Venetoclax: a new player in the treatment of children with high-risk myeloid malignancies?

Venetoclax selectively inhibits B-cell lymphoma 2 (BCL-2) and restores apoptotic signaling of hematologic malignant cells. Venetoclax, in combination with hypomethylating and low-dose cytotoxic agents, has revolutionized the management of older patients affected by acute myeloid leukemia (AML) and that of patients unfit to receive intensive chemotherapy. In a single phase 1 pediatric trial conducted on relapsed or refractory AML, the combination of venetoclax and intensive chemotherapy was shown to be safe and yielded promising response rates. In addition, several retrospective studies in children with AML reported that venetoclax, when combined with hypomethylating agents and cytotoxic drugs, seems to be a safe and efficacious bridge to transplant. The promising results on the use of venetoclax combinations in advanced myelodysplastic syndromes (MDS) and therapy-related MDS/AML have also been reported in small case series. This review summarizes the available current knowledge about venetoclax use in childhood high-risk myeloid neoplasms and discusses the possible integration of BCL-2 inhibition in the current treatment algorithm of these children. It also focuses on specific genetic subgroups potentially associated with response in preclinical and clinical studies.