Title: FIP1L1-PDGFR alpha D842V, a novel panresistant mutant, emerging after treatment of FIP1L1-PDGFR alpha T674I eosinophilic leukemia with single agent sorafenib
Authors: Lierman, Els
Michaux, Lucienne
Beullens, Els
Pierre, P
Marynen, Peter
Cools, Jan
Vandenberghe, Peter # ×
Issue Date: May-2009
Publisher: Nature publishing group
Series Title: Leukemia vol:23 issue:5 pages:845-851
Abstract: Chronic eosinophilic leukemia (CEL) is a rare myeloproliferative neoplasm characterized by the FIP1L1-PDGFRA fusion gene, variant PDGFRA fusions or other genetic lesions. Most FIP1L1-PDGFRA positive patients enjoy durable and complete molecular responses to low-dose imatinib (Glivec/Gleevec). However, resistance mediated by a T674I mutation in the ATP-binding pocket of PDGFRA has been reported in advanced disease, and sorafenib, a potent inhibitor of RAF-1, B-RAF, VEGFR and PDGFR, is active against this mutant in vitro. We describe a case of FIP1L1-PDGFR alpha T674I CEL in blast crisis that responded to sorafenib (Nexavar). However, this clinical response was short-lived because of the rapid emergence of a FIP1L1-PDGFR alpha D842V mutant. An N-Nitroso-N-ethylurea-mutagenesis screen indeed identified this mutant as a major sorafenib-resistant mutant. In vitro, the novel FIP1L1-PDGFR alpha D842V mutant is highly resistant to sorafenib, imatinib, dasatinib (Sprycell) and PKC412 (Midostaurin). Thus, sorafenib is clinically active in imatinib-resistant FIP1L1-PDGFR alpha T674I CEL, but the rapid emergence of other mutants may limit the response duration. The identification of new PDGFR inhibitors will be required to overcome resistance by this D842V mutant. Leukemia (2009) 23, 845-851; doi:10.1038/leu. 2009.2; published online 12 February 2009
ISSN: 0887-6924
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory of Molecular Biology of Leukemia
Clinical Genetics Section (-)
Laboratory for Genetics of Malignant Disorders
× corresponding author
# (joint) last author

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