Increased likelihood of post-polycythemia vera myelofibrosis in Ph-negative MPN patients with chromosome 12 abnormalities

Benton, Christopher B.; Tanaka, Maria; Wilson, Catherine; Pierce, Sherry; Zhou, Lingsha; Cortes, Jorge; Kantarjian, Hagop; Verstovšek, Srđan

doi:10.1016/j.leukres.2015.01.012

Cited by 9 publications

(12 citation statements)

References 19 publications

(20 reference statements)

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“…Molecular indicators of fibrotic progression from PV are not well characterized. Some evidence exists suggesting an association between chromosome 12 abnormalities and an increased risk of developing post-PV MF [ 176 ]. Evidence also exists to support a significantly higher JAK2 V617F allelic frequency [ 11 , 83 , 131 , 137 , 176 ] or a progressive increase [ 177 ] in patients who transform to SMF.…”

Section: Prognosismentioning

confidence: 99%

Recent Advances in the Use of Molecular Analyses to Inform the Diagnosis and Prognosis of Patients with Polycythaemia Vera

Stuckey

Gómez‐Casares

2021

IJMS

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Genetic studies in the past decade have improved our understanding of the molecular basis of the BCR-ABL1-negative myeloproliferative neoplasm (MPN) polycythaemia vera (PV). Such breakthroughs include the discovery of the JAK2V617F driver mutation in approximately 95% of patients with PV, as well as some very rare cases of familial hereditary MPN caused by inherited germline mutations. Patients with PV often progress to fibrosis or acute myeloid leukaemia, both associated with very poor clinical outcome. Moreover, thrombosis and major bleeding are the principal causes of morbidity and mortality. As a result of increasingly available and economical next-generation sequencing technologies, mutational studies have revealed the prognostic relevance of a few somatic mutations in terms of thrombotic risk and risk of transformation, helping to improve the risk stratification of patients with PV. Finally, knowledge of the molecular basis of PV has helped identify targets for directed therapy. The constitutive activation of the tyrosine kinase JAK2 is targeted by ruxolitinib, a JAK1/JAK2 tyrosine kinase inhibitor for PV patients who are resistant or intolerant to cytoreductive treatment with hydroxyurea. Other molecular mechanisms have also been revealed, and numerous agents are in various stages of development. Here, we will provide an update of the recent published literature on how molecular testing can improve the diagnosis and prognosis of patients with PV and present recent advances that may have prognostic value in the near future.

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Section: Prognosismentioning

confidence: 99%

Recent Advances in the Use of Molecular Analyses to Inform the Diagnosis and Prognosis of Patients with Polycythaemia Vera

Stuckey

Gómez‐Casares

2021

IJMS

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“…Preliminary evidence suggests that chromosome 12 abnormalities are associated with a greater likelihood to progress to PPV-MF. 27 Occurrence of PPV-MF signifies a dramatic shortening of PV survival to a median of approximately six years with an adjusted hazard ratio (HR) of 2.17. 26 A longer (>10 years) duration of the chronic PV phase is also associated with shortened survival after transformation to PPV-MF (HR 2.26).…”

Section: Diagnosis Of Transformation To Post-polycythemia Vera Myelofmentioning

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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“…It has been reported that older age, leukocytosis, splenomegaly, thrombocytosis, a masked-PV phenotype (PV characteristics with lower hemoglobin levels than criteria targets), a high JAK2 V617F allele burden, and chromosome 12 abnormalities are associated with the evolution of MF in PV ( 16 , 36 ). Among these factors, only old age and splenomegaly fit our case, and the cause of his MF evolution remains unknown.…”

Section: Discussionmentioning

confidence: 99%

The Amelioration of Myelofibrosis with Thrombocytopenia by a JAK1/2 Inhibitor, Ruxolitinib, in a Post-polycythemia Vera Myelofibrosis Patient with a <i>JAK2</i> Exon 12 Mutation

et al. 2017

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Less than 5% of patients with polycythemia vera (PV) show JAK2 exon 12 mutations. Although PV patients with JAK2 exon 12 mutations are known to develop post-PV myelofibrosis (MF) as well as PV with JAK2V617F, the role of JAK inhibitors in post-PV MF patients with JAK2 exon 12 mutations remains unknown. We describe how treatment with a JAK1/2 inhibitor, ruxolitinib, led to the rapid amelioration of marrow fibrosis, erythrocytosis and thrombocytopenia in a 77-year-old man with post-PV MF who carried a JAK2 exon 12 mutation (JAK2H538QK539L). This case suggests that ruxolitinib is a treatment option for post-PV MF in patients with thrombocytopenia or JAK2 exon 12 mutations.

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Increased likelihood of post-polycythemia vera myelofibrosis in Ph-negative MPN patients with chromosome 12 abnormalities

Cited by 9 publications

References 19 publications

Recent Advances in the Use of Molecular Analyses to Inform the Diagnosis and Prognosis of Patients with Polycythaemia Vera

Recent Advances in the Use of Molecular Analyses to Inform the Diagnosis and Prognosis of Patients with Polycythaemia Vera

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

The Amelioration of Myelofibrosis with Thrombocytopenia by a JAK1/2 Inhibitor, Ruxolitinib, in a Post-polycythemia Vera Myelofibrosis Patient with a <i>JAK2</i> Exon 12 Mutation

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