the safety and preliminary efficacy of venetoclax combined with chemotherapy in pediatric and adolescent/young adult patients with relapsed/refractory ALL. Procedure: This phase 1, open-label, two-part, multicenter study evaluated venetoclax combined with chemotherapy in pediatric and adolescent/young adult patients (<25 years of age) with relapsed/refractory ALL. The study is registered with ClinicalTrials.gov, NCT03236857. Results: Thirty-one patients were treated and received venetoclax monotherapy (n = 1), venetoclax plus dexamethasone and/or vincristine and/or pegasparaginase (VXL; n = 20) or venetoclax plus cytarabine and/or etoposide and/or pegasparaginase (n = 10). Patients were heavily pretreated, with a median of 3 prior lines of therapy. The most common grade 3/4 treatment-emergent adverse event was febrile neutropenia (55%). One fatal adverse event possibly related to venetoclax occurred. The overall response rate of treated patients was 42%, with all responding patients achieving complete remission/complete remission with incomplete marrow recovery. In biomarker-evaluable patients, responses to venetoclax plus VXL-based or cytarabine-based chemotherapy were observed in patients harboring a range of genetic alterations and heterogeneous BH3 family member dependencies. Conclusions: Venetoclax plus VXL-based or cytarabine-based chemotherapy was overall well tolerated, with promising preliminary efficacy.