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.
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.
Jovanovic
Jelena V
JV
Department of Medical and Molecular Genetics, Guy's Hospital, King's College London, UK.
Score
Joannah
J
Waghorn
Katherine
K
Cilloni
Daniela
D
Gottardi
Enrico
E
Metzgeroth
Georgia
G
Erben
Philipp
P
Popp
Helena
H
Walz
Christoph
C
Hochhaus
Andreas
A
Roche-Lestienne
Catherine
C
Preudhomme
Claude
C
Solomon
Ellen
E
Apperley
Jane
J
Rondoni
Michela
M
Ottaviani
Emanuela
E
Martinelli
Giovanni
G
Brito-Babapulle
Finella
F
Saglio
Giuseppe
G
Hehlmann
Rüdiger
R
Cross
Nicholas C P
NC
Reiter
Andreas
A
Grimwade
David
D
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*
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