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Myeloproliferative Neoplasms - Clinical Merase Chain Reaction (PCR).The Patient Was Treated with Imatinib and Achieved Hematologic and Cytogenetic Remission

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Myeloproliferative Neoplasms - Clinical Merase Chain Reaction (PCR).The Patient Was Treated with Imatinib and Achieved Hematologic and Cytogenetic Remission Stockholm, Sweden, June 13 – 16, 2013 cific amplification of the genomic breakpoints and reverse transcription poly - Myeloproliferative neoplasms - Clinical merase chain reaction (PCR).The patient was treated with imatinib and achieved hematologic and cytogenetic remission. Minimal residual disease screening over 3 years with nested PCR failed to detect CEP85L-PDGFRB B1556 mRNA or genomic DNA, confirming a long term molecular remission on ima - RECURRENT CEP85L-PDGFRB FUSION IN A PATIENT WITH A TRANSLO - tinib. In our view, the detection of the exact gene fusion is clinically relevant for CATION T(5;6) AND AN IMATINIB-RESPONSIVE MYELOPROLIFERATIVE effective long term management of these neoplasms as it enables specific fol - NEOPLASM WITH EOSINOPHILIA low up by sensitive molecular analysis. N Winkelmann 1,2* , C Hidalgo-Curtis 1,3, K Waghorn 1,3, J Score 1,3, H Dickin - son 4, A Jack 5, S Ali 6, N Cross 1,3 1Leukaemia Research Group , Wessex Regional Genetics Laboratory, Salis - B1557 bury, United Kingdom, 2Klinik für Innere Medizin II , Universitätsklinikum Jena, CLINICAL SIGNIFICANCE OF IMMATURE PLATELET FRACTION IN BCR- Jena, Germany, 3Faculty of Medicine, University of Southampton, Southamp - ABL1-NEGATIVE CHRONIC MYELOPROLIFERATIVE NEOPLASMS ton, 4Cytogenetics Unit, St. James´s University Hospital, 5Haematological N Vazzana 1* , R Spadano 1, S Di Zacomo 2, G Rolandi 3, A Dragani 1 Malignancy Diagnostic Service, St James’s University Hospital, Leeds, 6Hull 1Department of Hematology, Centre for Hemophilia and Rare Blood Disorders, Royal Infirmary, Hull Royal Infirmary, Hull, United Kingdom 2Department of Transfusion Medicine, Molecular Biology Unit, 3Department of Transfusion Medicine, Coagulation Unit, Pescara, Italy Background: Fusion genes involving the catalytic domain of tyrosine kinases (TKs) play an important role in the pathogenesis of hematological malignancies Background: Platelet activation plays a pivotal role in the pathogenesis of and solid tumors. In BCR-ABL1 -negative myeloproliferative neoplasms (MPNs) BCR-ABL1-negative myeloproliferative neoplasms (MPN)-associated throm - several different tyrosine kinase fusion events have been described, most com - bosis. Evidence is mounting to support a potential usefulness of immature monly involving the genes encoding the platelet-derived growth factor recep - platelet fraction (IPF) measurement for vascular risk stratification in various tor alpha ( PDGFRA ) or beta ( PDGFRB ). Since the introduction of small mole - thrombotic disorders. cule kinase inhibitors, TK fusions have emerged as prime therapeutic targets. Aims: The aim of this study was to characterize the clinical and laboratory Here, we present the case of a 45 year old male with persistent unexplained determinants of IPF in patients with BCR-ABL1-negative MPN. In addition, we eosinophilia. A bone marrow aspirate and biopsy showed increased cellularity investigated the association between IPF and previous thrombosis. with myeloid expansion and marked eosinophilia without signs of monoclonal - Methods: One-hundred thirty-five patients have been studied. Sixty-one ity. Cytogenetic analysis on a bone marrow aspirate revealed a patients (45.2%) had ET, 25 (18.5%) PV, and 21 (15.6%) MPN-U. Among the 46,XY,t(5;6)(q3?3;q2?2). 28 (20.7%) patients with myelofibrosis, 25 patients had PMF, while 3 patients Aims: In this patient our objective was to investigate the underlying fusion gene had post-TE or post–PV myelofibrosis. Forty-eight patients had a history of of his translocation t(5;6) and if possible use it as a molecular marker during previous thrombotic event, including arterial thrombosis (n = 31), venous throm - treatment. bosis (n = 14), or both (n = 3) events. Complete blood counts, including the Methods: Break apart FISH using previously described in house probes measurement of IPF were performed in whole blood by the fully automated demonstrated that PDGFRB at 5q33 was disrupted but ETV6-PDGFRB, the hematology analyzer XE-2100 (Sysmex). most common fusion involving this gene, was not detected by RT-PCR.Stan - Results: In patients on cytoreductive therapy but not in untreated patients, dard Gold Taq Polymerase based PCRs were performed on cDNA and gDNA IPF% was significantly higher in those with previous thrombosis than in non - extracted from peripheral blood leukocytes. Sanger Sequencing was performed thrombotic patients [2.4 (1.7-3.4) vs. 3.3 (2.4-5.1) %, P=0.011]. Similarly, in on cDNA and gDNA in forward and reverse. Peripheral blood samples were patients aged ≥ 60 years but not in younger patients, IPF% was significantly received from this patient at 7 different time points before and after treatment. higher in those with previous thrombosis than in nonthrombotic patients [2.6 (1.8 -3.7) vs. 3.6 (2.4 - 5.2)]. In the entire population, a significant inverse correla - tion has been observed between platelet count and IPF% (Rho = - 0.23, P=0.008). In addition, in non-PV patients, IPF% was not significantly different between JAK2 V617F positive vs. negative patients. Multivariate logistic regres - sion showed that only male gender (odds ratio, 3.3; 95% CI, 1.4 to 8.0; P=0.007) and the upper tertile of IPF% (odds ratio, 3.7; 95% CI, 1.2 to 10.7; P=0.018) are independently associated with a history of previous thrombosis, after adjust - ing for age, hematocrit, white blood cell count, platelet count, cardiovascular risk factors, underlining diagnosis, JAK2 mutational status and cytoreductive ther - apy. Summary / Conclusion: We found that increased platelet turnover, as reflect - ed by high IPF%, is associated with a history of thrombotic events in patients with MPN. In addition, our data support the hypothesis that current antithrom - botic therapy might not specifically address this mechanism of thrombogene - sis. New prospective studies are warranted to evaluate the usefulness of incor - porating IPF% in risk stratification models to better identify patients at increased risk for thrombotic complications and/or treatment failure. B1558 DISEASE CHARACTERISTICS AND PERIPHERAL BLOOD CD34+ CELLS IN IDIOPATHIC MYELOFIBROSIS S Improta 1, M Villa 1* , A Gagliardi 1, C Tommasino 2, G Fossati 2, L Mastrullo 1 1U.O.C. Ematologia, 2U.O.C. Patologia Clinica, P.O. San Gennaro ASL Napoli Results: At the time of initial analysis no similar translocation had been report - 1 Centro, Napoli, Italy ed and therefore the diagnostic investigations suggested the likely presence of a novel fusion involving PDGFRB and an unknown partner gene on chromo - Background: Idiopathic Myelofibrosis (IMF) is chronic myeloproliferative neo - some 6. Initial attempts at RACE-PCR were unsuccessful and hampered by lim - plasm characterized by constitutive mobilization of hematopoietic stem cells ited availability of suitable pre-treatment material. Subsequently, a novel (HSC) and progenitor cells (HPC) into the peripheral blood (PB). The interac - C6orf204 -PDGFRB (now known as CEP85L-PDGFRB ) fusion was reported in tion between the chemokine CXCL12 and its receptor CXCR4 plays a pivotal a patient with T-cell acute lymphoblastic leukemia (T-ALL). Thus, we hypothe - role in determining the trafficking of CD34+ cells between the bone marrow (BM) sized that our patient may harbour the same or similar genetic defect. For the and the PB. RT-PCR, a product was amplified from the patient with the t(5;6) but not con - Aims: IMF is associated with downregulation of CXCR4 by CD34+ cells due trols which upon sequencing revealed an in frame cDNA fusion between exon to epigenetic events. Altered gene expression was corroborated by the detec - 11 of CEP85L and exon 12 of PDGFRB. For gDNA, Sequencing showed the tion of abnormally high CD9 or CD164, and low CXCR4, membrane protein genomic fusion was between intron 12 of CEP85L and exonic sequence of expression in IMF CD34+ cells. Moreover, endothelial precursor cells PDGFRB exon 11 (Figure 1) .Five months after the start of imatinib treatment (CD34+/CD133+) are increased in the blood of a subset of patients with IMF, neither the genomic nor the mRNA fusion was detectable by nested PCR or RT- and peripheral endothelial cells bear the same molecular markers as PCR. CEP85L-PDGFRB remained undetectable in all subsequent samples hematopoietic cells, suggesting a primary role of pathological endothelial cells with a follow up of over 3 years. Imatinib was continued without interruption dur - in this disease. ing this time The sensitivity of the PCR assay to detect the CEP85L-PDGFRB - Methods: We evaluated, by flow cytometry, the number of CD34 positive cells fusion gene was 10 -4 . in peripheral blood and the expression of CXCR4, CD9, CD117 and CD133 on Summary / Conclusion: Here, we report a recurrent CEP85L-PDGFRB fusion these cells. In our institution we are following 31 patients affected by IMF, in a patient with eosinophilia and an MPN. The fusion was confirmed by spe - according to WHO criteria (M: 18, F: 13; median age: 57 years, range: 48-68 haematologica | 2013; 98(s1) | 619 18 th Congress of the European Hematology Association years). Hôpital Haut-Lévêque, Bordeaux, 3Shire, Boulogne-Billancourt, France, 4Shire Results: In all patients, at diagnosis, we found a high count of CD34+ cells in Pharmaceuticals Ltd, Basingstoke, United Kingdom, 5Centre d’Investigation PB (greater than 15x10 6/l; median: 2, 4x10 6/l, range: 1, 8-3,2x10 6/l) compared Clinique, Hôpital Saint Louis et Université Paris 7, Paris, France with normal controls and other Philadelphia-negative chronic myeloproliferative neoplasms. In all cases CD34+ cells were negative for CXCR4 while express - Background: Anagrelide (ANA) is indicated in the EU for at-risk patients (pts) ing high intensity CD9. About 40% of CD34+ cells expressed CD133, while 20% with essential thrombocythemia (ET) and at least one of: >60 years; platelet expressed CD117 at low intensity. In no case was detected coexpression of count >1000x10 9/L; history of thrombo-hemorrhagic events; in whom prior ther - CD133 and CD117, suggesting a simultaneous presence of two distinct apy (PT) is not sufficiently effective or well tolerated.
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