6 results on '"Waghorn K"'
Search Results
2. 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.
- Author
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Jovanovic JV, Score J, Waghorn K, Cilloni D, Gottardi E, Metzgeroth G, Erben P, Popp H, Walz C, Hochhaus A, Roche-Lestienne C, Preudhomme C, Solomon E, Apperley J, Rondoni M, Ottaviani E, Martinelli G, Brito-Babapulle F, Saglio G, Hehlmann R, Cross NC, Reiter A, and Grimwade D
- Subjects
- Benzamides, Chronic Disease, DNA Primers chemistry, Exons, Humans, Imatinib Mesylate, Kinetics, Polymerase Chain Reaction, Remission Induction, Time Factors, Treatment Outcome, United Kingdom, Antineoplastic Agents administration & dosage, Hypereosinophilic Syndrome drug therapy, Hypereosinophilic Syndrome genetics, Piperazines administration & dosage, Pyrimidines administration & dosage, Receptor, Platelet-Derived Growth Factor alpha biosynthesis, mRNA Cleavage and Polyadenylation Factors biosynthesis
- 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.
- Published
- 2007
- Full Text
- View/download PDF
3. Durable responses to imatinib in patients with PDGFRB fusion gene-positive and BCR-ABL-negative chronic myeloproliferative disorders.
- Author
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David M, Cross NC, Burgstaller S, Chase A, Curtis C, Dang R, Gardembas M, Goldman JM, Grand F, Hughes G, Huguet F, Lavender L, McArthur GA, Mahon FX, Massimini G, Melo J, Rousselot P, Russell-Jones RJ, Seymour JF, Smith G, Stark A, Waghorn K, Nikolova Z, and Apperley JF
- Subjects
- Adult, Aged, Aged, 80 and over, Benzamides, Biomarkers, Tumor blood, Child, Child, Preschool, Drug Evaluation, Eosinophilia etiology, Female, Follow-Up Studies, Humans, Imatinib Mesylate, Infant, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative blood, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative drug therapy, Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative genetics, Male, Middle Aged, Myeloproliferative Disorders blood, Myeloproliferative Disorders genetics, Oncogene Proteins, Fusion genetics, RNA, Messenger blood, RNA, Neoplasm blood, Receptor, Platelet-Derived Growth Factor beta genetics, Retrospective Studies, Reverse Transcriptase Polymerase Chain Reaction, Translocation, Genetic, Treatment Outcome, Antineoplastic Agents therapeutic use, Fusion Proteins, bcr-abl blood, Myeloproliferative Disorders drug therapy, Oncogene Proteins, Fusion blood, Piperazines therapeutic use, Protein Kinase Inhibitors therapeutic use, Pyrimidines therapeutic use, Receptor, Platelet-Derived Growth Factor beta blood
- Abstract
Fusion genes derived from the platelet-derived growth factor receptor beta (PDGFRB) or alpha (PDGFRA) play an important role in the pathogenesis of BCR-ABL-negative chronic myeloproliferative disorders (CMPDs). These fusion genes encode constitutively activated receptor tyrosine kinases that can be inhibited by imatinib. Twelve patients with BCR-ABL-negative CMPDs and reciprocal translocations involving PDGFRB received imatinib for a median of 47 months (range, 0.1-60 months). Eleven had prompt responses with normalization of peripheral-blood cell counts and disappearance of eosinophilia; 10 had complete resolution of cytogenetic abnormalities and decrease or disappearance of fusion transcripts as measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Updates were sought from 8 further patients previously described in the literature; prompt responses were described in 7 and persist in 6. Our data show that durable hematologic and cytogenetic responses are achieved with imatinib in patients with PDGFRB fusion-positive, BCR-ABL-negative CMPDs.
- Published
- 2007
- Full Text
- View/download PDF
4. Identification of a novel imatinib responsive KIF5B-PDGFRA fusion gene following screening for PDGFRA overexpression in patients with hypereosinophilia.
- Author
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Score J, Curtis C, Waghorn K, Stalder M, Jotterand M, Grand FH, and Cross NC
- Subjects
- Antineoplastic Agents therapeutic use, Benzamides, Cohort Studies, Gene Rearrangement, Humans, Hypereosinophilic Syndrome drug therapy, Imatinib Mesylate, In Situ Hybridization, Fluorescence, Male, Middle Aged, Piperazines therapeutic use, Protein-Tyrosine Kinases drug effects, Pyrimidines therapeutic use, RNA, Messenger drug effects, RNA, Messenger genetics, Receptor, Platelet-Derived Growth Factor alpha antagonists & inhibitors, Remission Induction, Reverse Transcriptase Polymerase Chain Reaction methods, Sensitivity and Specificity, Treatment Outcome, Antineoplastic Agents pharmacology, Gene Expression Regulation, Neoplastic drug effects, Genetic Testing, Hypereosinophilic Syndrome genetics, Oncogene Fusion genetics, Piperazines pharmacology, Protein-Tyrosine Kinases genetics, Pyrimidines pharmacology, Receptor, Platelet-Derived Growth Factor alpha genetics
- Abstract
Idiopathic hypereosinophilic syndrome (IHES) is a disease that is difficult to classify, and diagnosis is one of exclusion. The identification of a cytogenetically invisible interstitial deletion resulting in the fusion of FIP1-Like-1 (FIP1L1) to platelet-derived growth factor receptor alpha (PDGFRA) has enabled many IHES cases to be reclassified as chronic eosinophilic leukemia. As it is likely that PDGFRA may fuse to other partner genes, we established a reverse transcriptase-PCR test to detect specific overexpression of the PDGFRA kinase domain as an indicator of the presence of a fusion gene. Overexpression was detected in 12/12 FIP1L1-PDGFRA-positive patients, plus 9/217 (4%) patients with hypereosinophilia who had tested negative for FIP1L1-PDGFRA. One of the positive cases was investigated in detail and found to have a complex karyotype involving chromosomes 3, 4 and 10. Amplification of the genomic breakpoint by bubble PCR revealed a novel fusion between KIF5B at 10p11 and PDGFRA at 4q12. Imatinib, a known inhibitor of PDGFRalpha, produced a complete cytogenetic response and disappearance of the KIF5B-PDGFRA fusion by PCR, from both genomic DNA and mRNA. This study demonstrates the utility of screening for PDGFRA kinase domain overexpression in patients with IHES and has identified a third PDGFRA fusion partner in chronic myeloproliferative disorders.
- Published
- 2006
- Full Text
- View/download PDF
5. Minimal molecular response in polycythemia vera patients treated with imatinib or interferon alpha.
- Author
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Jones AV, Silver RT, Waghorn K, Curtis C, Kreil S, Zoi K, Hochhaus A, Oscier D, Metzgeroth G, Lengfelder E, Reiter A, Chase AJ, and Cross NC
- Subjects
- Adult, Aged, Alleles, Amino Acid Substitution, Benzamides, Biomarkers blood, Dose-Response Relationship, Drug, Female, Hematopoiesis drug effects, Hematopoiesis genetics, Humans, Imatinib Mesylate, Janus Kinase 2, Male, Middle Aged, Polycythemia Vera blood, Polycythemia Vera genetics, Protein-Tyrosine Kinases antagonists & inhibitors, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins antagonists & inhibitors, Proto-Oncogene Proteins genetics, Recombinant Proteins, Remission Induction methods, Antineoplastic Agents administration & dosage, Interferon Type I administration & dosage, Piperazines administration & dosage, Polycythemia Vera drug therapy, Protein Kinase Inhibitors administration & dosage, Pyrimidines administration & dosage
- Abstract
Imatinib and recombinant interferon alpha (rIFNalpha) can induce remission in polycythemia vera (PV) patients, but gauging the depth of responses has not been possible due to lack of a specific disease marker. We found that patients undergoing imatinib (n = 14) or rIFNalpha (n = 7) therapy remained strongly positive for V617F JAK2, although there was a significant reduction in the median percentage of mutant alleles that correlated with hematologic response (P = .001). Furthermore, individuals who achieved complete hematologic remission had lower levels of V617F than those who did not (P = .001). Of 9 imatinib-treated cases for whom pretreatment samples were available, 7 with no or partial hematologic responses showed a marginal increase (median, 1.2-fold; range, 1.0-1.5) in the percentage of V617F alleles on treatment, whereas the 2 patients who achieved complete hematologic remission showed a 2- to 3-fold reduction. Our data indicate that, although PV patients may benefit from imatinib or rIFNalpha, molecular responses are relatively modest.
- Published
- 2006
- Full Text
- View/download PDF
6. 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
- Author
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Finella Brito-Babapulle, Christoph Walz, Giuseppe Saglio, Rüdiger Hehlmann, Emanuela Ottaviani, Ellen Solomon, Andreas Hochhaus, Catherine Roche-Lestienne, Joannah Score, David Grimwade, Enrico Gottardi, Michela Rondoni, Andreas Reiter, Jelena V. Jovanovic, Katherine Waghorn, Jane F. Apperley, Nicholas C.P. Cross, Claude Preudhomme, Georgia Metzgeroth, Giovanni Martinelli, Helena Popp, Daniela Cilloni, Philipp Erben, Jovanovic JV, Score J, Waghorn K, Cilloni D, Gottardi E, Metzgeroth G, Erben P, Popp H, Walz C, Hochhaus A, Roche-Lestienne C, Preudhomme C, Solomon E, Apperley J, Rondoni M, Ottaviani E, Martinelli G, Brito-Babapulle F, Saglio G, Hehlmann R, Cross NC, Reiter A, and Grimwade D.
- Subjects
Oncology ,medicine.medical_specialty ,Receptor, Platelet-Derived Growth Factor alpha ,Time Factors ,Immunology ,Hypereosinophilia ,Antineoplastic Agents ,Biochemistry ,Polymerase Chain Reaction ,Piperazines ,Fusion gene ,Internal medicine ,hemic and lymphatic diseases ,Hypereosinophilic Syndrome ,Medicine ,Humans ,FIP1L1-PDGFRA ,Molecular lesion ,DNA Primers ,mRNA Cleavage and Polyadenylation Factors ,Chronic eosinophilic leukemia ,Hematology ,business.industry ,Remission Induction ,Imatinib ,Cell Biology ,Exons ,medicine.disease ,United Kingdom ,Kinetics ,Imatinib mesylate ,Pyrimidines ,Treatment Outcome ,Fusion transcript ,CHRONIC EOSINOPHILIC LEUKEMIA ,Benzamides ,Chronic Disease ,Imatinib Mesylate ,medicine.symptom ,business ,medicine.drug - 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 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 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 103-105). 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-PDGFRα fusion to imatinib, as compared with BCR-ABL, and underline the importance of RQ-PCR monitoring to guide management using molecularly targeted therapies.
- Published
- 2007
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