Age, JAK2V617F and SF3B1 mutations are the main predicting factors for survival in refractory anaemia with ring sideroblasts and marked thrombocytosis

Broséus, Julien; Alpermann, Tamara; Wulfert, Michael; Florensa, Lourdes; Jeromin, Sabine; Lippert, Éric; Rozman, Marı́a; Lifermann, François; Großmann, Vera; Haferlach, Torsten; Germing, Ulrich; Luño, Elisa; Girodon, François; Schnittger, Susanne

doi:10.1038/leu.2013.120

Cited by 98 publications

(92 citation statements)

References 36 publications

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“…The European group had proposed a prognostic model consisting of age > 80 years (1 point), SF3B1wt (1 point) and JAK2V617Fwt (1 point), stratifying patients into two groups, low (0 or 1 points) and high ( 2 points), with median OS of 8 and 1.6 years respectively [9]. These variables were not found to be prognostic in our study.…”

Section: Discussioncontrasting

confidence: 58%

“…In a European study (n 5 111), prognosticators associated with better survival included; age <80 years, JAK2V617F and SF3B1 mutational status [9]. Apart from SF3B1, JAK2 and MPL other myeloid relevant gene mutations were not analyzed.…”

Section: Discussionmentioning

confidence: 99%

“…The leukemic transformation (LT) rate per 100 years was similar in RARS-T (1.8) and RARS (2.4) and higher in RARS-T in comparison to ET (0.7). In a subsequent study (n 5 111), on multivariable analysis, risk factors positively affecting OS included age <80 years (P 5 0.044), presence of JAK2V617F (P 5 0.016), and SF3B1 (P 5 0.021) mutations [9]. Unlike in the prior study, the difference in survival between RARS-T and RARS was not statistically significant (10.7 versus 6.2 years, P > 0.05).…”

Section: Introductionmentioning

confidence: 98%

“…Prognostic factors impacting over-all survival (OS), leukemia free survival (LFS), and thrombosis rates in patients with RARS-T are not well defined [9]. In a large study comparing RARS (n 5 165), RARS-T (n 5 200), and ET (n 5 454), patients with RARS-T were found to have a better median OS than RARS (76 months versus 63 months), and an inferior OS in comparison to patients with ET (76 months versus 117 months) [4].…”

Section: Introductionmentioning

confidence: 99%

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Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

et al. 2016

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Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) shares overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). RARS-T is characterized by SF3B1 and JAK2 mutations and prognosis is considered to be better than MDS but not as good as MPN. The objective of the study was to identify predictors of survival in RARS-T. We analyzed clinical and laboratory variables in 82 patients and applied a 27-gene NGS assay to 48 marrow samples obtained at diagnosis. 94% of patients had 1 mutations; common mutations being: SF3B1 85%, JAK2V617F 33%, ASXL1 29%, DNMT3A 13%, SETBP1 13% and TET2 10%. In a multivariable survival analysis (n 5 82), anemia (P 5 0.02) [HB< 10 gm/dl: HR 2.3, 95% CI 1.2-4.6] and abnormal karyotype (P 5.01) [HR 6.1, 95% CI 2.7-13.8] were independently prognostic for inferior survival. In patients with NGS information (n 5 48), univariate analysis showed association between poor survival and presence of SETBP1 (P 5 0.04) or ASXL1 (P 5 0.08) mutations whereas the absence of these mutations (ASXL1wt/SETBP1wt) was favorable (P 5 0.04); the number of concurrent mutations did not provide additional prognostication (P 5 0.3). We developed a HR-weighted prognostic model, with 2 points for an abnormal karyotype, 1 point for either ASXL1 and/or SETBP1 mutations, and 1 point for a HB level < 10 gm/dl, which effectively stratified patients into three risk categories; low (0 points), intermediate (1 point) and high ( 2 points), with median survivals of 80, 42 and 11 months respectively (P 5 0.01). In summary, we confirm the unique mutational landscape in RARS-T and provide a novel mutationenhanced prognostic model.

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Section: Discussioncontrasting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

et al. 2016

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“…Mutational profiles of MDS/MPN-RS-T (RARS-T) have also been studied in several large cohorts [11][12][13]. According to these studies, commonly mutated genes in MDS/MPN-RS-T include SF3B1 (85-90%), JAK2V617F (33-77%), TET2 (10-25%), DNMT3A (13-15%), and ASXL1 (15-29%).…”

Section: Genetic Profiles Of Rars and Mds/mpn-rs-t And Their Impact Omentioning

confidence: 99%

Splicing factor mutations in MDS RARS and MDS/MPN-RS-T

Yoshimi

Abdel‐Wahab

2017

Int J Hematol

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Myeloproliferative Neoplasms

2015

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Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) constitute the BCR-ABL1-negative myeloproliferative neoplasms and are characterized by mutually exclusive Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL) mutations; respective frequencies of these mutations are approximately 95%, 0%, and 0% in PV, 60%, 20%, and 3% in ET, and 60%, 25%, and 7% in PMF. These mutations might be accompanied by other mutations that are less specific to myeloproliferative neoplasms but are prognostically relevant, such as additional sex combs-like 1 (ASXL1). Characteristic bone marrow morphology is required for World Health Organization-compliant diagnosis, especially in distinguishing ET from prefibrotic PMF and masked PV. Survival is the longest in ET, although still inferior to that of the age- and sex-matched control population; median survivals for patients younger than 60 years are approximately 33 years for ET, 24 for PV, and 15 for PMF. Major disease complications include thrombosis and leukemic or fibrotic transformation. In PV and ET, risk factors for survival include older age, leukocytosis, and thrombosis, whereas JAK2 mutation in ET is associated with increased risk of thrombosis. In PMF, type 1 or type 1-like CALR mutations are associated with superior and ASXL1 with inferior survival. Prevention of thrombosis in PV is secured by phlebotomy (hematocrit target <45%) and in both PV and ET by low-dose aspirin therapy; high-risk patients derive additional antithrombotic benefit from cytoreductive therapy with hydroxyurea as first-line and interferon-alfa and busulfan as second-line drugs of choice. Although the JAK inhibitor ruxolitinib was recently approved for use in hydroxyurea-resistant PV, its role in routine clinical practice remains debatable. In myelofibrosis, stem cell transplant is the current treatment of choice for genetically or clinically high-risk disease; for all other patients requiring treatment, participation in clinical trials may be preferred because currently available drugs, including JAK inhibitors, are palliative and not shown to be disease modifying.

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Age, JAK2V617F and SF3B1 mutations are the main predicting factors for survival in refractory anaemia with ring sideroblasts and marked thrombocytosis

Cited by 98 publications

References 36 publications

Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

Predictors of survival in refractory anemia with ring sideroblasts and thrombocytosis (RARS‐T) and the role of next‐generation sequencing

Splicing factor mutations in MDS RARS and MDS/MPN-RS-T

Myeloproliferative Neoplasms

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