BACKGROUND: Venetoclax is a potent, oral BCL-2 inhibitor approved as combination therapy for the treatment of adults with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy. This study evaluated the safety and preliminary efficacy of venetoclax alone or combined with chemotherapy in paediatric and adolescent/young adult patients with relapsed/refractory AML.

PROCEDURE: In this phase 1, open-label, two-part, multicentre study, paediatric and adolescent/young adult patients (<25 years of age) with relapsed/refractory AML were treated with venetoclax alone or in combination with hypomethylating agents or cytarabine. The study is registered with ClinicalTrials.gov, NCT03236857.

RESULTS: A total of 37 patients received treatment with either venetoclax as a monotherapy (n = 3) or in combination with decitabine (n = 5), azacitidine (n = 19), low-dose cytarabine (n = 1) or high-dose cytarabine (HDAC; n = 9). Febrile neutropenia (57%), hypokalaemia (38%), and thrombocytopenia (35% [thrombocytopenia, 19%; platelet count decreased, 16%]) were the most common grade 3/4 treatment-emergent adverse events. Across all venetoclax combinations, the overall response rate (ORR) was 24% (9/37), and the median duration of response was 2.6 months (95% CI, 0.5-7.9). Among the combinations, ORR was 44% with venetoclax plus HDAC and 21% with venetoclax plus azacitidine. In biomarker-evaluable patients, responses to venetoclax plus chemotherapy were observed in patients harbouring mutations across a range of functional classifications and heterogeneous BH3 family member dependencies.

CONCLUSIONS: Venetoclax alone or combined with chemotherapy was well tolerated in paediatric and adolescent/young adult patients with relapsed/refractory AML, with promising, although transient, responses with venetoclax plus HDAC or azacitidine.