Venetoclax and pegcrisantaspase for complex karyotype acute myeloid leukemia.

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Emadi A, Kapadia B, Bollino D, Bhandary B, Baer MR, Niyongere S, Strovel ET, Kaizer H, Chang E, Choi EY, Ma X, Tighe KM, Carter-Cooper B, Moses BS, Civin CI, Mahurkar A, Shetty AC, Gartenhaus RB, Kamangar F, Lapidus RG

Venetoclax and pegcrisantaspase for complex karyotype acute myeloid leukemia.

Leukemia. 2021 Jul;35(7):1907-1924. doi: 10.1038/s41375-020-01080-6. Epub 2020 Nov 16.

PubMed ID

33199836 [ View in PubMed

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Abstract

Complex karyotype acute myeloid leukemia (CK-AML) has a dismal outcome with current treatments, underscoring the need for new therapies. Here, we report synergistic anti-leukemic activity of the BCL-2 inhibitor venetoclax (Ven) and the asparaginase formulation Pegylated Crisantaspase (PegC) in CK-AML in vitro and in vivo. Ven-PegC combination inhibited growth of multiple AML cell lines and patient-derived primary CK-AML cells in vitro. In vivo, Ven-PegC showed potent reduction of leukemia burden and improved survival, compared with each agent alone, in a primary patient-derived CK-AML xenograft. Superiority of Ven-PegC, compared to single drugs, and, importantly, the clinically utilized Ven-azacitidine combination, was also demonstrated in vivo in CK-AML. We hypothesized that PegC-mediated plasma glutamine depletion inhibits 4EBP1 phosphorylation, decreases the expression of proteins such as MCL-1, whose translation is cap dependent, synergizing with the BCL-2 inhibitor Ven. Ven-PegC treatment decreased cellular MCL-1 protein levels in vitro by enhancing eIF4E-4EBP1 interaction on the cap-binding complex via glutamine depletion. In vivo, Ven-PegC treatment completely depleted plasma glutamine and asparagine and inhibited mRNA translation and cellular protein synthesis. Since this novel mechanistically-rationalized regimen combines two drugs already in use in acute leukemia treatment, we plan a clinical trial of the Ven-PegC combination in relapsed/refractory CK-AML.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Venetoclax	Apoptosis regulator Bcl-2	Protein	Humans	Yes	Antagonist Inhibitor	Details