Preclinical efficacy of azacitidine and venetoclax for infant KMT2A-rearranged acute lymphoblastic leukemia reveals a new therapeutic strategy.

Cheung LC, Aya-Bonilla C, Cruickshank MN, Chiu SK, Kuek V, Anderson D, Chua GA, Singh S, Oommen J, Ferrari E, Hughes AM, Ford J, Kunold E, Hesselman MC, Post F, Faulk KE, Breese EH, Guest EM, Brown PA, Loh ML, Lock RB, Kees UR, Jafari R, Malinge S, Kotecha RS

Leukemia 37 (1) 61-71 [2023-01-00; online 2022-11-15]

Infants with KMT2A-rearranged B-cell acute lymphoblastic leukemia (ALL) have a dismal prognosis. Survival outcomes have remained static in recent decades despite treatment intensification and novel therapies are urgently required. KMT2A-rearranged infant ALL cells are characterized by an abundance of promoter hypermethylation and exhibit high BCL-2 expression, highlighting potential for therapeutic targeting. Here, we show that hypomethylating agents exhibit in vitro additivity when combined with most conventional chemotherapeutic agents. However, in a subset of samples an antagonistic effect was seen between several agents. This was most evident when hypomethylating agents were combined with methotrexate, with upregulation of ATP-binding cassette transporters identified as a potential mechanism. Single agent treatment with azacitidine and decitabine significantly prolonged in vivo survival in KMT2A-rearranged infant ALL xenografts. Treatment of KMT2A-rearranged infant ALL cell lines with azacitidine and decitabine led to differential genome-wide DNA methylation, changes in gene expression and thermal proteome profiling revealed the target protein-binding landscape of these agents. The selective BCL-2 inhibitor, venetoclax, exhibited in vitro additivity in combination with hypomethylating or conventional chemotherapeutic agents. The addition of venetoclax to azacitidine resulted in a significant in vivo survival advantage indicating the therapeutic potential of this combination to improve outcome for infants with KMT2A-rearranged ALL.

PubMed 36380143

DOI 10.1038/s41375-022-01746-3

Crossref 10.1038/s41375-022-01746-3

pmc: PMC9883157
pii: 10.1038/s41375-022-01746-3