Crenolanib is a type I kinase inhibitor with activity against FLT3-ITD and secondary FLT3 mutants.

  • Major finding: Crenolanib is a type I kinase inhibitor with activity against FLT3-ITD and secondary FLT3 mutants.

  • Clinical relevance: Crenolanib synergizes with sorafenib to inhibit FLT3-ITD–positive AML cell growth.

  • Impact: Crenolanib may be effective in FLT3-ITD–positive AML and overcome resistance to FLT3 inhibitors.

Internal tandem duplication (ITD) mutations of fms-related tyrosine kinase 3 (FLT3) are frequently observed in acute myeloid leukemia (AML) and associated with poor outcome. Type II tyrosine kinase inhibitors (TKI) such as sorafenib and quizartinib that preferentially bind and stabilize inactive kinase conformations have shown clinical activity in patients with FLT3-ITD–positive AML, but resistance quickly develops as a result of secondary kinase domain (KD) mutations that lock FLT3 in an auto-activated state. Hypothesizing that type I kinase inhibitors capable of binding active FLT3 might be effective against secondary FLT3 KD mutations, Zimmerman and colleagues tested the activity of crenolanib, a potent, well-tolerated platelet-derived growth factor receptor inhibitor that also has high affinity for FLT3. Crenolanib had greater affinity for FLT3-ITD and FLT3 KD mutants than sorafenib and had higher affinity for active, phosphorylated kinases than inactive, nonphosphorylated kinases, indicating that crenolanib is a type I kinase inhibitor. Crenolanib potently inhibited the growth of AML cell lines expressing FLT3-ITD in vitro and in vivo and synergized with sorafenib to induce tumor regression and significantly prolong survival time in mice, suggesting that combining type I and type II kinase inhibitors may be an effective strategy to treat FLT3-ITD–positive AML. Crenolanib also potently reduced the viability of AML cell lines expressing FLT3 KD mutants associated with acquired sorafenib and quizartinib resistance and moderately inhibited the growth of cells harboring both ITD and KD mutations in vitro. Furthermore, unlike sorafenib, crenolanib significantly blocked the leukemic infiltration of AML cells expressing drug-resistant FLT3 mutants and inhibited the ex vivo growth of primary blasts from two patients with TKI-resistant FLT3-ITD–positive AML. These preclinical studies support further study of crenolanib in TKI-naïve and TKI-resistant FLT3-ITD–positive AML.

Zimmerman EI, Turner DC, Buaboonnam J, Hu S, Orwick S, Roberts MS, et al. Crenolanib is active against models of drug-resistant FLT3-ITD–positive acute myeloid leukemia. Blood 2013 Sept 17 [Epub ahead of print].

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