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

Venetoclax selectively inhibits BCL-2 and restores apoptotic signaling of hematological malignant cells. Venetoclax in combination with hypomethylating and low-dose cytotoxic agents has revolutionized the management of elderly patients affected by acute myeloid leukemia (AML), as well as that of patients unfit to receive intensive chemotherapy. In a single phase 1 pediatric trial conducted on relapsed/refractory AML, the combination of venetoclax with intensive chemotherapy was shown to be safe and yielded promising response rates. In addition, several retrospective studies in children with AML reported that venetoclax combined with hypomethylating agents and cytotoxic drugs appears a safe and efficacious bridge to transplant. 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, discussing a 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.