In vivo activity of the dual SYK/FLT3 inhibitor TAK‐659 against pediatric acute lymphoblastic leukemia xenografts

Abstract

AbstractBackgroundWhile children with acute lymphoblastic leukemia (ALL) experience close to a 90% likelihood of cure, the outcome for certain high‐risk pediatric ALL subtypes remains dismal. Spleen tyrosine kinase (SYK) is a prominent cytosolic nonreceptor tyrosine kinase in pediatric B‐lineage ALL (B‐ALL). Activating mutations or overexpression of Fms‐related receptor tyrosine kinase 3 (FLT3) are associated with poor outcome in hematological malignancies. TAK‐659 (mivavotinib) is a dual SYK/FLT3 reversible inhibitor, which has been clinically evaluated in several other hematological malignancies. Here, we investigate the in vivo efficacy of TAK‐659 against pediatric ALL patient‐derived xenografts (PDXs).MethodsSYK and FLT3 mRNA expression was quantified by RNA‐seq. PDX engraftment and drug responses in NSG mice were evaluated by enumerating the proportion of human CD45+ cells (%huCD45+) in the peripheral blood. TAK‐659 was administered per oral at 60 mg/kg daily for 21 days. Events were defined as %huCD45+ ≥ 25%. In addition, mice were humanely killed to assess leukemia infiltration in the spleen and bone marrow (BM). Drug efficacy was assessed by event‐free survival and stringent objective response measures.ResultsFLT3 and SYK mRNA expression was significantly higher in B‐lineage compared with T‐lineage PDXs. TAK‐659 was well tolerated and significantly prolonged the time to event in six out of eight PDXs tested. However, only one PDX achieved an objective response. The minimum mean %huCD45+ was significantly reduced in five out of eight PDXs in TAK‐659‐treated mice compared with vehicle controls.ConclusionsTAK‐659 exhibited low to moderate single‐agent in vivo activity against pediatric ALL PDXs representative of diverse subtypes.