In Vivo Activity of the Dual SYK/FLT3 Inhibitor TAK-659 Against Pediatric Acute Lymphoblastic Leukemia Xenografts

Overview

Journal Pediatr Blood Cancer

Specialties Hematology
Oncology
Pediatrics

Date 2023 Jun 20

PMID 37339930

Authors

Keira Hughes

Kathryn Evans

Eric J Earley

Christopher M Smith

Stephen W Erickson

Tim Stearns

Vivek M Philip

Steven B Neuhauser

Jeffrey H Chuang

Emily L Jocoy

Carol J Bult

Beverly A Teicher

Malcolm A Smith

Richard B Lock

Affiliations

Soon will be listed here.

Abstract

Background: While 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).

Methods: SYK 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.

Results: FLT3 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.

Conclusions: TAK-659 exhibited low to moderate single-agent in vivo activity against pediatric ALL PDXs representative of diverse subtypes.

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