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Crenolanib is active against models of drug-resistant FLT3-ITD-positive acute myeloid leukemia

Eric I. Zimmerman, David C. Turner, Jassada Buaboonnam, Shuiying Hu, Shelley Orwick, Michael S. Roberts, Laura J. Janke, Abhijit Ramachandran, Clinton F. Stewart, Hiroto Inaba and Sharyn D. Baker

Key points

  • The tyrosine kinase inhibitor crenolanib has type 1 inhibitor properties and has potent activity against FLT3 activating mutations.

  • Crenolanib is active in vitro and in vivo against FLT3 inhibitor-resistant FLT3-ITD/D835 mutations.

Abstract

FLT3 kinase internal tandem duplication (ITD) mutations are common in acute myeloid leukemia (AML) and are associated with poor clinical outcome. While initial responses to FLT3 tyrosine kinase inhibitors (TKIs) are observed in FLT3-ITD-positive patients, subsequent relapse often occurs upon acquisition of secondary FLT3 kinase domain (KD) mutations, primarily at residues D835 and F691. Using biochemical assays, we determined that crenolanib, a novel TKI, demonstrates type I properties and is active against FLT3 containing ITD and/or D835 or F691 activating mutations. Potent activity was observed in FLT3-ITD-positive AML cell lines. Crenolanib delayed the outgrowth of MV4-11 cells in a xenograft mouse model, whereas in combination with the type II TKI sorafenib, a significant decrease in leukemic burden (P < 0.001) and prolonged survival (P < 0.01) was observed compared to either TKI alone. Crenolanib was active against Ba/F3 cells harboring FLT3-ITD and secondary KD mutations and sorafenib-resistant MOLM-13 cells containing FLT3-ITD/D835Y both in vitro and in vivo. In addition, crenolanib inhibited drug-resistant AML primary blasts with FLT3-ITD and D835H/Y mutations. These preclinical data demonstrate that crenolanib is effective against FLT3-ITD containing secondary KD mutations, suggesting that crenolanib may be a useful therapeutic agent for TKI-naive and drug-resistant FLT3-ITD-positive AML.

  • Submitted July 9, 2013.
  • Accepted September 12, 2013.