I-009 RARS-T: Molecular and clinical features of refractory anemia with ringed sideroblasts associated with marked thrombocytosis

Abstract

A proportion of patients with refractory anemia and ringed sideroblasts (RARS) show a high platelet count, associated with an increased number of abnormal megakaryocytes, as observed in myeloproliferative neoplasms. On the basis of the co-existence of both myelodysplastic and myeloproliferative features, this disorder, identified as RARS associated with marked thrombocytosis (RARS-T), has been included as a provisional entity in the WHO classification of myeloid neoplasm within the category of myelodysplastic/myeloproliferative neoplasms unclassifiable. Interestingly, this entity was found to be significantly associatedwith JAK2 mutation. Forty to 76 percent of patients with RARS-T were found to carry the classical JAK2(V617F) mutation, with a percentage of mutant allele similar to that observed in patients with essential thrombocythemia and primary myelofibrosis. Homozygous cases have also been described, as well as occasional patients with mutations in MPL. Recently, a high prevalence of SF3B1 mutations was also observed in patients with RARS-T. The proportion of mutated patients ranged from 67% to 91% in the published studies. The mutant allele burden ranged from 17% to 62% (median, 41%), and was not significantly different from that of other WHO categories with ring sideroblasts. The high frequency of SF3B1 mutation together with mutant allele burden analysis suggest that RARS-T may result from a combination of SF3B1, responsible for myelodysplastic features (i.e. ring sideroblasts), and JAK2 or MPL mutations, conferring the myeloproliferative phenotype (i.e. thrombocytosis). A recent collaborative retrospective study across Europe including 200 patients with RARS-T showed that, compared with RARS patients, RARS-T individuals had a higher hemoglobin level, white blood cell count (WBC) and platelet count, with similar MCV. In contrast, RARS-T patients showed lower hemoglobin levels, WBC and platelet counts, but higher MCV than did patients with essential thrombocythemia. Of note, occasional patients classified as having RARS at diagnosis had a subsequent increase in platelet count with RARS-T features after variable delay, and were thus recorded as RARS-T. Two of them carried the JAK2(V617F) mutation at the time of diagnosis of RARS, whereas for 2 others, the evolution toward the RARS-T diagnosis was associated with the detection of the JAK2(V617F) mutation that had not been observed at the RARS state. Patients with RARS-T had shorter overall survival and leukemia-free survival with a lower risk of thrombotic complications than did patients with essential thrombocythemia, but better survival and a higher risk of thrombosis than patients with refractory anemia with ring sideroblasts.