Abstract
Treatment of relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) remains a challenge, particularly in patients who do not respond to traditional chemotherapy or immunotherapy. The objective of this study was to assess the efficacy of fedratinib, a semi selective JAK2 inhibitor and venetoclax, a selective BCL-2 inhibitor, on human B-ALL using both single-agent and combinatorial treatments. The combination treatment of fedratinib and venetoclax improved killing of the human B-ALL cell lines RS4;11 and SUPB-15 in vitro over single-agent treatments. This combinatorial effect was not detected in the human B-ALL cell line NALM-6, which was less responsive to fedratinib due to the absence of Flt3 expression. The combination treatment induces a unique gene expression profile relative to single-agent treatment and with an enrichment in apoptotic pathways. Finally, the combination treatment was superior to single agent treatment in an in vivo xenograft model of human B-ALL with a two-week treatment regimen significantly improving overall survival. Overall, our data demonstrates the efficacy of a combinatorial treatment strategy of fedratinib and venetoclax against human B-ALL expressing high levels of Flt3.
Key points
Combination fedratinib and venetoclax reduces the survival and proliferation of FLT3+ B-ALL in vitro.
Gene set enrichment analysis of RNA from B-ALL treated with fedratinib and venetoclax identified dysregulation of pathways associated with apoptosis, DNA repair and proliferation.
Combination fedratinib and venetoclax reduces the number of peripheral blood B-ALL blasts in vivo, improving overall survival while also increasing CD19 expression.
Competing Interest Statement
C.M.C receives honorarium for advisory board membership for Bayer, Elephas, Nektar Therapeutics, Novartis and WiCell Research Institute, who had no input in the study design, analysis, manuscript preparation or decision to submit. All other authors declare they have no competing interests.