Diagnostic Usefulness of JAK2 Mutation in Manistest or Latent Polycythemia Vera and Secondary Polycythemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4901-4901
Author(s):  
Soo-Mee Bang ◽  
Eun Mi Nam ◽  
Jeong Yeal Ahn ◽  
Jae-Hoon Lee ◽  
Bong-Seog Kim ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Janus Kinase ◽  
Vascular Events ◽  
Jak2 Mutation ◽  
Specific Pcr ◽  
Mutational Status ◽  
Number Of Patients ◽  
Positive Rate ◽  
Clinical Records ◽  
Secondary Polycythemia

Abstract Backgrounds: The discovery of Janus kinase 2 (JAK2) mutation make it easy to diagnose polycythemia vera (PV) in which the prevalence of this mutation is reported up to 96%. The latent PV is defined in patients who show the lower hemoglobin than WHO criteria at the time of diagnosis without any cause of secondary erythrocytosis; 17~18.5g/dL in male and 15 ~16.5g/dL in female. We investigated the mutational status of JAK2 in polycythemia vera either of latent or manifest type and secondary polycythemia. Methods : We reviewed the clinical records of 182 patients from 8 centers, who underwent bone marrow (BM) examination with a suspicion of non-BCR/ABL myeloproliferative diseases (nMPD). JAK2 mutation was examined by allele-specific PCR in 110 patients. Results : The positive rate of JAK2 mutation was 69% of 48 patients with PV, 54% in 41 patients with essential thrombocythemia (ET), 25% of 8 patients with chronic idiopathic myelofibrosis and 100% of 1 patient with unclassifiable MPD. JAK2 mutation was not detected in 7 patients with secondary polycythemia and 5 with reactive thrombocytosis. The number of patients with latent PV was eleven (23%) among the 48 PV patients. Nine of these 11 patients were positive for JAK2 mutation. Finally, sensitivity of JAK2 mutation was 69% (33/48) in all PV, 82% (9/11) in latent PV, and 65% (24/37) in manifest PV. The specificity of JAK2 mutation was 100% for secondary polycythemia. Among the 41 patients with ET, four patient had high hemoglobin met the latent PV criteria. Only one patient among them showed JAK2 mutation. The presence of a JAK2 mutation was closely correlated with the diagnosis of PV (p=0.006), leukocytosis (p=0.000), increased megakaryocytes (p=0.013), and decreased serum EPO (p=0.034) in 98 nMPD patients. In these patients, vascular events before or after the diagnosis and survival were not affected according to JAK2 status during the median follow-up of 25 months (range; 0~211). Conclusions : The JAK2 mutation help diagnose PV with higher sensitivity in latent PV than manifest PV. This finding can be adopted in the diagnosis of PV in newly visited polycythemic patient whose hemoglobin were under the criteria and condition could be excluded for secondary erythrocytosis. Therefore, JAK2 mutation should be incorporated into the work-up of nMPD including PV for accurate diagnosis. In the meeting, we can present the additional JAK2 data of untested 72 patients.

Significance of the JAK2V617F mutation in patients with chronic myeloproliferative neoplasia

2011 ◽  
Vol 152 (45) ◽  
pp. 1795-1803 ◽  
Author(s):  
János László Iványi ◽  
Éva Marton ◽  
Márk Plander
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Philadelphia Chromosome ◽  
Janus Kinase ◽  
Thrombotic Complication ◽  
Idiopathic Myelofibrosis ◽  
Jak2 Mutation ◽  
Course Of Illness ◽  
Mutational Status ◽  
Outpatient Departments

In Philadelphia chromosome-negative chronic myeloproliferative neoplasia, i.e. polycythemia vera, essential thrombocythemia and primary idiopathic myelofibrosis enhanced risk of thrombosis could be connected with Janus kinase 2 gene mutation occurring in various frequency in these diseases (JAK2V617F). Since 2002 the presence of JAK2 mutation in chronic myeloproliferative neoplasia has been regularly detected. Aims: In a retrospective survey the possible connection between JAK2 mutation and thrombosis was analyzed in patients with chronic myeloproliferative neoplasia subgroups cared and treated in their hospital and outpatient departments. Patients and methods: Between 2007-2010 peripheral blood samples of 171 patients with chronic myeloproliferative neoplasia (68 patients of polycythemia vera, 84 of essential thrombocythemia and 19 ones with primary idiopathic myelofibrosis) were sent to several molecular biological laboratories, where V617F mutation from DNA specimens was detected by allele-specific polymerase chain reaction, as well. Thromboembolic complications (arterial, i.e. cerebro-and cardiovascular and venous thrombosis) occurred during course of illness of patients were registered. Statistical analysis was made by statistical software program for Windows. Results: JAK2 mutation in 53 patients with polycythemia vera (77.9%) was detected, whilst in essential thrombocythemia 55 patients (65.4%) and in primary idiopathic myelofibrosis 7 patients (36.8%) proved to be JAK2 positive. In 18 JAK2 positive patients of polycythemia vera thromboembolic episodes were observed (18/53, 33.9%), whilst in essential thrombocythemia JAK2 mutational status was accompanied with thromboembolic events in 17/55 patients (30.9%). In the 7 JAK2 positive ones with primary idiopathic myelofibrosis thrombotic complication did not occurred. However, in JAK2 negative cases thrombotic events could also be detected (from 10 JAK2 negative patients with polycythemia vera in four ones, and in six with JAK2 negative 23 essential thrombocythemic patients. Conclusions: Incidence of the JAK2 mutation in their patients with chronic myeloproliferative neoplasia subgroups mainly corresponds to the literary data. Thrombosis ensued both in JAK positive polycythemia vera and essential thrombocythemia cases occurred nearly in the same number, but the incidence of thrombosis ensued in JAK2 negative cases did not differ significantly from the JAK2 positive patients. From these results it could be suggested that the presence or absence of JAK2 mutation in the development of thrombosis has no predictive value in patients with chronic myeloproliferative neoplasia. Orv. Hetil., 2011, 152, 1795–1803.

JAK2 Mutations Are Present in All Cases of Polycythemia Vera.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4669-4669
Author(s):  
Y. Lynn Wang ◽  
Katherine Vandris ◽  
Amy V. Jones ◽  
Nicholas C.P. Cross ◽  
Paul J. Christos ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Mononuclear Cells ◽  
False Positive Rate ◽  
Amplification Refractory Mutation System ◽  
Peripheral Blood Mononuclear ◽  
Jak2 Mutation ◽  
Normal Peripheral Blood ◽  
Hel Cells ◽  
Positive Rate ◽  
Pyrosequencing Method

Abstract The JAK2V617F point mutation has been described in 65 to 97% of patients with polycythemia vera (PV). Previously, 17 phenotypical cases of PV from a large group of patients from three institutions were initially reported as JAK2V617F negative. These cases were re-analyzed in detail to determine the cause, if any, of the JAK2V617F negativity. Reasons for this initial negativity included inaccurate clinical diagnosis, relatively insensitive laboratory techniques, insufficient material for re-testing, and possible treatment effect. It was predicted that when tested appropriately, a JAK2V617F mutation would be found in all new cases of PV. We developed a highly sensitive amplification refractory mutation system assay (ARMS) for the detection of JAK2V617F. The analytic sensitivity of the assay is 0.05-0.1% as defined by mixing JAK2V617F-containing HEL cells with normal peripheral blood mononuclear cells. At this level of sensitivity, the assay has a false positive rate of less than 1% (we found 1 positive case in 300 individuals without myeloid disorders). Pyrosequencing involves synthetic nucleotide extension by DNA polymerase. Unlike ARMS, the PCR pyrosequencing method reliably detects JAK2V617F only when the mutant allele is more than 5%. The sensitivity of the ARMS assay is therefore approximately 50 times greater than the pyrosequencing method. Of 105 PV cases diagnosed by Polycythemia Vera Study Group criteria, pyrosequencing detected the mutation in 96 cases. The ARMS technique detected JAK2V617F alleles in 8 of the remaining 9 cases. Of the 8, 2 had been treated by phlebotomy only, 4 had been on interferon for a median of 13 years, and 2 on imatinib for 3 years. In the last patient, who was negative by both assays, the JAK2 exon 12 deletion (E543-D544) was detected. This patient had been on imatinib for 3 years and remains in complete remission. We conclude that a sensitive assay is required to detect the JAK2 mutations in patients with polycythemia vera, especially in patients whose JAK2 mutation load might be affected by treatment.

scholarly journals JAK2 Negative Polycythemia Vera

2010 ◽  
Vol 2 (02) ◽  
pp. 114-116 ◽  
Author(s):  
Geetha J P. ◽  
Arathi C A. ◽  
Shalini M. ◽  
Srinivasa Murthy A G.
Keyword(s):  
Stem Cell ◽  
Polycythemia Vera ◽  
Intracellular Signaling ◽  
Janus Kinase ◽  
Jak2 Mutation ◽  
Myeloproliferative Diseases ◽  
British Committee ◽  
Clonal Mutation ◽  
Serum Erythropoietin ◽  
Cell Disorder

ABSTRACTPolycythemia vera (PV) is a stem cell disorder, characterized as a panhyperplastic, malignant, and neoplastic marrow disorder. Several reasons suggest that a mutation on the Janus kinase-2 gene (JAK2) is the most probable candidate gene involved in PV pathogenesis, as JAK2 is directly involved in intracellular signaling, following its exposure to cytokines, to which PV progenitor cells display hypersensitivity. A recurrent unique acquired clonal mutation in JAK2 was found in most patients with PV and other myeloproliferative diseases (MPDs). A female patient of age 50 years, presented with hemiplegia, diplopia, and had a consistent rise in hemoglobin and hematocrit. Serum Erythropoietin (Epo) was decreased. JAK2 mutation analysis was found to be negative. A diagnosis of polycythemia vera was made on the basis of the British Committee for Standards in Hematology (BCSH) guidelines.

scholarly journals Clinicopathologic Characteristic and Natural History of Patients with Non Hereditary, Non Polycythemia Vera (NH/NPV) Persistent Polycythemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4617-4617
Author(s):  
Omar Mahmood ◽  
Hanson Mouanoutoua ◽  
Tanjot Saini ◽  
Marcel Okura ◽  
Mahboub Rahman Noori ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Polycythemia Vera ◽  
Diagnostic Criteria ◽  
Janus Kinase ◽  
Adult Patients ◽  
Molecular Profile ◽  
Normal Range ◽  
Bone Marrow Biopsies ◽  
Number Of Patients

Abstract Introduction; Polycythemia Vera (PV), is one of the most common Philadelphia chromosome negative myeloproliferative disorders. The identification of Janus Kinase (JAK) 2 mutations and the publication of 2016 revision of WHO classification of myeloid neoplasms has improved diagnostic accuracy of PV. The lower cut-off values of Hemoglobin (Hb) and hematocrit (Hct) used in WHO diagnostic criteria, however, resulted in increased number of adult patients undergoing further evaluation for PV leading to identification of patients with acquired, idiopathic Persistent polycythemia (PP) who not meet WHO criteria for PV despite extensive work up. The clinicopathologic features, disease course, treatment and outcomes of these patients has not been well characterize. This study seeks to described clinicopathologic and molecular profile of cohort of adult patients with Non Hereditary, Non-Polycythemia Vera (NHNPV) Persistent Polycythemia. Methodology; Patients with PP diagnosed and followed up in Fresno community regional medical center/University of San Francisco (UCSF) Fresno, from January 2010 to December 2020 were reviewed. Patients who didn't meet WHO diagnostic criteria for PV after full evaluation including bone marrow biopsies were included in the study. Those with incomplete evaluation, clearly attributable secondary causes of polycythemia or erythropoietin (EPO) level above institutional laboratory reference range (2-18), were excluded from the study. Patients with polycythemia diagnosed at pediatric age were also excluded. The study was approved by institutional review board of UCSF Fresno. Results; 129 subjects with JAK 2 Negative PP were reviewed of which 63 had EPO levels within or below the normal range (2-18). Of 36 patients who met the study inclusion and exclusion criteria, majority were males (70% N= 28) and non-Hispanic (56% N=20) with median age at diagnosis of 48.5 years (range 18-70 years). Half of the patients (N=18) have no identifiable etiology of PP. In patients with associated conditions, the most common is non-oxygen requiring clinical OSA (36%) and tobacco smoking (19.4%). Of note, all these patients have EPO level less than 10 which represents the median value of the local institutional defined normal range for EPO. Four (11%) patients have non-iron overloaded hemochromatosis gene mutation (1 Homozygous H63D HFE gene, 2 heterozygous mutation and one with unspecified mutation type). Average Hb and Hct at diagnosis was (17.26+/- 2.23) and (49.76+/- 6.34) respectively. Mean EPO level 7.05+/-2.75 with less than third of patients 8 (22%) with level less or equal to in 5 units. There is no statistically significance difference between mean diagnostic EPO level between males and females in the study (7.20+/-2.89 vs.6.51+/-2.26) and so is the Hct though males have numerically higher levels. The most common bone marrow morphology includes normocellularity (51.76+/-10.36) with erythroid hyperplasia (25%) or megakaryocyte hyperplasia without dysplasia (17%) and grade 1/3 fibrosis 6/36. Abnormal mutations were identified in 17 patients whose bone marrow biopsies were evaluated with limited or extensive next generation sequencing (NGS). Of those patients with available results, 6 patients (35% out of those with NGS) have identifiable previously well described genetic mutations {FANCA S1311fs*1, HGF R134H, TP53 splice site 97-2A>G, KMT2A (Gain), MLL3 (KMT2C) and AFF4, ASXL1 c.1934dupG/TrpfsX12 (p. Gly646)}. 9 patients had variance of unknown significant (VUS) mutations (Table 1) with average of 6.2 mutation per patient. Only 1 VUS (TSC1 K587R) was reported in 2 different patients (#7, #9) Mild Myeloproliferative neoplasia (MPN) associated symptoms was reported in 22% of patient with Intermittent phlebotomy (72% N= 26) and aspirin (75% N=27) was the treatment for majority of patients. One patient died during the follow up period. No patient progressed to other MPN, myelofibrosis or AML during the study period. Conclusion; With improved diagnostic criteria and accuracy of PV, increased number of patients are diagnosed with NHNPV Persistent polycythemia. None of the mutation or VUS identified from extensive evaluation is recurrent in our cohort of patient. Longer follow up is needed to delineate clinical significance and prognosis of these mutation in patients with NHNPV persistent Polycythemia. Figure 1 Figure 1. Disclosures Abdulhaq: BMS, Alexion, Oncopeptides, Morphosys, Pfizer, Norvartis: Honoraria; Oncopeptides, Alexion, Amgen: Speakers Bureau; Morphosys, BMS, Amgen: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Janus kinase 2 negative polycythemia vera

2017 ◽  
Vol 9 (5) ◽  
pp. 697-700
Author(s):  
Pravinwan Thungthong ◽  
Supat Chamnanchanunt ◽  
Tawatchai Suwanban ◽  
Chajchawan Nakhakes ◽  
Kunapa Iam-arunthai
Keyword(s):  
Polycythemia Vera ◽  
Previous History ◽  
Rare Condition ◽  
Janus Kinase ◽  
Janus Kinase 2 ◽  
Jak2 Mutation ◽  
History Of ◽  
British Committee ◽  
Common Manifestation ◽  
Cell Disorder

Abstract Background A Janus kinase 2 (JAK2) mutation polycythemia vera (PV) is a common manifestation of stem cell disorder. However, available data on the clinical and treatment response of JAK2-negative PV patients are limited. Objectives We report the case and clinical course of a patient with PV and left hemiparesis who was JAK2V617-negative. Methods We conducted a literature review and compared our patient with previously published reports of JAK2-negative patients with P V. Results Our patient presented with hemiparesis without a previous history of hematological disease. He was diagnosed with PV based on the British Committee for Standards in Haematology guidelines 2007. He underwent only phlebotomy with subsequent improvement of his neurological condition. He was discharged with therapeutic phlebotomy for one and a half months. Conclusions Although this rare condition required complex diagnostic criteria, the patient achieved good clinical outcome with therapeutic phlebotomy alone.

Presence of JAK2 Mutations in MDS/MPD-u WHO Classified Patients and Not Other Forms of MDS Suggests Their Derivation from Classical Myeloproliferative Syndrome.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 369-369
Author(s):  
Hadrian Szpurka ◽  
Ramon Tiu ◽  
Eric Hsi ◽  
Alan E. Lichtin ◽  
Mikkael A. Sekeres ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Detection Rate ◽  
Myeloproliferative Disorders ◽  
Disease Category ◽  
Jak2 Mutation ◽  
Specific Pcr ◽  
Mutational Status ◽  
Specific Pcr Assay ◽  
Atypical Cml ◽  
Normal Cytogenetics

Abstract The WHO classification of myeloid neoplasms recognizes a category of myeloid disorders that overlaps traditional myelodysplastic syndromes (MDS) and myeloproliferative disorders (MPD) as the entity MDS/MPD disease. This disease category includes CMML, JMML, atypical CML and MDS/MPD unclassifiable (MDS/MPD-u). The provisional entity termed RARS associated with marked thrombocytosis (RARS-t) is currently best classified as MDS/MPD-u until further information is available regarding its pathogenesis. Recently a JAK2 mutation V617F (G→T) was identified as a pathogenetic lesion in typical myeloproliferative disorders (Kralovics et al, NEJM, 2005). Subsequent studies of the JAK2 mutation concentrated on more proliferative forms of MDS or MDS/MPD such as CMML and CNL (Steensma et al, Blood, 2005). These studies demonstrated that homo- and heterozygous JAK2 mutants are present in a rather small proportion of these patients. Based on similar clinical features, we theorized that JAK2 mutants might be also found in patients with MDS/MPD-u. We have collected a cohort of these patients (N=202) and analyzed them for the presence of JAK2 mutation using a molecular allele-specific PCR assay. Positive cases were confirmed by sequencing with a sensitivity of about 20% of mutated cells. A group of patients with PV, MF and ET served as positive controls (N=66). In agreement with previous reports, the detection rate of JAK2 mutants for PV, MF and ET was 92%, 55% and 55%, respectively. Our experimental group included 104 patients with MDS or MDS/MPD (53 RA/RS, 14 RAEB, 22 RAEB-t/sAML, and 15 CMML). Most significantly, the RA/RS group contained 13 patients with WHO-defined MDS/MPD overlap and 3 with RARS-t (among these patients, 3 were JAK2 mutants; all of them were heterozygous - 18.8%). Within 16 patients with CMML1 or 2 we found only 2 heterozygous for JAK2 mutation (12.5%). The remaining cohort of 73 patients in MDS categories revealed only 1 patient to be heterozygous for JAK2 mutation (RARS, 1.4%). As expected MDS/MPD patients with JAK2 mutation showed various degrees of BM fibrosis, splenomegaly and less pronounced cytopenias. Except for one patient, JAK2 mutants had normal cytogenetics. All had normal MCV and ANC. In 4/5 increased megakaryocytes with/or without atypia was seen. One CMML patient with abnormal cytogenetics showed an unusual translocation t(8;9)(q22;p24). JAK2 is located at 9p24 so it is possible that the JAK2 gene was involved in the translocation generating a novel fusion protein in addition to an activating JAK2 mutant. Our results showed that JAK2 mutations are rarely found in typical cases of MDS or CMML. However, further analysis of JAK2 mutational status in patients with MDS/MPD-u is warranted. The reported detection rate may suggest that the pathogenesis of these entities is more akin to myeloproliferative than myelodysplastic syndromes.

Transformation to Myelofibrosis and Blastic Transformation of PV Are Associated with Higher JAK2 Mutation Levels.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1555-1555
Author(s):  
Maya Koren-Michowitz ◽  
Ninette Amariglio ◽  
Joseph Landman ◽  
Gideon Rechavi ◽  
Elena Ribakovsky ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Mutation Analysis ◽  
Negative Correlation ◽  
Clinical Symptoms ◽  
Jak2 V617f ◽  
Vascular Events ◽  
Jak2 Mutation ◽  
Blastic Transformation ◽  
Thrombotic Complications ◽  
The Mean

Abstract The JAK2 V617F mutation is found in 80–97% of polycythemia vera (PV) pts. The aim of the current study was to correlate the JAK2 mutation level with clinical symptoms and complications including vascular events and late hematological complications. Thirty-nine JAK2 V617F positive PV pts were included; M-19, F- 20; mean age at diagnosis was 55 (range 25–89) years. JAK2 mutation was analyzed in the PB using a quantitative MALDI-TOF based assay (Leuk Res 2007) after a mean of 130 (range 0–429) months from diagnosis. There was no correlation between the JAK2 mutation level and the time elapsed between the diagnosis and JAK2 mutation analysis. The mean JAK2 mutation level was 59% (range 2.5–95%). A negative correlation was found between the JAK2 mutation level and the pts age both at diagnosis (r=−0.3439, p=0.0321) as well as at the time of analysis (r=−0.3285, p=0.0412). JAK2 mutation levels were higher in pts with late hematological complications including transformation to myelofibrosis and blastic transformation compared to those without hematological complications (mean mutation level 77% vs. 51%, respectively p=0.0019). The best cut off value for the development of late hematological complications was above 50% (p=0.0336) which suggests the presence of homozygous JAK2 clones in pts that develop these complications. Similarly, there was a trend towards higher mean mutation levels in symptomatic pts (69% vs. 54%, p=0.096), pts with splenomegaly (62% vs. 47%, p=0.077) and pts that received cytoreductive therapy (63% vs. 47%, respectively p=0.077), while there was no difference between the levels of mutation in pts with thrombotic events compared to those without thrombotic complications. Our findings of: association between the JAK2 mutation level and late hematological complications and no association between the JAK2 mutation level and thrombotic events concur with the results of Vannucchi et al (Blood 2007) that reported on a higher rate of transformation to myelofibrosis in PV patients with homozygous JAK2 status and no association between homozygosity for the JAK2 mutation in PV and thrombotic events. In conclusion, we found that late hematological complications including transformation to myelofibrosis and blastic transformation in PV pts are associated with higher JAK2 mutation levels while thrombotic events are not associated with higher JAK2 levels. These results may be of clinical and therapeutic significance pending their further confirmation by a larger cohort of patients.

Hemizygous/Homozygous and Heterozygous JAK2 Mutation Detected in Plasma of Patients with Myeloproliferative Diseases: Correlation with Clinical Behavior.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2593-2593
Author(s):  
W. Ma ◽  
H. Kantarjian ◽  
I. Jilani ◽  
M. Gorre ◽  
F. Giles ◽  
...  
Keyword(s):  
Lymphoid Cells ◽  
Janus Kinase ◽  
Heterozygous Mutation ◽  
Homozygous Mutation ◽  
Jak2 Mutation ◽  
Cell Counts ◽  
Number Of Patients ◽  
Significant Difference ◽  
Myeloproliferative Diseases ◽  
Chronic Myeloproliferative Diseases

Abstract The Val617Phe mutation in JAK2 (Janus kinase) has been reported in approximately 90% of patients with polycythemia vera (PV) and in almost 40% of patients with essential thrombocythemia (ET) or idiopathic myelofibrosis (IMF). JAK2 is a cytoplasmic tyrosine kinase that binds to growth factor receptors and phosphorylates several downstream proteins that are involved in cell proliferation and growth. The Val617Phe mutation can be detected in circulating granulocytes. Homozygous as well as hemizygous (deletion of 1 allele and mutation in the second) mutations have been reported. The clinical importance of hemi/homozygous as compared to heterozygous mutation is not known. Furthermore, the presence of normal lymphoid cells or non-neoplastic cells in samples makes it difficult to be certain whether the mutation is homozygous in a subpopulation of cells, or heterozygous. Since we have shown that the plasma of patients with leukemia is enriched with leukemia-specific DNA, RNA, and protein, we tested the possibility of detecting JAK2 mutations in patients with chronic myeloproliferative diseases using RNA from peripheral blood (PB) plasma rather than cells. In this study, PB plasma was obtained from 39 patients with IMF, 16 with PV, 8 with ET, and 23 with other chronic myeloproliferative disease not otherwise classified (MPD-NC). Bi-directional direct sequencing of RNA extracted from plasma was used to detect mutations in the JAK2 transcript. The Val617Phe mutation was detected in 88% of PV patients, of whom 50% (44% of all samples) were hemi/homozygous. This mutation was detected in 56% of IMF patients, 41% of whom were hemi/homozygous. The number of patients with ET was small, but 25% (2 patients) had hemi/homozygous mutation. 26% of the patients with MPD-NC had JAK2 mutation; of these, 33% had hemi/homozygous mutation. The plasma of 31 normal control individuals showed no evidence of mutation and mixing studies showed that the Val617Phe mutation was easily detectable when lysate from HEL cell line (homozygous for the mutation) were mixed with plasma down to 5 cell/1ml plasma. Patients with hemi/homozygous mutation had significantly larger spleens (P=0.0001), increased white cell counts (P=0.001), and increased monocyte counts in bone marrow (P=0.03). We cannot demonstrate statistically significant difference in survival between hemi/homozygous and heterozygous, however, the number of cases is too small. The presence of mutation (hemi/homozygous or heterozygous) was associated with better overall survival in patients <65 years of age irrespective of the type of MPD (n=54, P=0.05). Patients with MPD-NC had more aggressive disease than other patients (ET, PV and IMF) (P=0.02), but presence of the Val617Phe mutation was associated with longer survival in the MPD-NC group (P=0.05). This does not only confirm that PB plasma is a reliable source for detecting JAK2 mutations, but also show that this mutation is often hemi/homozygous. The presence of JAK2 mutation as detected in plasma of patients with various types of chronic myeloproliferative diseases is associated with longer survival in patients <65 years and is also a favorable prognostic factor in patients with MPD-NC.

Sequential Measurement Of JAK2 V617F Allele Burden In Polycythemia Vera and Essential Thrombocythemia Reveals Different Evolution Profiles: First Results Of Jaksuivi, a Multicentre Study By The French Intergroup Of Myeloproliferative Neoplasms (FIM)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1593-1593
Author(s):  
Caroline Buors ◽  
Françoise Boyer ◽  
Aline Tanguy-Schmidt ◽  
Aurélie Chauveau ◽  
Lydia Roy ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Study Cohort ◽  
Cytotoxic Therapy ◽  
Vascular Events ◽  
Clinical Evolution ◽  
Number Of Patients

Abstract Introduction The JAK2 V617F mutation is present in almost all Polycythemia Vera (PV) and in 60-70% of Essential Thrombocythemia (ET) cases. There are experimental evidences that this acquired clonal driving mutation is involved in disease phenotype in murine models and in humans. However, it is still unclear if the %V617F changes over time and if it is necessary to systematically quantify %V617F at diagnosis and during follow-up. Patients and Methods We are conducted a prospective multicentre (n=5) study cohort in newly diagnosed PV and ET patients, harvested before any cytotoxic therapy and at 3 years, with the aim to correlate the %V617F at diagnosis, the %V617F 3 years later, and the variation of the %V617F between y0 and y3 with clinical evolution. Primary or secondary myelofibrosis, and secondary leukemia were not included. The primary objective is to determine whether an increase of %V617F between diagnosis and after 3 years could be related to a poor evolution of the disease. A secondary objective is to determine whether the %V617F at diagnosis is associated with the evolution at 3y. The primary endpoint is the worsening (Y / N) at y3 defined by the presence of at least one of the following criteria: leukocytosis >12G / L or immature granulocytes >2% or erythroblasts >1%; anemia or thrombocytopenia not related to treatment toxicity; development or progressive splenomegaly; thrombocytosis on cytoreductive therapy; patients inadequately controlled with treatment (defined by at least one treatment change for reason other than an adverse event). Results To date, 201 patients have been included. Clinical datas are currently available for the 176 first included (91 PV and 85 ET; 90 females and 86 males) and %V617F measurement for 167 cases. At diagnosis, overall median age was 65, identical for PV and ET patients, but curiously women were a little older than men (72 vs 65, p<0.001). Family history of hematological malignancies was identified in 11% of the cohort. Thrombotic events (arterial or venous) were noted in 35% before or at the time of MPN diagnosis. A cytotoxic therapy has been introduced during the first 3 months after diagnosis in 73.9% of cases. After 3 years 10/91 PV patients still need phlebotomies and only 20 patients remains without any myelosuppressive therapy. The median %V617F at diagnosis was 27.5%. As expected the median %V617F was significantly higher in PV than in ET pts (42.7% and 16.8% respectively, p <0.0001) and a high %V617F is correlated with the presence of a splenomegaly, asthenia, pruritus, a higher hemoglobin level, and a more frequently need for cytoreductive therapy (29% versus 17%, p=0.01). After 3y of evolution, clinical evaluation reveals 36 major events: - 3 patients experienced an hematologic transformation: 2 post-PV myelofibrosis and one ET which has evolved in PV and none secondary acute leukemia. These 2 transformed-PV displayed a very high initial %V617F (over 90%) that remained high during evolution. - 10 patients (5,6%) experienced a poor evolution (7 PV and 3 ET) as defined in the method section. Interestingly, these 10 patients who worsened have an higher initial %V617F than others (44.17% versus 25.73% p=0.03). This seems to be true when we look at PV and ET separately, but the results did not reach statistical significance probably due to the low number of patients. When %V617F at y3 is used the difference increased (40.9% vs 17.4%, p=0.002). - 23 new vascular events occurred: thrombosis in 17 cases and hemorrhages in 6 cases. Finally, we identified three distinct molecular evolutive profiles that represent each one third of the cases: stable %V617F, increasing %V617F and decreasing %V617F. It is too early to draw definitive conclusions about clinical evolution and these groups, but first analysis suggest that patients who have an unfavorable evolution are more common among those with an increased %V61F during follow-up. Discussion and conclusion Despite the short 3-years follow-up, we already recorded several major events and found that a high %V617F at diagnosis is correlated with a poorer evolution of the disease, suggesting that these patients could have a more advanced disease despite a classical hematological phenotype of ET or PV. Furthermore, the increase of %V617F seemed higher in evoluted PV in comparison to stable PV. In contrast, we didn't found any correlation between %V617F and thrombotic or bleeding events. Disclosures: No relevant conflicts of interest to declare.

Vascular events in Korean patients with myeloproliferative neoplasms and their relationship to JAK2 mutation

2009 ◽  
Vol 101 (03) ◽  
pp. 547-551 ◽  
Author(s):  
Soo-Mee Bang ◽  
Jong-Seok Lee ◽  
Jeong Yeal Ahn ◽  
Jae Hoon Lee ◽  
Myung Soo Hyun ◽  
...  
Keyword(s):  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Primary Myelofibrosis ◽  
Older Age ◽  
Janus Kinase ◽  
Homozygous Mutation ◽  
Vascular Events ◽  
Jak2 Mutation ◽  
Korean Patients ◽  
Before And After

SummaryEvaluation of the Janus kinase 2 (JAK2) V617F mutation has been widely used for the diagnosis of myeloproliferative neoplasms (MPN). However, its prognostic relevance to clinical outcome is not completely understood. We investigated the association of JAK2 V617F with vascular events in Korean patients with myeloproliferative neoplasms (MPN). We studied 283 patients from 15 centers, who were diagnosed with MPN. The JAK2 V617F status was evaluated by allele-specific polymerase chain reaction (PCR) and sequencing. The patients’ diagnoses were essential thrombocythemia (ET n=146), polycythemia vera (PV n=120), primary myelofibrosis (n=12), and unclassifiable MPN (MPNu n=5). JAK2 V617F was detected in 89 (61%) patients with ET, 103 (86%) with PV, four (33%) with myelofibrosis, and four (80%) with MPNu. A higher number of leukocytes, haemoglobin levels and BM cellularity as well as an older age, lower platelet counts, and diagnosis of PV were significantly correlated with JAK2 V617F. Eighty-three and 43 episodes of thrombosis and bleeding occurred in 100 patients each before and after the diagnosis. Vascular events more frequently occurred in 37% of patients with JAK2 V617F than in 29% of those without the mutation (p=0.045). Among 175 patients whose samples were available for sequencing, 28 patients with homozygous JAK2 V617F had vascular events more frequently (57%) than those who were heterozygotes (39%) or had the wild type (27%) (p=0.03). The multivariate analysis showed that a JAK2 homozygous mutation, hypercholesterolemia and older age were independent risk factors for a vascular event. The results of this study showed that Korean patients with MPN had a similar JAK2 mutation rate and frequency of vascular events when compared to Western patients. The presence of V617F was significantly related to vascular events. Therefore, initial evaluation for the JAK2 mutation and careful monitoring for vascular events should be performed in MPN patients.

Sign in / Sign up

Export Citation Format

Share Document