Residency · Residency · Hematology Thrombosis

Myelodysplastic Syndromes

Introduction

The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell neoplasms characterized by one or more peripheral blood cytopenias, morphologic dysplasia in the bone marrow, and a variable but clinically significant risk of transformation to acute myeloid leukemia. The median age at diagnosis is 70 to 75 years, with a male predominance. The clinical spectrum ranges from indolent disease, such as MDS with isolated del(5q) that may remain stable for years, to aggressive forms with excess blasts and complex karyotype that progress rapidly to AML. The WHO 5th Edition (2022) and the International Consensus Classification (ICC, 2022) represent major updates that integrate molecular genetic data alongside traditional morphologic and cytogenetic criteria.

Pathogenesis

The development of MDS is increasingly understood as a multi-step process that begins with clonal hematopoiesis. Clonal hematopoiesis of indeterminate potential (CHIP), in which somatic mutations are detected in hematopoietic cells without cytopenias or dysplasia, may progress to clonal cytopenia of undetermined significance (CCUS), in which cytopenias are present but morphologic criteria for MDS are not met, and ultimately to overt MDS. This continuum reflects the progressive accumulation of somatic mutations in hematopoietic stem cells over time.

Somatic mutations are detectable in 80 to 90% of MDS patients, and their identification has transformed our understanding of disease biology and prognosis. Driver mutations can be organized by functional category. Splicing factor mutations are among the most common, with SF3B1 mutations (present in approximately 30% of cases) being associated with ring sideroblasts and a favorable prognosis, while SRSF2, U2AF1, and ZRSR2 mutations are also frequently encountered. DNA methylation pathway genes including TET2, DNMT3A, and IDH1/2 are commonly mutated. Chromatin modification genes such as ASXL1 (which carries an unfavorable prognosis) and EZH2 are altered in a significant subset of patients. Transcription factor mutations, including RUNX1 and ETV6, and tumor suppressor mutations, particularly TP53 (where multi-hit or biallelic inactivation portends a very poor prognosis), are important prognostic determinants. Signal transduction pathway genes (NRAS, KRAS, CBL, JAK2) and cohesin complex genes (STAG2, RAD21, SMC1A, SMC3) round out the mutation landscape.

The central pathologic feature of MDS is ineffective hematopoiesis, in which clonal hematopoietic progenitors undergo excessive apoptosis during maturation, resulting in peripheral cytopenias despite a typically hypercellular bone marrow. Immune dysregulation, characterized by elevated levels of TNF-alpha and interferon-gamma, contributes to the suppression of hematopoiesis, and paradoxical autoimmune features are recognized in lower-risk MDS, providing rationale for immunosuppressive approaches in selected patients.

Classification (WHO 5th Edition 2022)

MDS with Defining Genetic Abnormalities

The WHO 5th Edition recognizes several MDS subtypes defined by specific genetic features. MDS with low blasts and isolated del(5q) is characterized by the presence of one or two cytogenetic abnormalities including deletion of the long arm of chromosome 5, with blast counts below 5% in the marrow and below 2% in the blood. This subtype carries a good prognosis and is specifically responsive to lenalidomide. MDS with low blasts and SF3B1 mutation is defined by the presence of 15% or more ring sideroblasts (or 5% or more with a confirmed SF3B1 mutation) and carries a favorable prognosis. MDS with biallelic TP53 inactivation is a distinct biological entity defined by two or more TP53 mutations (or one mutation with concurrent del(17p) or loss of heterozygosity at the TP53 locus) and carries a very poor prognosis regardless of the blast count.

MDS Defined Morphologically

When no defining genetic abnormality is present, MDS is classified based on morphologic features. MDS with low blasts (MDS-LB) has fewer than 5% blasts in the marrow and fewer than 2% in the blood. MDS with increased blasts 1 (MDS-IB1) has 5 to 9% blasts in the marrow or 2 to 4% in the blood. MDS with increased blasts 2 (MDS-IB2) has 10 to 19% blasts in the marrow or 5 to 19% in the blood or Auer rods. MDS with fibrosis is defined by the presence of MDS-IB1 or MDS-IB2 with grade 2 to 3 reticulin fibrosis, a variant that often has a particularly aggressive clinical course.

Hypoplastic MDS

Hypoplastic MDS, defined by bone marrow cellularity below 25% for age, accounts for approximately 10 to 15% of MDS cases. This variant overlaps clinically and pathologically with aplastic anemia, and PNH clones may be present. Importantly, hypoplastic MDS may respond to immunosuppressive therapy with ATG and cyclosporine, similar to aplastic anemia, making accurate diagnosis particularly consequential for treatment selection.

Risk Stratification

IPSS-R (Revised International Prognostic Scoring System)

The IPSS-R integrates five clinical and pathologic variables to assign a prognostic risk score: cytogenetic risk group (divided into five categories from very good to very poor), bone marrow blast percentage, hemoglobin level, platelet count, and absolute neutrophil count. The resulting risk groups range from Very Low (score 1.5 or less, with a median overall survival of 8.8 years) through Low, Intermediate, and High to Very High (score above 6, with a median overall survival of only 0.8 years). The time to 25% AML transformation ranges from 14.5 years in the Very Low risk group to 0.7 years in the Very High risk group.

IPSS-M (Molecular IPSS)

The IPSS-M represents a major advance in MDS prognostication by integrating molecular data from a panel of 31 genes with the clinical variables of the IPSS-R. This molecular-integrated scoring system reclassifies approximately 46% of patients compared to their IPSS-R categorization, with both upgrades and downgrades in risk assignment. The IPSS-M defines six risk categories: Very Low, Low, Moderate Low, Moderate High, High, and Very High. Molecular features that are particularly prognostic include TP53 multi-hit status, FLT3 mutations, RUNX1 mutations, and NRAS mutations (all adverse), and isolated SF3B1 mutations (favorable). The IPSS-M calculator is freely available online and should be used at the time of diagnosis to guide treatment decisions.

<image>A risk stratification comparison chart for MDS showing IPSS-R and IPSS-M side by side. On the left, show the IPSS-R scoring system with its five components (cytogenetics risk groups with specific abnormalities listed, blast percentage categories, hemoglobin thresholds, platelet thresholds, and ANC thresholds) and the five resulting risk categories with median overall survival for each. On the right, show the IPSS-M with its additional molecular inputs (key genes color-coded by prognostic impact: SF3B1 in green as favorable, TP53/FLT3/RUNX1 in red as adverse) and six risk categories. Include arrows showing how patients are reclassified between systems (e.g., 46% reclassified). At the bottom, show a treatment decision framework: lower-risk (IPSS-M Very Low through Moderate Low) → supportive care, ESAs, lenalidomide; higher-risk (Moderate High through Very High) → HMA, transplant consideration. Medical education format with clean tables and color gradient.</image>

Treatment - Lower-Risk MDS

Supportive Care

The foundation of management for lower-risk MDS is supportive care. Red blood cell transfusions are administered for symptomatic anemia, and platelet transfusions are reserved for active bleeding or procedural requirements. Iron chelation therapy should be considered when the serum ferritin exceeds 1000 ng/mL and the patient has received more than 20 units of red cells, provided the expected survival exceeds 2 years, in order to prevent the organ toxicity of iron overload. Deferasirox is the preferred chelation agent in this setting due to its oral administration.

Erythropoiesis-Stimulating Agents (ESAs)

Erythropoiesis-stimulating agents remain an important treatment modality for the anemia of lower-risk MDS. Epoetin alfa is administered at 40,000 to 60,000 units subcutaneously weekly, while darbepoetin alfa is dosed at 300 micrograms subcutaneously every 2 to 3 weeks. The best predictors of response are a baseline serum erythropoietin level below 200 to 500 mU/mL and a low transfusion burden (fewer than 2 units per month). In well-selected patients, response rates range from 40 to 60%, with a median duration of response of 18 to 24 months. The Nordic scoring system provides a useful tool for predicting ESA response based on the endogenous erythropoietin level and transfusion requirement.

Luspatercept (Reblozyl)

Luspatercept, an activin receptor IIA ligand trap that promotes late-stage erythroid maturation, has emerged as a significant advance in the treatment of lower-risk MDS. The MEDALIST trial demonstrated that in lower-risk MDS patients with ring sideroblasts who were refractory to or ineligible for ESAs, 38% achieved red blood cell transfusion independence for 8 or more weeks compared to 13% with placebo. The practice-changing COMMANDS trial, which compared luspatercept directly against epoetin alfa as first-line therapy for lower-risk MDS, demonstrated superiority for luspatercept in achieving transfusion independence (58.5% versus 31.2%). These results have led to the positioning of luspatercept as a first-line agent, particularly in ring sideroblast-positive disease. The dose is 1 mg/kg subcutaneously every 3 weeks, with titration to a maximum of 1.75 mg/kg in MDS (higher than the maximum dose permitted in thalassemia).

Lenalidomide

Lenalidomide is the standard of care for MDS with del(5q). Its mechanism of action involves targeting casein kinase 1-alpha (CK1-alpha), encoded by the CSNK1A1 gene located on chromosome 5q. In the del(5q) setting, haploinsufficiency of CSNK1A1 renders the MDS clone hypersensitive to lenalidomide-mediated CK1-alpha degradation through the cereblon E3 ubiquitin ligase complex. The MDS-004 trial demonstrated that 67% of patients achieved red blood cell transfusion independence, with complete cytogenetic responses in 45%. The standard dose is 10 mg daily for 21 days of a 28-day cycle, with dose adjustments for cytopenias. An important caveat is that del(5q) MDS with concurrent TP53 mutations may respond initially to lenalidomide but carries a high risk of TP53-mutant clone expansion and subsequent AML transformation, warranting consideration of early transplant referral.

Immunosuppressive Therapy

Immunosuppressive therapy with ATG and cyclosporine may be considered for selected patients with hypoplastic MDS, particularly those who are younger, have a PNH-positive clone, or carry the HLA-DR15 allele. Response rates of approximately 30 to 40% are achievable in appropriately selected patients.

Imetelstat

Imetelstat is a first-in-class telomerase inhibitor that targets MDS stem cells with active telomerase. In the IMerge trial, which enrolled patients with lower-risk MDS who were transfusion-dependent and refractory to ESAs, 40% achieved transfusion independence for 8 or more weeks. Imetelstat received FDA approval in 2024 for this indication, providing an additional option for patients with lower-risk MDS who have failed ESA therapy.

Treatment - Higher-Risk MDS

Hypomethylating Agents (HMAs)

Hypomethylating agents are the backbone of treatment for higher-risk MDS. Azacitidine, administered at 75 mg/m2 subcutaneously or intravenously for 7 days of each 28-day cycle, is the preferred agent based on the AZA-001 trial, which demonstrated a median overall survival of 24.5 months compared to 15 months with conventional care regimens. This was the first agent to demonstrate a survival benefit in higher-risk MDS. A minimum of 4 to 6 cycles is required to adequately assess response, and treatment should be continued until disease progression or intolerance, as premature discontinuation is a common clinical error that may deprive patients of a response that has not yet had time to develop.

Decitabine at 20 mg/m2 intravenously for 5 days of each 28-day cycle achieves similar response rates but has not demonstrated a survival benefit in a randomized trial. Oral decitabine-cedazuridine (Inqovi) is a fixed-dose oral combination that is bioequivalent to intravenous decitabine and offers improved patient convenience. Overall response rates to HMAs range from 40 to 50%, with complete remission achieved in 15 to 20% of patients. The median overall survival on HMA therapy for higher-risk MDS is approximately 18 to 24 months.

Allogeneic HSCT

Allogeneic hematopoietic stem cell transplantation remains the only curative therapy for MDS. Transplantation should be considered for patients with higher-risk MDS (IPSS-R or IPSS-M High or Very High categories), lower-risk MDS with adverse molecular features such as TP53 multi-hit, and transfusion-dependent disease refractory to available therapies. Patients should ideally have fewer than 10% blasts at the time of transplant, and bridging therapy with a hypomethylating agent to reduce blast counts is often employed. Reduced-intensity conditioning (RIC) regimens have extended the applicability of transplant to patients up to age 70 to 75 who are otherwise fit. TP53-mutated MDS carries poor post-transplant outcomes, with overall survival of approximately 20% at 3 years, and novel conditioning strategies and post-transplant maintenance approaches are under active investigation for this population.

Emerging Therapies

Several promising therapeutic approaches are in development for MDS. Venetoclax combined with hypomethylating agents has shown activity in higher-risk MDS and is being evaluated in multiple ongoing clinical trials. Magrolimab, an anti-CD47 monoclonal antibody that functions as a macrophage checkpoint inhibitor to enhance phagocytosis of malignant cells, is being studied in the ENHANCE trial. Sabatolimab, an anti-TIM-3 antibody, was evaluated in the STIMULUS-MDS1 trial, which was negative, but further evaluation continues. IDH1 and IDH2 inhibitors, specifically ivosidenib and enasidenib, represent targeted therapeutic options for the subset of MDS patients harboring IDH mutations.

Key Clinical Pearls

• IPSS-M reclassifies nearly half of MDS patients compared to IPSS-R; molecular profiling is now essential at diagnosis
• SF3B1 mutation defines a biologically favorable subtype of MDS with excellent response to luspatercept
• TP53 multi-hit MDS (biallelic inactivation) has uniformly poor prognosis regardless of blast count and should be treated as high-risk disease
• Luspatercept has moved to first-line therapy for lower-risk MDS based on the COMMANDS trial, even ahead of ESAs in ring sideroblast-positive disease
• HMAs require a minimum of 4-6 cycles before declaring failure; premature discontinuation is a common error
• Hypoplastic MDS can mimic aplastic anemia; cytogenetics, dysplasia, and molecular profiling are essential for differentiation

References

1. Khoury JD, et al. The 5th Edition of the WHO Classification of Haematolymphoid Tumours. Leukemia. 2022;36(7):1703-1719.
2. Bernard E, et al. Molecular International Prognostic Scoring System for Myelodysplastic Syndromes (IPSS-M). NEJM Evid. 2022;1(7).
3. Fenaux P, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count AML (AZA-001). J Clin Oncol. 2010;28(4):562-569.
4. Platzbecker U, et al. Luspatercept for anaemia in lower-risk myelodysplastic syndromes (COMMANDS). Lancet. 2023;402(10399):373-385.
5. Greenberg PL, et al. Revised international prognostic scoring system for myelodysplastic syndromes (IPSS-R). Blood. 2012;120(12):2454-2465.

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