Refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis: "2019 Update on Diagnosis, Risk-stratification, and Management"

Abstract

Disease overview: Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include refractory anemia with ring sideroblasts (RARS), now classified under myelodysplastic syndromes with RS (MDS-RS) and RARS with thrombocytosis (RARS-T); now called myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T).

Diagnosis: MDS-RS is a lower-risk MDS, with single or multilineage dysplasia (SLD/MLD), <5% bone marrow (BM) blasts and ≥ 15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥450 × 10(9)/L and large atypical megakaryocytes.

Mutations and karyotype: Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F, ASXL1, DNMT3A, SETBP1, and TET2 mutations. Cytogenetic abnormalities are uncommon in both.

Risk stratification: Most patients with MDS-RS-SLD are stratified into lower-risk groups by the revised-IPSS. Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia. Both diseases have a low risk of leukemic transformation.

Treatment: Anemia and iron overload are complications seen in both and are managed similar to lower-risk MDS and MPN. The advent of luspatercept, a first-in-class erythroid maturation agent will tremendously boost the ability to manage anemia. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs remains uncertain.

Figure 1-

Bone marrow aspirate findings in patients with myelodysplastic syndrome with ring sideroblasts and single lineage dysplasia (MDS-RS-SLD).

Figure 2-. A schematic approach to the differential diagnosis of bone marrow ring sideroblasts.

Key- BM- bone marrow, RS- ring sideroblasts, MDS-RS-SLD- myelodysplastic syndrome with ring sideroblasts and single lineage dysplasia (previously called RARS), MDS-RS-MLD- myelodysplastic syndromes with ring sideroblasts and multilineage dysplasia (previously called RCMD-RS), MDS-EB- myelodysplastic syndrome with excess blasts (previously called RAEB), PMF- primary myelofibrosis, CMML- chronic myelomonocytic leukemia, PB- peripheral blood, XLSA- X linked sideroblastic anemia, XLSA/A- XLSA with ataxia, SA- sideroblastic anemia.

Figure 3-

Physiological role of Splicing Factor 3 Binding Partner 1 (SF3B1).

Figure 4-. Schematic approach for the management of myelodysplastic syndromes with single lineage dysplasia and ring sideroblasts

Key- MDS-RS- myelodysplastic syndrome with ring sideroblasts, EPO- erythropoietin, rH- recombinant human, G-CSF- granulocyte colony stimulating factor, ESA- erythropoiesis stimulating agents. * Immunosuppressive therapy could be considered in individuals with hypoplastic bone marrows and a HLA-DR-15 phenotype.

Figure 5-

5A: Over-all survival of 82 patients with MDS/MPN-RS-T, stratified by the Mayo Clinic prognostic model. 5B: Thrombosis free survival in 48 patients with MDS/MPN-RS-T, stratified by their SF3B1 mutation status.

Figure 6-

Management of thrombocytosis in patients with MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).