Screening for <i><scp>ASXL</scp>1</i> and <i><scp>SRSF</scp>2</i> mutations is imperative for treatment decision‐making in otherwise low or intermediate‐1 risk patients with myelofibrosis

Tefferi, Ayalew; Lasho, Terra L.; Hanson, Curtis A.; Ketterling, Rhett P.; Gangat, Naseema; Pardanani, Animesh

doi:10.1111/bjh.15010

Cited by 22 publications

(14 citation statements)

References 12 publications

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“…In PV and ET, mutation-enhanced risk strati cation system appeared to select low risk patients among patients with clinical and laboratory risk variables. By contrast, in PMF, mutation and additional karyotype-enhanced risk strati cation systems identi ed higher risk patients among low or intermediate-1 risk groups, as supported by a previous nding that demonstrated the signi cance of ASXL1 and SRSF2 mutations for treatment decision-making in low or intermediate-1 risk patients with PMF [39].…”

Section: Discussionsupporting

confidence: 62%

Impact of Integrated Genetic Information on Diagnosis and Prognostication for Myeloproliferative Neoplasms in the Next-Generation Sequencing Era

Lee

Eom

et al. 2020

Preprint

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Background: Since next-generation sequencing has been widely used in clinical laboratory, diagnosis and risk stratification of hematologic malignancies are greatly dependent on genetic aberrations.Methods: In this study, we analyzed the genomic landscape of 200 patients with myeloproliferative neoplasms (MPNs) using targeted panel sequencing covering including 86 genes. Conventional bone marrow karyotyping was also performed to determine chromosomal aberration. We analyzed relationships between genetic profiles and clinical outcomes including acute transformation, bone marrow fibrosis and death.Results: Mutations in JAK2, CALR, and MPL were detected in 76.4% of MPNs. The proportion of patients with clonal genetic markers increased up to 86.4% when all detectable genetic aberrations were included. Significant co-occurring genetic aberrations potentially associated with phenotype and/or disease progression, including those in JAK2/SF3B1 (P = 0.017) and TP53/del(13q), del(5q), -7/del(7q) and complex karyotypes (P = 0.038, P < 0.001, P < 0.001 and P < 0.001, respectively) were detected. We also identified genetic aberrations associated with patient outcomes: TP53 and -7/del(7q) for inferior survival (HR, 95% CI: 64.2, 3.8-1096.5, P = 0.0041, HR, 95% CI: 14.0, 1.5-132.7, P = 0.0219), RUNX1, TP53 and IDH1/2 for leukemic transformation (HR, 95% CI: 68.1, 3.6-1300.4, P = 0.005, HR, 95% CI: 16.3, 1.2-222.7, P = 0.0364, HR, 95% CI: 32.5, 2.8-371.1, P = 0.0051), SF3B1, IDH1/2, ASXL1 and del(20q) for fibrotic progression (HR, 95% CI: 31.5, 4.1-243.3, P = 0.0009, HR, 95% CI: 21.2, 3.4-132.2, P = 0.0011, HR, 95% CI: 4.3, 1.1-16.4, P = 0.0358, HR, 95% CI: 44.5, 6.1-323.0, P = 0.0002). We compared risk stratification systems and found that mutation-enhanced prognostic scoring systems could identify lower risk polycythemia vera and essential thrombocythemia and higher risk primary myelofibrosis (P < 0.001, P < 0.001 and P < 0.001, respectively). Furthermore, the new risk stratification systems showed better predictive capacity of patient outcome. Conclusions: These results collectively indicate that integrated genetic information can enhance diagnosis and prognostication in patients with myeloproliferative neoplasms.

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Section: Discussionsupporting

confidence: 62%

Impact of Integrated Genetic Information on Diagnosis and Prognostication for Myeloproliferative Neoplasms in the Next-Generation Sequencing Era

Lee

Eom

et al. 2020

Preprint

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“…The observed mitigating effect of HCT on high risk and unfavorable karyotype was encouraging and underline the power of immunotherapy, as opposed to drug therapy alone, in eradicating cytogenetically aggressive clones in MF. Whether or not the same holds true for adverse mutations, as has been previously suggested for other chronic myeloid neoplasms, is currently under investigation and such information might also further clarify the interaction between DIPSS and transplant outcome. Finally, we recognize several limitations of the current study, including its retrospective design, relatively small sample size and the inclusion of post‐ET and post‐PV cases; the latter point was especially noteworthy considering the fact that our control group consisted entirely of patients with PMF and that both the revised cytogenetic risk stratification and DIPSS are based on PMF patients, although potentially applicable to secondary MF .…”

Section: Discussionmentioning

confidence: 63%

Allogeneic hematopoietic stem cell transplant overcomes the adverse survival effect of very high risk and unfavorable karyotype in myelofibrosis

et al. 2018

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The prognostic importance of genetic information in primary myelofibrosis (PMF) was recently highlighted in a study of over 1000 cytogenetically-annotated patients; 5-year survival rates were 8% for very high risk (VHR), 27% "unfavorable" and 45% "favorable" karyotype. The current study addresses the practice-relevant question of whether or not allogeneic hematopoietic stem cell transplant (HCT) can overcome the detrimental survival effect of VHR or unfavorable karyotype. The study included 67 patients with PMF or secondary MF who received HCT at the Mayo Clinic and in whom pretransplant cytogenetic information was available. Dynamic international prognostic scoring system (DIPSS) risk distribution was 13% high, 66% intermediate-2 and 21% intermediate-1. Cytogenetic risk distribution was 11% VHR, 34% unfavorable and 55% favorable. At median post-HCT follow-up of 60 months for living patients (range 34-170), 28 (42%) deaths were recorded. Five-year survival was 62% and was not affected by VHR or unfavorable karyotype (P = .68). The salutary effect of HCT in patients with VHR or unfavorable karyotype was also apparent during analysis of a combined dataset that included a nontransplant cohort of 383 patients with PMF; multivariable analysis of the combined dataset (n = 450) resulted in HRs (95% CI) of 2.4 (1.6-3.6) for absence of transplant, 3.3 (2.2-4.8) for VHR karyotype, 1.6 (1.2-2.1) for unfavorable karyotype, 2.9 (2.0-4.2) for DIPSS high and 1.7 (1.4-2.2) for DIPSS intermediate-2. These observations were further confirmed by analysis of more stringently matched case-control subset cohorts and provide the evidence for the therapeutic preference of HCT in cytogenetically high risk patients with MF.

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“…SRSF2 and U2AF1 belong to a group of factors that are involved in the regulation of mRNA splicing and contain the most prevalent of the spliceosome regulator mutations. The mutations are associated with a poor prognosis and the prevalence in PMF patients of SRSF2 and U2AF1 mutations is 15% and 22%, respectively [62][63][64][65]. Mutations in the ZRSR2 gene are predominantly non-sense and frameshift mutations that accumulate during the progression of disease and are generally found in PMFs [48].…”

Section: Spliceosome Regulatorsmentioning

confidence: 99%

Clonal Hematopoiesis and Mutations of Myeloproliferative Neoplasms

Kjær

2020

Cancers

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Myeloproliferative neoplasms (MPNs) are associated with the fewest number of mutations among known cancers. The mutations propelling these malignancies are phenotypic drivers providing an important implement for diagnosis, treatment response monitoring, and gaining insight into the disease biology. The phenotypic drivers of Philadelphia chromosome negative MPN include mutations in JAK2, CALR, and MPL. The most prevalent driver mutation JAK2V617F can cause disease entities such as essential thrombocythemia (ET) and polycythemia vera (PV). The divergent development is considered to be influenced by the acquisition order of the phenotypic driver mutation relative to other MPN-related mutations such as TET2 and DNMT3A. Advances in molecular biology revealed emergence of clonal hematopoiesis (CH) to be inevitable with aging and associated with risk factors beyond the development of blood cancers. In addition to its well-established role in thrombosis, the JAK2V617F mutation is particularly connected to the risk of developing cardiovascular disease (CVD), a pertinent issue, as deep molecular screening has revealed the prevalence of the mutation to be much higher in the background population than previously anticipated. Recent findings suggest a profound under-diagnosis of MPNs, and considering the impact of CVD on society, this calls for early detection of phenotypic driver mutations and clinical intervention.

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Screening for ASXL1 and SRSF2 mutations is imperative for treatment decision‐making in otherwise low or intermediate‐1 risk patients with myelofibrosis

Cited by 22 publications

References 12 publications

Impact of Integrated Genetic Information on Diagnosis and Prognostication for Myeloproliferative Neoplasms in the Next-Generation Sequencing Era

Impact of Integrated Genetic Information on Diagnosis and Prognostication for Myeloproliferative Neoplasms in the Next-Generation Sequencing Era

Allogeneic hematopoietic stem cell transplant overcomes the adverse survival effect of very high risk and unfavorable karyotype in myelofibrosis

Clonal Hematopoiesis and Mutations of Myeloproliferative Neoplasms

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