Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors

Cerquozzi, Sonia; Tefferi, Ayalew

doi:10.1038/bcj.2015.95

Cited by 212 publications

(175 citation statements)

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“…This was in line with a previously published population based study, which showed that patients with MPN have significantly reduced life expectancy than the general population [14]. Major causes of death in ET include leukemic or fibrotic transformation, whose rates at 20 years are estimated to be between 5 and 10% [6,15,16]. 1 In one of the original descriptions on CALR mutations, CALRmutated patients with ET, compared to their JAK2-mutated counterparts, were reported to have better survival [7].…”

Section: Introductionsupporting

confidence: 80%

Calreticulin variant stratified driver mutational status and prognosis in essential thrombocythemia

et al. 2016

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About 85% of patients with essential thrombocythemia (ET) harbor one of three driver mutations: JAK2, calreticulin (CALR), and MPL; the remaining (~15%) are wild type for all three mutations and are referred to as being "triple negative." Furthermore, CALR mutations in ET are structurally classified as type 1/type 1-like or type 2/type 2-like variants. The objective of the current study was to examine the impact of CALR mutation variant stratified driver mutational status on overall (OS), myelofibrosis-free (MFFS), thrombosis-free, and leukemia-free survival (LFS) in ET; 495 patients (median age 58 years; 61% females) with ET were fully annotated for the their driver mutational status: 321 (65%) harbored JAK2, 109 (22%) CALR, and 12 (2%) MPL mutations and 11% were triple-negative. Among the 109 CALR-mutated cases, 52% were classified as type 1/type 1-like and 48% as type 2/type 2-like. In univariate analysis, triple-negative patients displayed the best and MPL mutated the worst OS (P 5 0.007); however, the difference in OS was no longer apparent on multivariable analysis that included age and sex as covariates (P 5 0.5). LFS was also similar among the different mutational groups (P 5 0.6) whereas MFFS was significantly shorter in MPLmutated patients on both univariate and multivariable analyses (age-adjusted P 5 0.02; HR 7.9, 95% CI 2.0-31.5). Also in multivariable analysis that included thrombosis history, age, and cardiovascular risk factors, the presence of JAK2 or MPL mutations was independently associated with higher risk of thrombosis (P 5 0.02; HR 1.9, 95% CI 1.1-3.4). In conclusion, driver mutational status in ET does not appear to influence overall or LFS, even after CALR variant stratification. However, the presence of MPL mutations might be associated with a higher risk of fibrotic transformation and the presence of JAK2/MPL mutations with higher risk of thrombosis.

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Section: Introductionsupporting

confidence: 80%

Calreticulin variant stratified driver mutational status and prognosis in essential thrombocythemia

et al. 2016

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“…23,36 Risk factors for leukemic transformation include advanced age, leukocytosis, splenomegaly and abnormal karyotype. 22,23 There is no specific molecular marker that is predictive of blast transformation; interestingly, leukemic blasts may result JAK2 wild type, suggesting the emergence of an unrelated leukemic clone. 37 The promoting role of cytotoxic therapy in the events leading to blast transformation of PV remains a subject of major debate.…”

Section: Diagnosis Of Transformation To Blast Phasementioning

confidence: 99%

“…An important element for risk stratifıcation is the comprehensive assessment of additional risk factors for thromboembolism, including smoking, 59 hypertension, diabetes, abnormal lipid levels, and obesity. The individual should be made aware of the value of a healthy life style in minimizing thrombotic risk, and encouraged to adopt appropriate A.M. Vannucchi 22 haematologica | 2017; 102(1) 59 and higher JAK2V617F allele burden, 60 that have all been associated with higher risk of thrombosis, are not formally integrated into current scores.…”

Section: Risk Stratificationmentioning

confidence: 99%

From leeches to personalized medicine: evolving concepts in the management of polycythemia vera

Vannucchi

2016

Haematologica

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© Ferrata Storti Foundationing to the level of knowledge we have now. Table 1 lists some of these landmark studies; due to space constraints, I will not be able to address all of them in detail. Evolving concepts in diagnosis Making a diagnosis of polycythemia veraThe World Health Organization (WHO) recently released a revised classification of MPN in which important changes to the 2008 version were introduced (Table 2). 8 In the 2008 version, the most compelling innovation had been the introduction of JAK2V617F and "similar" mutations (involving JAK2 exon 12 in 3%-4% of patients) as major diagnostic criteria.3-6 Although JAK2V617F mutation is associated with PV in more than 95% of cases, it does not represent a clear diagnosis since it is found also in 50%-60% of ET and PMF. However, the use of JAK2V617F as a marker of clonal myeloproliferation greatly facilitates the distinction of PV from reactive or congenital erythrocytosis.Considering that isotope-based assays for measuring red cell mass (RCM) and plasma volume are not routinely available even in most tertiary centers, the 2008 WHO classification listed a hemoglobin level more than 185 g/L and 165 g/L in men and women, respectively, as a strong surrogate marker of absolute increase of RCM. Since some PV patients do not fulfill such high levels, other criteria were added to facilitate diagnosis, including: 1) hemoglobin or hematocrit level that is more than 99 th percentile of reference range for age, sex, or altitude of residence; 2) an RCM that is more than 25% above mean normal predicted value;3) a hemoglobin level more than 170 g/L and 150 g/L in men and women, associated with a sustained increase of 20 g/L from baseline not attributable to correction of iron deficiency. According to the pragmatic British standards, hematocrit more than 52% in males and more than 48% in females, or an RCM more than 25% above predicted value, are sufficient to establish a diagnosis of PV if JAK2 mutation is present. 9 However, a reassessment of how far the WHO criteria can be applied in a real-life setting raised the issue of JAK2V617F mutated patients with only a borderline increase in hemoglobin. It was shown that BM morphology, according to WHO guidelines, accurately reflected a condition of increased RCM, since all patients with increased RCM also had a BM morphology consistent with PV.

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“…Reported rates of transformation are 10-15 and 5-10%, respectively for PV and ET, at 15 years from initial diagnosis, but these figures may be inaccurate due to the retrospective nature of studies, small series reported, variability of diagnostic criteria [2]. More recently, strict criteria for diagnosing transformation to PPV-MF and PET-MF have been delineated by the International Working Group for Myeloproliferative neoplasms Research and Treatment (IWG-MRT), that should result in more homogeneous patient series and facilitate controlled studies [3].…”

Section: Introductionmentioning

confidence: 99%

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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Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors

Cited by 212 publications

References 100 publications

Calreticulin variant stratified driver mutational status and prognosis in essential thrombocythemia

Calreticulin variant stratified driver mutational status and prognosis in essential thrombocythemia

From leeches to personalized medicine: evolving concepts in the management of polycythemia vera

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

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