Prognostic value of CALR vs. JAK2V617F mutations on splenomegaly, leukemic transformation, thrombosis, and overall survival in patients with primary fibrosis: a meta-analysis

Pei, Yuqing; Wu, Yue; Wang, Fei; Cui, Wei

doi:10.1007/s00277-016-2712-0

Cited by 20 publications

(20 citation statements)

References 35 publications

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“…Overall survival is also comparatively higher in CALR positive MF [47]. The rate of leukaemic transformation in CALR patients was similar to JAK2 V617F patients in a meta-analysis of twelve studies in PMF [49]. The presence of type 1 CALR mutations was prognostically favourable for overall survival with regards to type 2 CALR mutations in PMF.…”

Section: Main Textmentioning

confidence: 99%

The ruxolitinib effect: understanding how molecular pathogenesis and epigenetic dysregulation impact therapeutic efficacy in myeloproliferative neoplasms

et al. 2018

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The myeloproliferative neoplasms (MPN), polycythaemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are linked by a propensity to thrombosis formation and a risk of leukaemic transformation. Activation of cytokine independent signalling through the JAK/STAT cascade is a feature of these disorders. A point mutation in exon 14 of the JAK2 gene resulting in the formation of the JAK2 V617F transcript occurs in 95% of PV patients and around 50% of ET and PMF patients driving constitutive activation of the JAK/STAT pathway. Mutations in CALR or MPL are present as driving mutations in the majority of remaining ET and PMF patients. Ruxolitinib is a tyrosine kinase inhibitor which inhibits JAK1 and JAK2. It is approved for use in intermediate and high risk PMF, and in PV patients who are resistant or intolerant to hydroxycarbamide. In randomised controlled trials it has demonstrated efficacy in spleen volume reduction and symptom burden reduction with a moderate improvement in overall survival in PMF. In PV, there is demonstrated benefit in haematocrit control and spleen volume. Despite these benefits, there is limited impact to induce complete haematological remission with normalisation of blood counts, reduce the mutant allele burden or reverse bone marrow fibrosis. Clonal evolution has been observed on ruxolitinib therapy and transformation to acute leukaemia can still occur. This review will concentrate on understanding the clinical and molecular effects of ruxolitinib in MPN. We will focus on understanding the limitations of JAK inhibition and the challenges to improving therapeutic efficacy in these disorders. We will explore the demonstrated benefits and disadvantages of ruxolitinib in the clinic, the role of genomic and clonal variability in pathogenesis and response to JAK inhibition, epigenetic changes which impact on response to therapy, the role of DNA damage and the role of inflammation in these disorders. Finally, we will summarise the future prospects for improving therapy in MPN in the JAK inhibition era.

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Section: Main Textmentioning

confidence: 99%

The ruxolitinib effect: understanding how molecular pathogenesis and epigenetic dysregulation impact therapeutic efficacy in myeloproliferative neoplasms

et al. 2018

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“…Currently there are different research approaches to address this group of diseases, which allows the evaluation of a large number of variables to compare various characteristics of patients with PV, ET and PMF. With the diversity of studies, some systematic reviews have focused on molecular issues such as the relationship of a specific mutation with clinical characteristics or prognosis of a single disease [20, 21], the comparison of two types of mutations at the prognostic level [22, 23], diagnosis and therapy related to a single mutation [24] and factors associated with the lifestyle, environmental, ethnic and family conditions of patients [25].…”

Section: Introductionmentioning

confidence: 99%

Systematization of analytical studies of polycythemia vera, essential thrombocythemia and primary myelofibrosis, and a meta-analysis of the frequency of JAK2, CALR and MPL mutations: 2000–2018

2019

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Background Research into Philadelphia-negative chronic myeloproliferative neoplasms is heterogeneous. In addition, no systematization of studies of polycythemia vera (PV), essential thrombocythemia (ET) or primary myelofibrosis (PMF) have been carried out. The objective of this review is to characterize studies on BCR-ABL1 -negative chronic myeloproliferative neoplasms and to compare the frequency of JAK2, MPL and CALR mutations in PV, ET and PMF. Method A systematic review of the scientific literature was conducted, as was meta-analysis with an ex-ante selection of protocol, according to phases of the PRISMA guide in three interdisciplinary databases. To guarantee reproducibility in the pursuit and retrieval of information, the reproducibility and methodological quality of the studies were evaluated by two researchers. Results Fifty-two studies were included, the majority having been carried out in the United States, China, Brazil and Europe. The frequency of the JAK2V617F mutation ranged from 46.7 to 100% in patients with PV, from 31.3 to 72.1% in patients with ET, and from 25.0 to 85.7% in those with PMF. The frequency of the MPL mutation was 0% in PV, from 0.9 to 12.5% in ET, and from 0 to 17.1% in PMF. The CALR mutation occurred at a frequency of 0.0% in PV, whereas in ET, it ranged from 12.6 to 50%, and in PMF, it ranged from 10 to 100%. The risk of this mutation presenting in PV is 3.0 times that found for ET and 4.0 times that found for PMF. Conclusion Given the specificity and reported high frequencies of the JAK2V617F, MPL and CALR mutations in this group of neoplasms, the diagnosis of these diseases should not be made on clinical and hematological characteristics alone but should include genetic screening of patients.

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“…1 12 As noted earlier, human studies suggest that JAK2V617F mutations in PMF are associated with higher rates of thrombosis, and increased platelet activation, with a greater allele burden portending the highest risk. 13 14 Mimicking human phenotypes in mice has uncovered an interesting interplay of different components driving thrombosis in various types of MPN. For example, models using mainly polycythemia vera/PMF phenotype showed highly unstable thrombi in a ferric chloride-induced injury model of thrombosis and prolonged bleeding times, compared with matching controls.…”

Section: From Pathological Fibrosis In Primary Myelofibrosis To Thrommentioning

confidence: 99%

Emerging Factors Implicated in Fibrotic Organ–Associated Thrombosis: The Case of Two Organs

Leiva

Bekendam

Garcia

et al. 2019

TH Open

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Thrombosis is at the heart of cardiovascular complications observed in specific diseases. A heightened thrombosis risk above that in general population in diseases such as myelofibrosis and chronic kidney disease implicates disease-specific mediators of thrombosis. This relative lack of information regarding the mechanisms of thrombosis in specific organ pathologies hitherto has remained limited. Evolving literature implicates some soluble factors in the blood of patients with discrete disorders, inflicting fundamental changes in the components of thrombosis. In this era of precision medicine, integrating these disease-specific factors in a comprehensive thrombotic risk assessment of patients is imperative in guiding therapeutic decisions. A complex network of mechanisms regulates each organ pathology and resultant thrombotic phenotypes. This review surveys different effectors of thrombogenicity associated with two pathologically fibrotic organs used as model systems, the bone marrow and kidney, as well as focuses attention to a common inducer of fibrosis and thrombosis, lysyl oxidase.

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Prognostic value of CALR vs. JAK2V617F mutations on splenomegaly, leukemic transformation, thrombosis, and overall survival in patients with primary fibrosis: a meta-analysis

Cited by 20 publications

References 35 publications

The ruxolitinib effect: understanding how molecular pathogenesis and epigenetic dysregulation impact therapeutic efficacy in myeloproliferative neoplasms

The ruxolitinib effect: understanding how molecular pathogenesis and epigenetic dysregulation impact therapeutic efficacy in myeloproliferative neoplasms

Systematization of analytical studies of polycythemia vera, essential thrombocythemia and primary myelofibrosis, and a meta-analysis of the frequency of JAK2, CALR and MPL mutations: 2000–2018

Emerging Factors Implicated in Fibrotic Organ–Associated Thrombosis: The Case of Two Organs

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