Myelodysplastic syndromes with ring sideroblasts (MDS‐RS) and MDS/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN‐RS‐T) – “2021 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 myelodysplastic syndromes with RS (MDS‐RS) and MDS/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN‐RS‐T). Diagnosis MDS‐RS is a lower risk MDS, with single or multilineage dysplasia (MDS‐RS‐SLD/MLD), <5% bone marrow (BM) blasts, <1% peripheral blood 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 × 109/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 (50%), DNMT3A, TET2 and ASXL1 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 (MPN). Both diseases are associated with 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. Luspatercept, a first‐in‐class erythroid maturation agent is now approved for the management of anemia in patients with MDS‐RS and MDS/MPN‐RS‐T. Aspirin therapy is reasonable in MDS/MPN‐RS‐T, especially in the presence of JAK2V617F, but the value of platelet‐lowering drugs remains to be defined.

Navigating Myelodysplastic and Myelodysplastic/Myeloproliferative Overlap Syndromes

“…107,133,134 MDS/MPN with ring sideroblasts and thrombocytosis is characterized by the presence of bone marrow ring sideroblasts: erythroid precursors in which, after Prussian blue staining, a minimum of five siderotic granules cover at least a third of the nuclear circumference. 135 In most instances, MDS/MPN with ring sideroblasts and thrombocytosis develops on the background of SF3B1-(90%) or DNMT3A-(10%) mutated age-related clonal cytopenias, with additional mutations like TET2, DNMT3A, ASXL1, and SETBP1 resulting in evolution to MDS-RS, followed by acquisition of signaling mutations such as JAK2V617F (50%), MPL, and SH2B3 (5% each) giving rise to defining proliferative features, including thrombocytosis. 106,135 SF3B1 mutations are seen in 90% of patients and impact canonical mRNA splicing, resulting in the downregulation of genes such as ABCB7 and PPOX, giving rise to the bone marrow ring sideroblasts.…”

“…135 In most instances, MDS/MPN with ring sideroblasts and thrombocytosis develops on the background of SF3B1-(90%) or DNMT3A-(10%) mutated age-related clonal cytopenias, with additional mutations like TET2, DNMT3A, ASXL1, and SETBP1 resulting in evolution to MDS-RS, followed by acquisition of signaling mutations such as JAK2V617F (50%), MPL, and SH2B3 (5% each) giving rise to defining proliferative features, including thrombocytosis. 106,135 SF3B1 mutations are seen in 90% of patients and impact canonical mRNA splicing, resulting in the downregulation of genes such as ABCB7 and PPOX, giving rise to the bone marrow ring sideroblasts. 136 Although MDS/MPN with ring sideroblasts and thrombocytosis is associated with an increased risk of thrombosis, the risk is lower than that associated with essential thrombocythemia (a pure MPN).…”

“…60, history of thrombosis, and presence of the JAK2V617F mutation). 51,135 Lenalidomide, an immunomodulatory agent, has been associated with improvements in anemia and thrombocytosis as well as deeper molecular responses in this disease. 139…”

EnvIRONmental Aspects in Myelodysplastic Syndrome

“…GDF-11 has long been handled as the target for luspatercept, a recently approved activin receptor ligand trap for treating LR-MDS with ring sideroblasts (RS) [ 62 ]. RS are erythroid precursors with iron overloaded mitochondria, visualized via Prussian blue staining [ 63 , 64 ]. If the following criteria are met, diagnosing MDS-RS can be made: (1) ≥15% BM RS (≥5% in the presence of SF3B1 mutations), (2) <5% bone marrow (BM) blasts and (3) <1% peripheral blood blasts.…”

Molecular Targeted Therapy and Immunotherapy for Myelodysplastic Syndrome

“…Patients with lower-risk MDS (LR-MDS) are managed largely with supportive care and agents targeting improvements in anemia. Patients with higher-risk MDS (HR-MDS) are treated with the hypomethylating agents, azacitidine (AZA) or decitabine (DEC) [ 1 ]. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only curative treatment for HR-MDS patients but is only limited to younger patients who are fit for allogeneic HSCT with suitable donors [ 2 ].…”