<i>JAK2</i><sup>V617F</sup> mutation in essential thrombocythaemia: clinical associations and long‐term prognostic relevance

Wolanskyj, Alexandra P.; Lasho, Terra L.; Schwager, Susan M.; McClure, Rebecca F.; Wadleigh, Martha; Lee, Stephanie J.; Gilliland, D. Gary; Tefferi, Ayalew

doi:10.1111/j.1365-2141.2005.05764.x

Cited by 289 publications

(286 citation statements)

References 31 publications

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“…The role of JAK2 V617F , mutation as independent factor for thrombosis is still debated [7,[16][17][18][19][20]. In our series, we did not find any significant role of JAK2 V617F for predicting thrombosis, but some limit of our analysis should be considered because we cannot exclude that this may reflect an inadequate sample size.…”

Section: Discussionmentioning

confidence: 56%

“…In the last few years, new information on the pathogenesis of thrombosis in MPNs became available, including the role of leukocyte activation and interaction with platelets as well as the presence of JAK2 V617F mutation [5,6]. Very recently, leukocytosis has been reported as an independent risk factor for thrombosis in both PV and ET [7][8][9][10] and this is particularly true in "low-risk" patients who normally do not require cytoreductive therapy. However, additional data are required to firmly establish the role of such predictors for thrombosis as well as their clinical advantage.…”

Section: Introductionmentioning

confidence: 99%

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Correlation between leukocytosis and thrombosis in Philadelphia-negative chronic myeloproliferative neoplasms

et al. 2009

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International audienceThe evidence that leukocytes may contribute to the pathogenesis of thrombosis in Chronic Myeloproliferative Neoplasms is increasing but not definitive. To further enforces whether an increased leukocyte count is associated with thrombosis and whether this effect can be modulated by cytoreductive therapy, we analyzed the clinical course of 187 patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET) followed at two Italian Institutions over a period of 7 years. The association was measured at diagnosis or before thrombotic events: a multivariable analysis was carried out using data at baseline and time-dependent covariates. We found that white blood cells (WBC) count above 9.5 × 10/L at diagnosis (baseline analysis) was associated with thrombosis during the follow-up (Hazard Ratio [HR] of 1.8, 0.03). At the time-dependent analysis, therapy with hydroxyurea (HU), lowering by 35% the baseline WBC level, reduced such strength of association giving a HR of 1.3 ( value non significant). We found a trend between WBC level and thrombosis in untreated low-risk patients (RR of 1.9, 95% CI 0.9 to 3.1); in high-risk patients treated with HU this correlation was clearly lost (RR 1.1, 95% CI 0.2 to 2.7). Finally, we could not identify the presence of as a risk factor for thrombosis. Properly designed prospective studies should corroborate such results

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Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

Correlation between leukocytosis and thrombosis in Philadelphia-negative chronic myeloproliferative neoplasms

et al. 2009

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“…negative for all three mutations) [4,42]. It is also important to note that other JAK2/CALR/MPL mutated MPN (or myelodysplastic syndromes [MDS]/MPN) can mimic ET in their presentation; these include prefibrotic PMF [4,43] and refractory anemia with ring sideroblasts with marked thrombocytosis (RARS-T) [4,44].…”

Section: Diagnosismentioning

confidence: 99%

Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk‐stratification and management

2015

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Disease overview: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms, respectively characterized by erythrocytosis and thrombocytosis. Other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. Diagnosis: PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely. Differential diagnosis in ET includes reactive thrombocytosis, chronic myeloid leukemia, and prefibrotic myelofibrosis. Janus kinase 2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL) mutations occur in approximately 55%, 25%, and 3% of ET patients, respectively. The same molecular markers are also present in prefibrotic myelofibrosis, which needs to be morphologically distinguished from ET. Survival and leukemic/fibrotic transformation: Median survivals are ∼14 years for PV and 20 years for ET; the corresponding values for younger patients are 24 and 33 years. Life‐expectancy in ET is inferior to the control population. JAK2/CALR mutational status does not affect survival in ET. Risk factors for survival in ET and PV include advanced age, leukocytosis, and thrombosis. Leukemic transformation rates at 20 years are estimated at <10% for PV and 5% for ET; fibrotic transformation rates are slightly higher. Thrombosis risk stratification: Current risk stratification in PV and ET is designed to estimate the likelihood of recurrent thrombosis: high‐risk is defined by the presence of age >60 years or presence of thrombosis history; low‐risk is defined by the absence of both of these two risk factors. Recent data consider JAK2V617F and cardiovascular risk factors as additional risk factors. Presence of extreme thrombocytosis might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. Risk‐adapted therapy: The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. In low risk patients, this is accomplished by the use of low‐dose aspirin and phlebotomy (hematocrit target <45%) in PV. In high risk (for thrombosis) patients, treatment with hydroxyurea is additionally recommended. Treatment with busulfan or interferon‐α is usually effective in hydroxyurea failures and the additional value of JAK inhibitor therapy in such cases is limited. Screening for AvWS is recommended before administrating aspirin, in the presence of extreme thrombocytosis. Am. J. Hematol. 90:163–173, 2015. © 2014 Wiley Periodicals, Inc.

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“…Subsequent studies confirmed the presence of JAK2V617F in almost all patients with PV [28,29] and in 50-60% of those with ET [30][31][32][33] or PMF [34,35]. In 2006, a somatic MPLW515L exon 10 mutation (a G to T transition at nucleotide 1544 resulting in a tryptophan to leucine substitution at codon 515 of the transmembrane region) was described in JAK2V617F-negative PMF [24].…”

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confidence: 87%

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

2015

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Myeloproliferative neoplasms (MPN) are clonal stem cell diseases, first conceptualized in 1951 by William Dameshek, and historically included chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). In 1960, Nowell and Hungerford discovered an invariable association between the Philadelphia chromosome (subsequently shown to harbor the causal BCR‐ABL1 mutation) and CML; accordingly, the term MPN is primarily reserved for PV, ET, and PMF, although it includes other related clinicopathologic entities, according to the World Health Organization (WHO) classification system. In 2005, William Vainchenker and others described a Janus kinase 2 mutation (JAK2V617F) in MPN and this was followed by a series of additional descriptions of mutations that directly or indirectly activate JAK‐STAT: JAK2 exon 12, myeloproliferative leukemia virus oncogene (MPL) and calreticulin (CALR) mutations. The discovery of these, mostly mutually exclusive, “driver” mutations has contributed to revisions of the WHO diagnostic criteria and risk stratification in MPN. Mutations other than JAK2, CALR and MPL have also been described in MPN and shown to provide additional prognostic information. From the standpoint of treatment, over the last 50 years, Louis Wasserman from the Unites States and Tiziano Barbui from Italy had skillfully organized and led a number of important clinical trials, whose results form the basis for current treatment strategies in MPN. More recently, allogeneic stem cell transplant, as a potentially curative treatment modality, and JAK inhibitors, as palliative drugs, have been added to the overall therapeutic armamentarium in myelofibrosis. In the current review, I will summarize the important advances made in the last 10 years regarding the science and practice of MPN. Am. J. Hematol. 91:50–58, 2016. © 2015 Wiley Periodicals, Inc.

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JAK2^V617F mutation in essential thrombocythaemia: clinical associations and long‐term prognostic relevance

Cited by 289 publications

References 31 publications

Correlation between leukocytosis and thrombosis in Philadelphia-negative chronic myeloproliferative neoplasms

Correlation between leukocytosis and thrombosis in Philadelphia-negative chronic myeloproliferative neoplasms

Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk‐stratification and management

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

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JAK2V617F mutation in essential thrombocythaemia: clinical associations and long‐term prognostic relevance

Cited by 289 publications

References 31 publications

Correlation between leukocytosis and thrombosis in Philadelphia-negative chronic myeloproliferative neoplasms

Correlation between leukocytosis and thrombosis in Philadelphia-negative chronic myeloproliferative neoplasms

Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk‐stratification and management

Myeloproliferative neoplasms: A decade of discoveries and treatment advances

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JAK2^V617F mutation in essential thrombocythaemia: clinical associations and long‐term prognostic relevance