HAEM4:Myelodysplastic Syndrome with Ring Sideroblasts (MDS-RS)

Primary Author(s)*

Xiaolin Hu, Ph.D; Teresa Smolarek, Ph.D, FACMG

Cancer Category/Type

Myelodysplastic Syndrome (MDS)

Cancer Sub-Classification / Subtype

Myelodysplastic Syndrome with Ring Sideroblasts (MDS-RS)

MDS with Ring Sideroblasts and Single Lineage Dysplasia (MDS-RS-SLD)
MDS with Ring Sideroblasts and Multilineage Lineage Dysplasia (MDS-RS-MLD)

Definition / Description of Disease

Myelodysplastic syndrome with ring sideroblasts (MDS-RS) is a type of MDS with defining features of the presence of ≥ 15% ring sideroblasts (RS) in erythroid precursor cells or ≥ 5% RS when SF3B1 mutation is present. According to 2016 WHO criteria, bone marrow (BM) blasts should be <5% and peripheral blood (PB) blast content should be <1%. In addition, MDS-RS is usually lack of Auer rods, and MDS with isolated del(5q) or RS with secondary causes must be excluded. Ring sideroblasts are erythroid precursor cells in which iron laden mitochondria form a perinuclear ring that can be visualized as blue granules by Prussian blue staining. RS can be found in other clonal neoplasms such as myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T). Two subtypes of MDS-RS are recognized as MDS with ring sideroblasts and single lineage dysplasia (MDS-RS-SLD) and MDS with ring sideroblasts and multilineage dysplasia (MDS-RS-MLD). In MDS-RS-SLD, the erythroid lineage is predominantly affected and the there is no significant dysplasia in non-erythroid lineage. In MDS-RS-MLD, cytopenias and dysplasia can be seen in two or three haematopoietic lineages.

Synonyms / Terminology

Refractory anaemia with ring sideroblasts (RARS);

Refractory cytopenia with multilineage dysplasia and ring sideroblasts (RCMD-RS)

Epidemiology / Prevalence

MDS-RS mainly affects elderly people with a median age of 60-73 years
MDS-RS-SLD accounts for approximately 3-11% of all MDS cases
MDS-RS-MLD accounts for approximately 13% of all MDS cases
No major sex predilection.

Clinical Features

MDS-RS-SLD
- Predominantly present with anaemia and erythroid dysplasia.
- Small portion of patients present with thrombocytopenia or neutropenia.
- Generally lower risk categories
- Revised International Prognostic Scoring System (IPSS-R): very low-34%, low-64% and intermediate-2%^[1].

MDS-RS-MLD
- Usually present with bicytopenia or pancytopenia.
- Frequently has a higher IPSS-R score than MDS-RS-SLD
Symptoms with iron overload may be seen.

Sites of Involvement

Primarily involves peripheral blood and bone marrow
Liver and spleen may be affected by iron overload

Morphologic Features

For MDS-RS-SLD, it mainly involves erythroid dysplasia ^[2]

Blood smears show dimorphic RBC, usually a mixture of normocytic or macrocytic RBC and hypochromic microcytic RBC. Basophilic stippling can be seen.
Bone marrow show erythroid hyperplasia, dysplastic features including megaloblastic changes, irregular nuclear shape, multinucleation, nuclear fragmentation, nuclear bridging. Minimum dysgranulopoiesis or megakaryocytic atypia. Absent of Auer rods. Ring sideroblasts are present usually at high percentage.
Ring sideroblasts are defined as ≥ 5 perinuclear granules encircling ≥ 1/3 of the circumference of nucleus. Must involve ≥ 15% erythroids or ≥5% erythroids with SF4B1 mutation.
Iron laden histiocytes usually present due to erythrocytes lysis.

For MDS-RS-MLD, it can involve more than two myeloid lineages (See MDS-RS-MLD)

Immunophenotype

Currently, morphologic evaluation remains the gold standard in diagnosis of MDS. Immunophenotyping provides supportive evidence to clarify the blasts nature and percentage ^[3] .Flow cytometry may be used to characterize erythroid precursor cells. Della Porta M.G. et al proposed a set of immunophenotypic variables such as cytosolic H-ferritin, CD71 and CD105 to predict functionally aberrant erythropoietic precursors. They also reported mitochondrial ferritin (MtF) correlates well with the presence of ring sideroblasts and suggested MtF can be used in diagnosis of sideroblastic anemia ^[4].

Chromosomal Rearrangements (Gene Fusions)

Not reported

Characteristic Chromosomal Aberrations / Patterns

About 10% of MDS-RS-SLD and 50% of MDS-RS-MLD have cytogenetic abnormalities [Cancer Cytogenetics]. These abnormalities mostly involve in single chromosome and are not specific for these disease entities. +8 is the most common chromosome abnormalities in MDS-RS and additional chromosomes reported include -7, 20q-, and -5 ^[5]. For chromosome abnormalities and prognostic values in MDS, please refer to MDS.

Genomic Gain/Loss/LOH

Please refer to MDS: Recurrent Genomic Alterations.

Gene Mutations (SNV/INDEL)

Somatic mutations in SF3B1 have been reported in several myeloid malignancies, especially MDS-RS ^[6]^[7]. High occurrence of SF3B1 mutations has been observed in about 80% of patients with MDS-RS-SLD and 40% of patients with MDS-RS-MLD. Most genetic alterations in SF3B1 are heterozygous missense variants that tend to cluster in C-terminal HEAT domains (residues 622–781). K700E accounts for 50% of these variants. Additional hotspots residues include 622, 625, 662 and 666. SF3B1 mutation is highly correlate with the presence of BM RS, and therefore was incorporated into 2018 WHO classification of MDS as a diagnostic criteria for MDS-RS when BM RS is over 5% or more. However, SF3B1 mutation alone does not confer diagnosis of MDS-RS. Several studies have demonstrated SF3B1 has a favorable prognostic impact ^[6]^[7]^[8] .

Gene	Mutation	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)	Prevalence (COSMIC/TCGA/Other)
SF3B1	p.K700E	Ribonucleoprotein	LOF	50%

Other Mutations

Type	Gene/Region/Other
Concomitant Mutations	DNMT3A, TET2
Secondary Mutations
Mutually Exclusive	SRSF2, U2AF1, ZRSR2

Epigenomics (Methylation)

Genes involved in epigenetic regulation are frequently mutated in MDS such as TET2, DNMT3A, IDH1, IDH2, AXSL1, and EZH2 ^[9] . These genes play a role in DNA methylation and chromatin modification as well as regulating gene expression. In low risk MDS such as MDS-RS, mutations in these genes can coexist with SF3B1 mutations and seem to be associated with MDS-RS-MLD ^[10] . Hypomethylating agents (HMA) are under investigation and current studies have not demonstrated clear advantage of HMA in low risk MDS ^[11].

Genes and Main Pathways Involved

SF3B1 gene encodes a protein that is part of the U2 snRNP protein complex which functions as splicing machinery to regulate pre-mRNA maturation. Studies have shown that mutated SF3B1 tends to utilize alternative branch point sequence to direct the U2 snRNP to an altered 3' splice site and therefore produces aberrantly spliced mRNAs which are frequently subjected to nonsense-mediated decay ^[12] . The mechanisms of how spliceosome defect leads to accumulation of BM RS are still unclear. In patients with SF3B1 mutations, the transcriptome profile shows that genes involved in mitochondrial ribosome and electron transport chain were significantly down-regulated ^[13] . ABCB7, a transporter gene that mediate heme homeostasis, previously known to cause congenital sideroblastic anemia, was found to be down-regulated by aberrant splicing in SF3B1 mutated erythroid blasts ^[14] . A recent study showed a variant transcript of erythroferrone was elevated in MDS patients with an SF3B1 mutations and is responsible for hepcidin suppression and iron overload ^[15] .

In addition to spliceosome pathway, DNA methylators, chromatin modifiers and transcription factors are among the most frequently mutated categories in MDS-RS. The prognostic and therapeutic values remain to be elucidated.

Diagnostic Testing Methods

Morphology
- Blood test
- BM aspirate
- Iron staining: Prussian blue (Peals reaction)
- Histomorphology
Cytogenetics/FISH studies
Molecular analysis: Sanger sequencing, Next Generation Sequencing

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

The diagnosis of MDS-RS include:

Refractory anemia: Hemoglobin <10 mg/dL, platelets <100×109/L, PB monocytes must be less than 1×109/L.
≥ 10% dysplasisa in erythroid (MDS-RS-SLD) or more myeloid lineages (MDS-RS-MLD), absolute neutrophil count (ANC) <1.8×109/L
<5% BM blasts, PB blasts <1%,
≥15% BM RS or ≥5% in the presence of SF3B1 mutations.
Exclusions include: non-clonal dysplasia, therapy-related myeloid neoplasm, isolated del(5q), and secondary causes of RS

Prognosis:

IPSS (international prognostic scoring system)^[16] , R-IPSS (revised IPSS)^[17] and WPSS (WHO classification based prognostic scoring system) ^[18]are widely used scoring systems to evaluate MDS prognosis. 80% of MDS-RS-SLD fall into low to intermediate risk groups based on IPSS score ^[19]^[20].
The median survival of MDS-RS-SLD is 69 to 108 months as compared to 28 months in MDS-RS-MLD [WHO].
About 1% to 2% of MDS-RS-SLD cases progress to acute myeloid leukemia as compared to 8% in MDS-RS-MLD[WHO].
SF3B1 mutation is thought to have favorable prognosis when no other adverse factors in present.
Mutations in the TP53, EZH2, ETV6, RUNX1, and ASXL1 are reported to be associated with shorter survival ^[21] . SF3B1^mutant/ASXL1^wildtype genotype is of the most favorable prognosis whereas ASXL1 independently confers adverse prognosis ^[22] .

Therapeutic Implications:

Allogeeic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for patients with MDS.

Treatment of anemia: recombinant human erythropoietin, darbepoetin
Immunomodulatory agents: Lenalidomide, TGF-β inhibitors such as Sotatercept and Luspatercept.
Iron chelation therapy if iron overload.
Hypomethylating agents are under investigation.

Familial Forms

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