title: Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia.
abstract: The FIP1L1-PDGFRA fusion gene is a recurrent molecular lesion in eosinophilia-associated myeloproliferative disorders, predicting a favorable response to imatinib mesylate. To investigate its prevalence, 376 patients with persistent unexplained hypereosinophilia were screened by the United Kingdom reference laboratory, revealing 40 positive cases (11%). To determine response kinetics following imatinib, real-time quantitative-polymerase chain reaction (RQ-PCR) assays were developed and evaluated in samples accrued from across the European LeukemiaNet. The FIP1L1-PDGFRA fusion transcript was detected at a sensitivity of 1 in 10(5) in serial dilution of the EOL-1 cell line. Normalized FIP1L1-PDGFRA transcript levels in patient samples prior to imatinib varied by almost 3 logs. Serial monitoring was undertaken in patients with a high level of FIP1L1-PDGFRA expression prior to initiation of imatinib (100 mg/d-400 mg/d). Overall, 11 of 11 evaluable patients achieved at least a 3-log reduction in FIP1L1-PDGFRA fusion transcripts relative to the pretreatment level within 12 months, with achievement of molecular remission in 9 of 11 (assay sensitivities 1 in 10(3)-10(5)). In 2 patients, withdrawal of imatinib was followed by a rapid rise in FIP1L1-PDGFRA transcript levels. Overall, these data are consistent with the exquisite sensitivity of the FIP1L1-PDGFRalpha fusion to imatinib, as compared with BCR-ABL, and underline the importance of RQ-PCR monitoring to guide management using molecularly targeted therapies.
authors.affiliation: Department of Medical and Molecular Genetics, Guy's Hospital, King's College London, UK.
authors.forename: Jelena V
authors.initials: JV
authors.lastname: Jovanovic
authors.forename: Joannah
authors.initials: J
authors.lastname: Score
authors.forename: Katherine
authors.initials: K
authors.lastname: Waghorn
authors.forename: Daniela
authors.initials: D
authors.lastname: Cilloni
authors.forename: Enrico
authors.initials: E
authors.lastname: Gottardi
authors.forename: Georgia
authors.initials: G
authors.lastname: Metzgeroth
authors.forename: Philipp
authors.initials: P
authors.lastname: Erben
authors.forename: Helena
authors.initials: H
authors.lastname: Popp
authors.forename: Christoph
authors.initials: C
authors.lastname: Walz
authors.forename: Andreas
authors.initials: A
authors.lastname: Hochhaus
authors.forename: Catherine
authors.initials: C
authors.lastname: Roche-Lestienne
authors.forename: Claude
authors.initials: C
authors.lastname: Preudhomme
authors.forename: Ellen
authors.initials: E
authors.lastname: Solomon
authors.forename: Jane
authors.initials: J
authors.lastname: Apperley
authors.forename: Michela
authors.initials: M
authors.lastname: Rondoni
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ottaviani
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Finella
authors.initials: F
authors.lastname: Brito-Babapulle
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Hehlmann
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.forename: Andreas
authors.initials: A
authors.lastname: Reiter
authors.forename: David
authors.initials: D
authors.lastname: Grimwade
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001549:Benzamides; D002908:Chronic Disease; D017931:DNA Primers / Q000737:chemistry; D005091:Exons; D006801:Humans; D017681:Hypereosinophilic Syndrome / Q000188:drug therapy* / Q000235:genetics*; D000068877:Imatinib Mesylate; D007700:Kinetics; D010879:Piperazines / Q000008:administration & dosage*; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000008:administration & dosage*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000096:biosynthesis*; D012074:Remission Induction; D013997:Time Factors; D016896:Treatment Outcome; D006113:United Kingdom; D039221:mRNA Cleavage and Polyadenylation Factors / Q000096:biosynthesis*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D017931:DNA Primers; C479818:FIP1L1 protein, human; D010879:Piperazines; D011743:Pyrimidines; D039221:mRNA Cleavage and Polyadenylation Factors; D000068877:Imatinib Mesylate; D020796:Receptor, Platelet-Derived Growth Factor alpha