JAK2V617F allele burden in polycythemia vera correlates with grade of myelofibrosis, but is not substantially affected by therapy

Silver, Richard T.; Vandris, Katherine; Wang, Y. Lynn; Adriano, Fernando; Jones, Amy V.; Christos, Paul J.; Cross, Nicholas C. P.

doi:10.1016/j.leukres.2010.06.017

Cited by 58 publications

(46 citation statements)

References 24 publications

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“…In a previous study [21], we found that MPL mutated ET patients had greater likelihood of transforming to PET-MF compared to other genotypes, but due to small number of events such difference did not reach the significance level; more recently, Elala et al reported shorter myelofibrosis-free survival in MPL mutated ET patients that remained significant in multivariate analysis, thereby corroborating our current findings [33]. On the other hand, results of this study validate and extend previous observations concerning the role of accumulation of mutated alleles of JAK2V617F [34][35][36] in the progression to PPV-MF and PET-MF, although we show here that allele burden did not impact on overall survival. We also report that CALR allele burden of PET-MF patients was significantly higher compared with a series of ET patients from our archives, indicating that a CALR allele burden greater than 50% is far more frequent in PET-MF than ET.…”

Section: Discussionsupporting

confidence: 83%

Epidemiology and clinical relevance of mutations in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 359 patients of the AGIMM group

et al. 2016

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Transformation to secondary myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PPV-MF) and essential thrombocythemia (PET-MF). Although primary (PMF) and secondary MF are considered similar diseases and managed similarly, there are few studies specifically focused on the latter. The aim of this study was to characterize the mutation landscape, and describe the main clinical correlates and prognostic implications of mutations, in a series of 359 patients with PPV-MF and PET-MF. Compared with PV and ET, the JAK2V617F and CALR mutated allele burden was significantly higher in PPV-MF and/or PET-MF, indicating a role for accumulation of mutated alleles in the process of transformation to MF. However, neither the allele burden nor the type of driver mutation influenced overall survival (OS), while absence of any driver mutation (triple negativity) was associated with significant reduction of OS in PET-MF, similar to PMF. Of the five interrogated subclonal mutations (ASXL1, EZH2, SRSF2, IDH1, and IDH2), that comprise a prognostically detrimental high molecular risk (HMR) category in PMF, only SRSF2 mutations were associated with reduced survival in PET-MF, and no additional mutation profile with prognostic relevance was highlighted. Overall, these data indicate that the molecular landscape of secondary forms of MF is different from PMF, suggesting that unknown mutational events might contribute to the progression from chronic phase disease to myelofibrosis. These findings also support more extended genotyping approaches aimed at identifying novel molecular abnormalities with prognostic relevance for patients with PPV-MF and PET-MF. Am. J. Hematol. 91:681–686, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc

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Section: Discussionsupporting

confidence: 83%

Epidemiology and clinical relevance of mutations in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 359 patients of the AGIMM group

et al. 2016

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“…These observations are supported by recently published, retrospective series of 105 patients with PV. A higher JAK2 V617F allele burden correlated with more advanced myelofibrosis, greater splenomegaly and higher white blood cell count [Silver et al 2010]. Although a significant correlation with thrombosis risk could not be defined, there was a trend towards increased frequency of thrombosis as the JAK2 V617F allele burden increased.…”

Section: Introductionmentioning

confidence: 86%

JAK2 allele burden in the myeloproliferative neoplasms: effects on phenotype, prognosis and change with treatment

Vannucchi

Pieri

Guglielmelli

2010

Therapeutic Advances in Hematology

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The field of Philadelphia-chromosome-negative chronic myeloproliferative neoplasms (MPNs) has recently witnessed tremendous advances in the basic knowledge of disease pathophysiology that followed the identification of mutations in JAK2 and MPL. These discoveries led to a revision of the criteria employed for diagnosis by the World Health Organization. The prognostic role of the JAK2 V617F mutation and of its allelic burden has been the objective of intensive research using a variety of cellular and animal models as well as in large series of patients. While a definitive position cannot yet been taken on all of the issues, there is a consensus that the presence of higher V617F allele burden, that is on the basis of a stronger activation of intracellular signalling pathways, is associated with the clinical phenotype of polycythemia vera and with defined haematological and clinical markers indicative of a more aggressive phenotype. On the other hand, a low allele burden in myelofibrosis is associated with reduced survival. Finally, a significant reduction of JAK2 V617F allele burden has been demonstrated in patients treated with interferon, while the effects of novel JAK1 and JAK2 inhibitors have not yet been fully ascertained.

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“…However, in patients that are suspected to evolve to post-PV myelofibrosis (PPV-MF), I repeat the test to document accumulation of mutated alleles that usually accompanies transition to PPV-MF. [25][26][27][28] At present, there is no evidence that assessing other MPN-associated mutations 14 provides prognostic information, unlike in PMF patients. [29][30][31] I routinely order quantification of serum erythropoietin (sEPO) levels before phlebotomy is started to avoid fluctuations.…”

Section: At Presentationmentioning

confidence: 99%

“…Of note, in the proposed revised diagnostic criteria (Table 3 32 ), BM biopsy is mandatory because it helps differentiate early PV with concomitant thrombocytosis from ET, 33 and in patients with increased Hb levels, yet below the WHO threshold, BM biopsy may be diagnostic. 34 A grade 1 reticulin fibrosis is found in 15% of PV patients at baseline and does not imply an alternative diagnosis 27 ; however, patients with fibrosis may have a more advanced phase and be more prone to develop PPV-MF. 35 An abnormal karyotype has prognostic relevance.…”

Section: At Presentationmentioning

confidence: 99%

How I treat polycythemia vera

Vannucchi

2014

Blood

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Polycythemia vera (PV) is a chronic myeloproliferative neoplasm associated with JAK2 mutations (V617F or exon 12) in almost all cases. The World Health Organization has defined the criteria for diagnosis, but it is still unclear which parameter (hemoglobin or hematocrit) is the most reliable for demonstrating increased red cell volume and for monitoring response to therapy; also, the role of bone marrow biopsy is being revisited. PV is associated with reduced survival because of cardiovascular complications and progression to post-PV myelofibrosis or leukemia. Criteria for risk-adapted treatment rely on the likelihood of thrombosis. Controlled trials have demonstrated that incidence of cardiovascular events is reduced by sustained control of hematocrit with phlebotomies (low-risk patients) and/or cytotoxic agents (high-risk patients) and antiplatelet therapy with aspirin. Hydroxyurea and interferon may be used as first-line treatments, whereas busulfan is reserved for patients that are refractory or resistant to first-line agents. However, there is no evidence that therapy improves survival, and the significance of reduction of JAK2 mutated allele burden produced by interferon is unknown. PV is also associated with a plethora of symptoms that are poorly controlled by conventional therapy. This article summarizes my approach to the management of PV in daily clinical practice.

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JAK2V617F allele burden in polycythemia vera correlates with grade of myelofibrosis, but is not substantially affected by therapy

Cited by 58 publications

References 24 publications

Epidemiology and clinical relevance of mutations in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 359 patients of the AGIMM group

Epidemiology and clinical relevance of mutations in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 359 patients of the AGIMM group

JAK2 allele burden in the myeloproliferative neoplasms: effects on phenotype, prognosis and change with treatment

How I treat polycythemia vera

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