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

BackgroundWhile 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.

Automated summary

Although the majority of children with acute lymphoblastic leukemia (ALL) can be cured, certain high-risk subtypes of pediatric ALL have poor treatment outcomes. This study investigated the in vivo efficacy of TAK-659 in patient-derived xenografts (PDXs) of pediatric ALL. The results showed that TAK-659 prolonged the time to event in six out of eight PDXs tested, but only one PDX achieved an objective response.