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RESEARCH ARTICLEDOI: 10.4274/tjh.2014.0136Turk J Hematol 2016;33:94-101Impact of JAK2V617F Mutational Status on Phenotypic Featuresin Essential Thrombocythemia and Primary MyelofibrosisEsansiyel Trombositemi ve Primer Miyelofibroziste JAK2V617F Mutasyonunun Fenotipik Etkileriİpek Yönal, Aynur Dağlar-Aday, Başak Akadam-Teker, Ceylan Yılmaz, Meliha Nalçacı, Akif Selim Yavuz, Fatma Deniz Sargınİstanbul University İstanbul Faculty of Medicine, Department of Internal Medicine, Division of Hematology, İstanbul, TurkeyAbstractObjective: The JAK2V617F mutation is present in the majorityof patients with essential thrombocythemia (ET) and primarymyelofibrosis (PMF). The impact of this mutation on diseasephenotype in ET and PMF is still a matter of discussion. This study aimsto determine whether there are differences in clinical presentationand disease outcome between ET and PMF patients with and withoutthe JAK2V617F mutation.Materials and Methods: In this single-center study, a total of184 consecutive Philadelphia-negative chronic myeloproliferativeneoplasms, 107 cases of ET and 77 cases of PMF, were genotyped forJAK2V617F mutation using the JAK2 Ipsogen MutaScreen assay, whichinvolves allele-specific polymerase chain reaction.Results: ET patients positive for JAK2V617F mutation had higherhemoglobin (Hb) and hematocrit (Hct) levels, lower platelet counts,and more prevalent splenomegaly at diagnosis compared to patientsnegative for the JAK2V617F mutation, but rates of major thromboticevents, arterial thrombosis, and venous thrombosis were comparablebetween the groups. At presentation, PMF patients with JAK2V617Fmutation had significantly higher Hb and Hct levels and leukocytecounts than patients without the mutation. Similar to the findings ofET patients, thromboembolic rates were similar in PMF patients withand without theJAK2V617F mutation. For ET and PMF patients, nodifference was observed in rates of death with respect to JAK2V617Fmutational status. Moreover, leukemic transformation rate was notdifferent in our PMF patients with and without JAK2V617F mutation.Conclusion: We conclude that JAK2V617F-mutated ET patients expressa polycythemia vera-like phenotype and JAK2V617F mutation in PMFpatients is associated with a more pronounced myeloproliferativephenotype.Keywords: JAK2V617F mutation, Essential thrombocythemia, PrimarymyelofibrosisÖzAmaç: Esansiyel trombositemi (ET) ve primer miyelofibrozis (PMF)tanılı hastaların büyük çoğunluğunda JAK2V617F mutasyonubulunmaktadır. ET ve PMF’de bu mutasyonun hastalık fenotipi üzerineetkisi halen tartışılmaktadır. Bu çalışmada, JAK2V617F mutasyonunutaşıyan ve taşımayan ET ve PMF hastalarının başvuru sırasındaki klinikparametreler ve hastalık seyri açısından karşılaştırılması amaçlanmıştır.Gereç ve Yöntemler: Tek merkezli olan bu çalışmada, 107 ETve 77 PMF olmak üzere toplam 184 Philadelphia-negatif kronikmiyeloproliferatif neoplazili hastada bir allel spesifik polimeraz zincirreaksiyonu olan JAK2 Ipsogen MutaScreen kullanılarak JAK2V617Fmutasyonu taranmıştır.Bulgular: JAK2V617F mutasyonunu taşıyan ET hastalarında, mutasyonbulunmayanlara göre tanı sırasındaki hemoglobin (Hb) ve hematokrit(Hct) düzeyleri anlamlı olarak daha yüksek, trombosit sayısı daha düşükve splenomegali oranları daha yüksek bulunmuştur. Fakat her iki gruparasında majör trombotik olay, arteriyel tromboz ve venöz trombozaçısından fark saptanmamıştır. JAK2V617F mutasyonu bulunan PMFhastalarında ise mutasyon taşımayan gruba göre başvuru anındaki Hb,Hct ve lökosit değerleri anlamlı olarak daha yüksek saptanmıştır. PMFhastalarında, ET hastalarında olduğu gibi tromboembolik olaylarınJAK2V617F mutasyonundan bağımsız olduğu görülmüştür. ET ve PMFhastalarında JAK2V617F mutasyonu varlığında ölüm oranında farklılıkgözlenmemiştir. Bunun yanında JAK2V617F mutasyonunu taşıyan vetaşımayan PMF hastaları arasında lösemik dönüşüm oranı açısındananlamlı bir fark bulunmamıştır.Sonuç: Bu çalışmanın sonucunda JAK2V617F mutasyonunu taşıyanET hastalarında polisitemia vera benzeri fenotipin ortaya çıktığıve bu mutasyonun varlığında PMF hastalarının daha belirgin birmiyeloproliferatif fenotiple ilişkili olduğu söylenebilir.Anahtar Sözcükler: JAK2V617F mutasyonu, Esansiyel trombositemi,Primer miyelofibrozisAddress for Correspondence/Yazışma Adresi: İpek YÖNAL, M.D.,İstanbul University İstanbul Faculty of Medicine, Department of Internal Medicine,Division of Hematology, İstanbul, TurkeyE-mail: ipekyon@istanbul.edu.trReceived/Geliş tarihi: March 30, 2014Accepted/Kabul tarihi: July 14, 201494
Turk J Hematol 2016;33:94-101Yönal İ, et al: Impact of JAK2V617F Mutational StatusIntroductionPhiladelphia-negative chronic myeloproliferative neoplasms(Ph-negative MPNs) are a heterogeneous group including 3 majordiseases: polycythemia vera (PV), essential thrombocythemia(ET), and primary myelofibrosis (PMF). Thrombotic events are themajor cause of morbidity and mortality in ET. Other complicationsinclude hemorrhage and progression to myelofibrosis or acutemyeloid leukemia [1,2]. PMF is characterized by a worse lifeexpectancy and a progressive disease course. The disease presentswith classically severe anemia, massive splenomegaly, and acuteleukemia [3]. JAK2V617F mutation is present in more than 95%of PV patients and approximately 50%-60% of ET and PMFpatients [4]. Several studies investigated the clinical relevanceof JAK2V617F mutation in ET and PMF patients [5,6,7,8,9,10].In ET, overall survival (OS) or leukemia-free survival was foundnot to be affected by the presence of JAK2V617F mutation,while the influence of JAK2V617F on thrombosis or fibrotictransformation remained less clear [5,7,11,12]. Conflictingresults have been reported regarding the impact on OS,leukemic transformation rate, and need for chemotherapy orsplenectomy in the presence of JAK2V617F mutation [8,9,10,13].We previously evaluated the clinical and laboratory correlatesin 184 patients with Ph-negative MPNs according to the alleleburden of JAK2V617F mutation (unpublished data). Herein,we investigate the usefulness of JAK2V617F mutational statusfor explaining phenotypic variability using the same group ofpatients, which includes a relatively large series of Ph-negativeMPN patients.Materials and MethodsA total of 184 consecutive Ph-negative MPN patients, 107 with ETand 77 with PMF, admitted to the Division of Hematology of theİstanbul University İstanbul Medical Faculty from 1995 to 2013were included in the study. ET and PMF patients were diagnosedbased on WHO criteria [14]. Informed consent was obtainedfrom all participants according to the local ethics committeeguidelines. Complete clinical history, blood count, lactatedehydrogenase (LDH) level, and thrombotic or hemorrhagiccomplications were recorded. Spleen longitudinal diametersof ≥130 mm to 160 mm and of ≥160 mm on ultrasound wereconsidered as mild and massive splenomegaly, respectively. Ascale of 0-3 was used to grade reticulin fibrosis on bone marrowtrephine biopsies [15]. The Dynamic International PrognosticScoring System (DIPSS) plus was used for risk stratificationin PMF [16]. Unfavorable karyotypes in PMF were defined ascomplex karyotype or sole or 2 abnormalities that included +8,-7/7q-, i(17q), inv(3), -5/5q-, 12p-, or 11q23 rearrangement[17]. Patients were genotyped for the JAK2V617F mutation byJAK2 MutaScreen assay (Ipsogen, Luminy Biotech, Marseille,France), which is a TaqMan allelic discrimination assay thatcontains fluorescent probes specific for wild-type (617V) andmutant (617F) alleles [18].Statistical AnalysisData were processed using SPSS 16 (SPSS Inc., Chicago,IL, USA). Continuous variables were summarized as mean[standard deviation (SD)]. Chi-square statistics were used tocompare categorical variables among the different patientgroups categorized according to the JAK2V617F mutationalstatus. Analysis of continuous variables among the groups wasperformed using the Mann-Whitney U test. A p-value of lessthan 0.050 was considered to indicate statistical significance;all tests were 2-tailed.ResultsA total of 184 patients (107 with ET and 77 with PMF) wereincluded. Bone marrow fibrosis was detected in 90.7% (97 in107) of ET and 100% of PMF patients. In ET patients, the gradeof bone marrow fibrosis was scaled as follows: grade 0, 9.3%;grade 1, 62.7%; grade 2, 25.2%; and grade 3, 2.8%. All PMFpatients had bone marrow fibrosis (grade 2 in 20.8% and grade3 in 79.2%).JAK2V617F mutation was identified in 64 of 107 ET (59.8%) and58 of 77 PMF (75.3%) patients (p=0.028). Clinical and laboratorycorrelates of ET patients according to JAK2V617F mutationalstatus are summarized in Tables 1 and 2.JAK2V617F-positive and -negative ET patients showed nosignificant differences with respect to sex and age at diagnosis.ET patients with JAK2V617F mutation presented with higherhemoglobin (Hb) and hematocrit (Hct) levels and lower plateletcount at diagnosis compared to patients without mutation(p=0.001, p=0.001, and p=0.043, respectively). The leukocytecount and LDH levels were similar for the 2 groups.The 2 groups showed no significant difference with respectto mean spleen size. However, JAK2V617F-positive ET patientspresented with more prevalent splenomegaly at diagnosiscompared to patients without the mutation (p=0.044).ET patients with JAK2V617F mutation showed a higher, albeitnot statistically significant, rate of bleeding events comparedto the JAK2V617F-negative group (15.6% and 7%, respectively;p=0.298).ET patients with and without JAK2V617F mutation showed nosignificant difference with respect to the degree of bone marrowfibrosis, prevalence of hydroxyurea use, and rate of splenectomy.In addition, no significant differences were observed in the useof other medical treatments in any of the categories (p>0.050).Duration of follow-up in patients with and without JAK2V617Fmutation was 69.7 months (SD: 63.7) and 70.1 months (SD:56.9), respectively (p=0.675). During follow-up, 3 of 64 (4.7%)JAK2V617F-positive ET and 2 of 43 (4.7%) JAK2V617F-negativeET patients succumbed to their disease (p=1.000).95
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