Durable responses to imatinib in patients with PDGFRB fusion gene–positive and BCR-ABL–negative chronic myeloproliferative disorders

Dávid, Marianna; Cross, Nicholas C. P.; Burgstaller, Sonja; Chase, Andrew; Curtis, Claire; Dang, Raymond; Gardembas, Martine; Goldman, John M.; Grand, Francis; Hughes, Gail; Huguet, Françoise; Lavender, Louise; McArthur, Grant A.; Mahon, François Xavier; Massimini, Giorgio; Melo, Junia V.; Rousselot, Philippe; Russell‐Jones, Robin; Seymour, John F.; Smith, Graeme; Stark, Alastair; Waghorn, Katherine; Nikolova, Zariana; Apperley, Jane F.

doi:10.1182/blood-2006-05-024828

Cited by 152 publications

(90 citation statements)

References 18 publications

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“…It is well documented that Caucasian populations carry the 8.1 ancestral haplotype (AH) that includes the TNF-308A allele (HLA-A1-B8-TNF-308A-DR3-DQ2). 3 Notably, the 8.1 AH is implicated in the risk of numerous autoimmune conditions, including those associated with NHL (for example, systemic lupus erythematosus and Sjogren's syndrome). [3][4][5] It remains unknown, however, whether the association reported for TNF-308A is due to or independent from HLA alleles and/or haplotypes.…”

Section: Conflict Of Interestmentioning

confidence: 99%

“…1,2 Myelodysplastic features and thrombocytopenia are often associated with PDGFRB translocations. 3 Here, we describe a new acquired t(5;9) chromosomal translocation in a 67-year-old male patient who presented with thrombocythemia (platelets, 904 Â 10 9 /l) without prominent eosinophilia or neutrophilia. Bone marrow smears showed an increased number of polymorphic megakaryocytes without any blast cells or dysplastic features.…”

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confidence: 99%

“…3 In FIP1L1-PDGFRa-positive myeloproliferative neoplasm, a dose of 100 mg/day was shown to be effective. 2 As PDGFRa and b have similar sensitivity to imatinib, a low dose is likely to be effective in the treatment of PDGFRBassociated myeloid neoplasms, as suggested by the present report, with potential benefits in terms of costs and side effects.…”

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confidence: 99%

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KANK1, a candidate tumor suppressor gene, is fused to PDGFRB in an imatinib-responsive myeloid neoplasm with severe thrombocythemia

et al. 2010

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the secondary malignancies and cardiovascular events, may not directly relate to SCT itself.Long-term follow-up should also consider issues of quality of life (QOL). This initial analysis shows that chronic graft-versushost disease rates and the duration of required immune suppression were lower after RIC. Chronic graft-versus-host disease is a dominant factor determining QOL, suggesting better long-term QOL with RIC; however, formal QOL assessment is required to determine this question.The major limitation of this study is the nonrandomized comparison and the selection biases in allocating patients to one of the regimens. However, because patients were selected for RIC based on high risk for non-relapse mortality, and because OS was similar among these patients given RIC and eligible patients given MAC, it is possible that results in standard risk patients may be similar. Randomized studies, for patients in CR (preferentially CR1) with long-term follow-up and assessment of late complication and QOL, will be needed to determine the best approach in this setting. MAC and possibly the new reduced toxicity myeloablative regimens are still the best approach in patients with active disease.

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Section: Conflict Of Interestmentioning

confidence: 99%

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confidence: 99%

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KANK1, a candidate tumor suppressor gene, is fused to PDGFRB in an imatinib-responsive myeloid neoplasm with severe thrombocythemia

et al. 2010

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“…12 Imatinib induces durable clinical responses in MPDs associated with PDGFRβ. 4,[13][14][15] One of the larger studies showed that with imatinib therapy blood counts underwent rapid…”

Section: Rationale and Clinical Evidence For Imatinibmentioning

confidence: 99%

New Haematological Indications for Imatinib

Verstovšek¹

2007

European Oncology &Amp; Haematology

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“…[1][2][3] Treatment with imatinib has proved to be highly effective in certain leukemias, most notably chronic myeloid leukemia with the BCR-ABL fusion gene 4 and myeloproliferative neoplasms (MPNs) with gene fusions involving PDGFRA 5 or PDGFRB. 6 Response to imatinib has also been described in some MPN patients in the absence of any cytogenetic or molecular indications of sensitive gene fusions. The aim of this study was to identify novel imatinib-sensitive abnormalities, and our strategy was to screen a panel of cell lines for imatinib sensitivity, followed by a detailed mutational analysis of candidate genes.…”

Section: Introductionmentioning

confidence: 99%

Imatinib sensitivity as a consequence of a CSF1R-Y571D mutation and CSF1/CSF1R signaling abnormalities in the cell line GDM1

et al. 2008

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Imatinib is usually a highly effective treatment for myeloproliferative neoplasms (MPNs) associated with ABL, PDGFRA or PDGFRB gene fusions; however, occasional imatinibresponsive patients have been reported without abnormalities of these genes. To identify novel imatinib-sensitive lesions, we screened 11 BCR-ABL-negative cell lines and identified GDM1, derived from a patient with an atypical MPN (aMPN), as being responsive to imatinib. Screening of genes encoding known imatinib targets revealed an exon 12 mutation in the colonystimulating factor 1 receptor (CSF1R; c-FMS) with a predicted Y571D amino-acid substitution. CSF1R in GDM1 was constitutively phosphorylated, but rapidly dephosphorylated on exposure to imatinib. Y571D did not transform FDCP1 cells to growth factor independence, but resulted in a significantly increased colony growth compared with controls, constitutive CSF1R phosphorylation and elevated CSF1R signaling. We found that GDM1 expresses CSF1, and CSF1 neutralization partially inhibited proliferation, suggesting the importance of both autocrine and intrinsic mechanisms of CSF1R activation. An extensive screen of CSF1R in aMPNs and acute myeloid leukemia identified three additional novel missense variants. None of these variants were active in transformation assays and are therefore likely to be previously unreported rare polymorphisms or non-pathogenic passenger mutations.

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Durable responses to imatinib in patients with PDGFRB fusion gene–positive and BCR-ABL–negative chronic myeloproliferative disorders

Abstract: Fusion genes derived from the plateletderived growth factor receptor beta (PDG-FRB

Cited by 152 publications

References 18 publications

KANK1, a candidate tumor suppressor gene, is fused to PDGFRB in an imatinib-responsive myeloid neoplasm with severe thrombocythemia

KANK1, a candidate tumor suppressor gene, is fused to PDGFRB in an imatinib-responsive myeloid neoplasm with severe thrombocythemia

New Haematological Indications for Imatinib

Imatinib sensitivity as a consequence of a CSF1R-Y571D mutation and CSF1/CSF1R signaling abnormalities in the cell line GDM1

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