Combination fedratinib and venetoclax has activity against human B-ALL with high FLT3 expression
Year: 2023
Type: preprint
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 while inducing CD19 expression. Overall, our data demonstrates the efficacy of a combinatorial treatment strategy of fedratinib and venetoclax against human B-ALL expressing high levels of Flt3.
Language: English
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G115506582, G1332332826, G1711654737, G1712026730, G3602384064, G4004214011, G4232064225, G42679306, G6523277953, G696271718, Epigenetic Gene Regulation by JAK1 Kinase in Diffuse Large B-Cell Lymphoma, G9000112581, G9000122792, G9000133220, G9000265189, G9000352744, University of Wisconsin Institute for Clinical and Translational Research
OpenAlex ID: W4380201863