Venetoclax and pegcrisantaspase for complex karyotype acute myeloid leukemia View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2020-11-16

AUTHORS

Ashkan Emadi, Bandish Kapadia, Dominique Bollino, Binny Bhandary, Maria R. Baer, Sandrine Niyongere, Erin T. Strovel, Hannah Kaizer, Elizabeth Chang, Eun Yong Choi, Xinrong Ma, Kayla M. Tighe, Brandon Carter-Cooper, Blake S. Moses, Curt I. Civin, Anup Mahurkar, Amol C. Shetty, Ronald B. Gartenhaus, Farin Kamangar, Rena G. Lapidus

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. More... »

PAGES

1907-1924

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  • Journal

    TITLE

    Leukemia

    ISSUE

    7

    VOLUME

    35

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41375-020-01080-6

    DOI

    http://dx.doi.org/10.1038/s41375-020-01080-6

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1132656597

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/33199836


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