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Blood, 1 June 2007, Vol. 109, No. 11, pp. 4635-4640.
Prepublished online as a Blood First Edition Paper on February 13, 2007February 27, 2007; DOI 10.1182/blood-2006-10-050054.
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Submitted October 13, 2006
Accepted February 6, 2007
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
Jelena V Jovanovic, Joannah Score, Katherine Waghorn, Daniela Cilloni, Enrico Gottardi, Georgia Metzgeroth, Philipp Erben, Helena Popp, Christoph Walz, Andreas Hochhaus, Catherine Roche-Lestienne, Claude Preudhomme, Ellen Solomon, Jane Apperley, Michela Rondoni, Emanuela Ottaviani, Giovanni Martinelli, Finella Brito-Bapapulle, Giuseppe Saglio, Rudiger Hehlmann, Nicholas CP Cross, Andreas Reiter, and David Grimwade*
Department of Medical & Molecular Genetics, King's College London, London, United Kingdom
Wessex Regional Genetics Laboratory, University of Southampton School of Medicine, Salisbury, United Kingdom
Department of Clinical & Biological Sciences, University of Turin, Turin, Italy
III. Medizinische Universitatsklinik, Medizinische Fakultat Mannheim, University of Heidelberg, Mannheim, Germany
Laboratoire d'Hematologie, Hopital Calmette, Lille, France
Department of Haematology, Imperial College, London, United Kingdom
Institute of Hematology & Medical Oncology, University of Bologna, Bologna, Italy
Department of Haematology, Ealing Hospital, London, United Kingdom
* Corresponding author; email: david.grimwade{at}genetics.kcl.ac.uk.
The FIP1L1-PDGFRA fusion gene is a recurrent molecular lesion in eosinophilia-associated myeloproliferative disorders, predicting a favorable response to imatinib. To investigate its prevalence, 376 patients with persistent unexplained hypereosinophilia were screened by the UK reference laboratory, revealing 40 positive cases (11%). To determine response kinetics following imatinib, real-time quantitative PCR (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 105 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 high level FIP1L1-PDGFRA expression prior to initiation of imatinib (100-400mg/d). Overall, 11/11 evaluable patients achieved at least a 3-log reduction in FIP1L1-PDGFRA fusion transcripts relative to the pre-treatment level within 12 months, with achievement of molecular remission in 9 of 11 (assay sensitivities 1 in 103-5). In two 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-PDGFR fusion to imatinib, as compared to BCR-ABL, and underline the importance of RQ-PCR monitoring to guide management using molecularly targeted therapies.
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