Clinical features and course of refractory anemia with ring sideroblasts associated with marked thrombocytosis

Broséus, Julien; Florensa, Lourdes; Zipperer, Esther; Schnittger, Susanne; Malcovati, Luca; Richebourg, Steven; Lippert, Éric; Čermák, Jaroslav; Evans, Jyoti; Mounier, Morgane; Raya, José María; Bailly, François; Gattermann, Norbert; Haferlach, Torsten; Garand, Richard; Allou, Kaoutar; Besses, Carlos; Germing, Ulrich; Haferlach, Claudia; Travaglino, Erica; Luño, Elisa; Piñán, M.A.; Arenillas, Leonor; Rozman, Marı́a; Sirvent, Maria Luz Perez; Favre, Bernardine; Guy, Julien; Alonso, Esther; Ahwij, Nuhri; Jerez, Andrés; Hermouet, Sylvie; Maynadié, Marc; Cazzola, Mario; Girodon, François

doi:10.3324/haematol.2011.053918

Cited by 87 publications

(116 citation statements)

References 26 publications

(46 reference statements)

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“…In addition, although 15% of patients had an abnormal karyotype, it is unclear if karyotype was included in the survival analysis. In a prior comparative study (n 5 200), survival in RARS-T was not impacted by the JAK2 mutation status or the platelet threshold (> or < 600 x 10(9)/L) [4]. To the best of our knowledge, we present the first study assessing the impact of multiple myeloid relevant gene mutations in RARS-T. We demonstrate the adverse prognostic impact of anemia (HB <10 gm/dl), abnormal cytogenetics (excluding -Y) and mutations involving ASXL1 and SETBP1.…”

Section: Discussionmentioning

confidence: 85%

“…In 2008, the minimum platelet count required for inclusion was lowered from 600 to 450 3 10(9)/L for consistency with the diagnostic criteria for essential thrombocythemia (ET) [1]. The median age at diagnosis ranges from 71 to 75 years and approximately 80% of patients do not have detectable clonal cytogenetic abnormalities [3,4]. The advent of next-generation sequencing (NGS) has helped define the molecular landscape of patients with RARS-T. Common abnormalities include: spliceosome component mutations-SF3B1 90%, SRSF2 7%, U2AF1 5%, ZRSR2 3%; signal pathway mutations-JAK2V617F 57%, MPL 3%, CBL 4%; mutations in epigenetic regulator genes-ASXL1 15%, TET2 25%, EZH2 7%, DNMT3A 15%, IDH2 4%, and mutations involving transcription factors-ETV6 3%, RUNX1 1% [3,4].…”

Section: Introductionmentioning

confidence: 99%

“…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]. Thrombotic events were similar in ET and RARS-T (3.9 and 3.6 thrombotic events per 100 patient years), but more frequent than in RARS (0.9 thrombotic events per 100 patient years).…”

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: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

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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“…8 A very large recent multicenter study with 175 RARS-T patients analyzed for JAK2V617F reported a frequency of 42.9%. 12 The only study of hematologic parameters in dependence of SF3B1mut in RARS-T patients detected no difference between SF3B1mut and SF3B1wt. 2 Our results confirmed this finding except that SF3B1mut cases had a significantly higher percentage of ring sideroblasts.…”

mentioning

confidence: 90%

“…Screening for SF3B1mut was performed by direct Sanger sequencing of exons [11][12][13][14][15][16]. Using cDNA, a 1kb amplicon was generated with primers 5`-TGACCAGCCATCTG-GAAATC-3` (forward, exon 10) and 5`-CACCATCT-GTCCCACAACAC-3` (reverse, exon 17).…”

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confidence: 99%

High frequencies of SF3B1 and JAK2 mutations in refractory anemia with ring sideroblasts associated with marked thrombocytosis strengthen the assignment to the category of myelodysplastic/myeloproliferative neoplasms

et al. 2012

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High frequencies of SF3B1 and JAK2 mutations in refractory anemia with ring sideroblasts associated with marked thrombocytosis strengthen the assignment to the category of myelodysplastic/myeloproliferative neoplasms Mutations of spliceosome genes were shown to occur frequently in different entities. 1 Remarkably, mutations in SF3B1 (splicing factor 3b, subunit 1) were associated with the morphological feature of ring sideroblasts 1-3 and were also found in refractory anemia with ring sideroblasts and marked thrombocytosis (RARS-T). 2,[4][5][6] This malignancy has been assigned as a provisional entity in the chapter "Myelodyplastic/myeloproliferative neoplasms, unclassifiable" of the WHO classification. 7 Patients have anemia, clinical and morphological features of myelodysplastic syndromes (MDS), but also show marked thrombocytosis associated with abnormal megakaryocytes resembling BCR-ABL1 negative myeloproliferative neoplasms (MPN). 7 In line with the myeloproliferative character of this disease, RARS-T patients often show JAK2V617F mutations and, much less common, MPLW515 mutations (MPLW515mut). 7,8 To further characterize this entity, we analyzed 47 RARS-T patients for the occurrence of mutations in SF3B1 (SF3B1mut) and its association with JAK2V617F and MPLW515mut. To our knowledge, this is the largest cohort studied so far. All patients strictly met the criteria for RARS-T according to the WHO classification 2008. 7 Twentyseven of 47 (57.4%) were female and 20 of 47 (42.6%) were male. The median age was 76 years (range 44-89 years), white blood cell count (WBC) 7.9x10 9 /L (range 2.9-60.0x10 9 /L), hemoglobin level (Hb) 9.7 g/dL (range 6.9-13.1 g/dL), platelet count 691x10 9 /L (range 466-1,500x10 9 /L), and percentage of ring sideroblasts 60% (range 18-97%). Most patients had a normal karyotype (39 of 47, 83.0%) and 8 of 47 (17.0%) had various chromosomal aberrations consistent with MDS/MPN. Screening for SF3B1mut was performed by direct Sanger sequencing of exons 11-16. Using cDNA, a 1kb amplicon was generated with primers 5`-TGACCAGCCATCTG-GAAATC-3` (forward, exon 10) and 5`-CACCATCT-GTCCCACAACAC-3` (reverse, exon 17). Sequencing was performed with previous primers and 5`-GCTTGCCAGGACTTCTTGCT-3` (reverse, exon 14), 5`-AGCTTTTGCTGTTGTAGCCTCTG-3` (forward, exon 14). Mutation load was determined according to the ratio of mutated/wild-type in the electropherograms of forward and reverse reaction. Cases being SF3B1 unmutated by Sanger sequencing were reanalyzed with a more sensitive 454 deep-sequencing approach (NGS) on genomic DNA. The lowest detectable mutation load with NGS was about 3% (1,013 reads) and, for Sanger sequencing, 5-10% as confirmed by NGS. JAK2V617F, JAK2exon12 and MPLW515 mutations were analyzed as published previously. 9-11 Sensitivities of the assays were approximately 1%, 10%, and 5%, respectively. The frequency of SF3B1mut was 41 of 47 (87.2%). The 6 patients without SF3B1mut were reanalyzed by NGS but, despite higher sensitivity, no SF3B1mut was found. In the 41 SF3B1mut patients, 43...

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The Myelodysplastic Syndromes and the Myelodysplastic/Myeloproliferative Neoplasms

2017

Leukaemia Diagnosis

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Clinical features and course of refractory anemia with ring sideroblasts associated with marked thrombocytosis

Cited by 87 publications

References 26 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

High frequencies of SF3B1 and JAK2 mutations in refractory anemia with ring sideroblasts associated with marked thrombocytosis strengthen the assignment to the category of myelodysplastic/myeloproliferative neoplasms

The Myelodysplastic Syndromes and the Myelodysplastic/Myeloproliferative Neoplasms

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