Anemia in Myelodysplastic Syndromes (MDS)

Article written and reviewed by Dr Luca Moretti

Anemia in myelodysplastic syndromes (MDS) is one of the most common and disabling clinical manifestations of this heterogeneous group of clonal hematopoietic stem cell disorders. MDS are characterized by ineffective and dysplastic production of blood cells, with a variable tendency toward cytopenias, risk of leukemic transformation and systemic complications related to both quantitative and qualitative defects of mature blood elements. In most cases, MDS associated anemia is a chronic and progressive condition, often refractory to conventional treatments, with a substantial impact on quality of life, prognosis and therapeutic choices. Understanding its pathophysiologic mechanisms, diagnostic criteria and treatment strategies is crucial for optimal and individualized patient management.

Etiology, pathogenesis and pathophysiology

The pathogenesis of anemia in MDS reflects the complex nature of the clonal abnormalities affecting the hematopoietic stem cell and the bone marrow environment. Unlike deficiency anemias, MDS associated anemia results from a qualitative defect of erythroid production, not merely a quantitative one. Acquisition of somatic mutations in key genes such as SF3B1, TET2, ASXL1, DNMT3A and TP53 leads to dysfunctional clonal proliferation accompanied by epigenetic alterations, aberrant RNA splicing and dysregulation of cell cycle control and programmed cell death mechanisms.

Ineffective erythropoiesis in MDS is manifested in the bone marrow by erythroid hyperplasia, nuclear cytoplasmic maturation asynchrony and a high proportion of precursors undergoing premature apoptosis. This results in reduced production of mature erythrocytes, which are often morphologically abnormal and functionally impaired. Morphologic findings include megaloblastoid changes, dyserythropoiesis with irregular nuclei, cytoplasmic vacuolization and nuclear budding, and sometimes ring sideroblasts, particularly in MDS with an SF3B1 mutation.

From a pathophysiologic standpoint, anemia is sustained by both failure of erythroid maturation and an ineffective response to endogenous erythropoietin, together with abnormalities of the bone marrow microenvironment, including chronic inflammation and increased proinflammatory cytokines such as TNF-α and IFN-γ, and intramedullary death or apoptosis of abnormal precursors. In some subtypes, ineffective erythropoiesis may reduce hepcidin and increase iron absorption; clinically relevant iron overload, however, is mainly related to repeated transfusions.

Risk factors for developing MDS include advanced age, particularly over 60 years, previous exposure to chemotherapy and radiotherapy, occupational contact with toxic substances, especially benzene, while evidence for other occupational agents is less consistent, the presence of germline mutations in predisposing genes such as RUNX1, GATA2 and DDX41, and a family history of myeloproliferative disorders or inherited predisposition syndromes. Nevertheless, in most cases MDS arises as a sporadic and multifactorial event.

Clinical presentation

Anemia is often the first clinical manifestation of MDS, but its presentation may be insidious, progressive and variably symptomatic depending on the rate of onset, age and comorbidities. In early disease, symptoms are often subtle: progressive fatigue, reduced exercise tolerance, palpitations, dyspnea and sometimes headache, tinnitus or mild jaundice. As cytopenia progresses, mucocutaneous pallor develops and, in frailer patients, signs of heart failure or angina appear.

Physical examination may reveal mild splenomegaly, hepatomegaly, petechiae or ecchymoses in patients with thrombocytopenia, as well as signs of infection in MDS with neutropenia. Over time, transfusion dependence may lead to hemosiderosis, with skin pigmentation, liver disease, cardiomyopathy and endocrine disorders.

The clinical picture is often made more complex by coexisting nonspecific systemic symptoms such as night sweats, weight loss, low grade fever and osteoarticular pain, which should raise suspicion of disease progression or evolution toward acute leukemia.

Diagnosis and investigations

Suspicion of MDS related anemia arises in the presence of chronic normocytic or macrocytic anemia, often associated with other cytopenias such as leukopenia or thrombocytopenia and not explained by iron or vitamin deficiencies; response to erythropoiesis stimulating agents is variable and is not a diagnostic criterion. A careful medical history is essential to identify risk factors, previous exposure to myelotoxic drugs, a family history of hematologic disorders and systemic symptoms suggestive of progressive disease.

The hematologic panel typically documents normocytic or macrocytic anemia with reticulocytopenia and variable leukopenia and/or thrombocytopenia. The peripheral blood smear shows anisopoikilocytosis, poikilocytosis, oval erythrocytes, Howell-Jolly bodies and sometimes circulating blasts. Hemolysis, when present, is mild and secondary to ineffective bone marrow maturation.

Definitive diagnosis is based on bone marrow examination: the aspirate may show erythroid hyperplasia, dyserythropoiesis with precursors having irregular nuclei, multinucleation, vacuolization and nuclear budding, dysplastic megakaryocytes and, in forms with an SF3B1 mutation, ring sideroblasts. Bone marrow biopsy more often shows normocellular or hypercellular marrow, although hypocellular forms exist; dysplasia may involve one or more hematopoietic lineages.

Genetic and molecular investigations are now fundamental for classification, prognosis and therapeutic decisions: an NGS panel, or Next Generation Sequencing, can identify pathogenic mutations and stratify the risk of leukemic progression. When a familial syndrome is suspected, germline testing for inherited mutations may guide genetic counseling.

To assess the risk of complications, iron burden should be monitored regularly using ferritin, transferrin saturation and tissue magnetic resonance imaging of the liver and heart, especially in transfusion dependent patients. The diagnostic workup also includes assessment of kidney, liver and endocrine function to identify the effects of secondary siderosis early.

The differential diagnosis includes deficiency anemias due to iron, vitamin B12 or folate deficiency, hemoglobinopathies, bone marrow aplasia and acute leukemias: the combination of cytopenias, bone marrow dysplasia and genetic abnormalities supports MDS, but requires exclusion of alternative diagnoses and integration of morphology, cytogenetics and molecular data.

Prognostic stratification must integrate validated risk systems. The IPSS-R uses cytopenias, bone marrow blasts and cytogenetics, whereas the IPSS-M also incorporates the mutational profile and provides a more up to date molecular prognostic assessment that helps guide follow up intensity and therapeutic choices.

Treatment and prognosis

Management of anemia in MDS is highly individualized and depends on age, comorbidities, severity of cytopenia and risk of leukemic progression. The therapeutic goal is twofold: to improve quality of life by correcting anemia and to delay disease progression.

In lower risk disease, treatment is based on recombinant erythropoietin, either EPO or darbepoetin, with or without growth factors such as G-CSF, and the probability of response depends mainly on endogenous erythropoietin level, transfusion requirement and risk profile. In patients with transfusion dependent anemia due to low or intermediate-1 risk MDS with an isolated 5q deletion, lenalidomide is indicated under the European authorization when other treatment options are insufficient or inadequate. Under the current European authorization, luspatercept is indicated for transfusion dependent anemia due to very low, low or intermediate risk MDS, not only in forms with ring sideroblasts or an SF3B1 mutation.

Imetelstat, a telomerase inhibitor, is authorized in the European Union as monotherapy in adults with transfusion dependent anemia due to very low, low or intermediate risk non-del(5q) MDS who have had an unsatisfactory response to erythropoietin based therapy or are ineligible for such therapy.

In transfusion dependent patients, prevention and management of iron overload are central: iron chelation therapy with deferasirox or deferoxamine is recommended in patients with elevated ferritin and a long life expectancy. The risk benefit balance of transfusions must be assessed carefully, with the aim of avoiding progression of systemic siderosis.

In intermediate to high risk disease, treatment with hypomethylating agents such as azacitidine and decitabine may stabilize the disease and, in a subset of selected patients with younger age, good performance status and an available donor, allogeneic hematopoietic stem cell transplantation represents the only curative option.

Regular follow up of hematologic parameters, iron burden and organ function is essential. In frail patients or those who are not candidates for disease modifying treatments, management may be predominantly symptomatic and palliative, but attention to quality of life and prevention of complications such as infections, bleeding and cardiovascular events remains a priority.

Prognosis: Anemia in MDS is associated with a variable prognosis, strongly influenced by genetic subtype, risk of leukemic progression and the ability to maintain effective and autonomous hematopoiesis. Mortality is mainly related to disease progression, infections, bleeding and leukemic transformation; iron overload may contribute to morbidity and mortality in transfusion dependent patients.

Complications

The complications of anemia in MDS are the direct consequence of chronic cytopenia and clonal disease progression. Severe anemia may precipitate heart failure or angina in predisposed patients and is associated with poorer performance and prognosis. Repeated transfusions cause iron overload, with possible hepatic, cardiac and endocrine injury; infection risk depends mainly on neutropenia, the disease and transfusion procedures.

Disease progression may lead to complete pancytopenia, with risk of bacterial, fungal and viral infections, severe bleeding due to thrombocytopenia and the appearance of circulating blasts. Progression to acute myeloid leukemia is the most feared complication, especially in subtypes with high risk genetic features.

The chronic nature of the condition, the need for prolonged supportive care and the frequent development of iatrogenic complications from iron chelators, hypomethylating agents and transfusions require multidisciplinary management and rigorous long term monitoring.

Bibliography
1. Cazzola M. Myelodysplastic syndromes. N Engl J Med. 2020;383(14):1358-1374.
2. Steensma DP. Myelodysplastic syndromes: diagnosis and treatment. Mayo Clin Proc. 2015;90(7):969-983.
3. Tefferi A, Vardiman JW. Myelodysplastic syndromes. N Engl J Med. 2009;361(19):1872-1885.
4. Greenberg PL, Tuechler H, Schanz J, et al. Revised international prognostic scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454–2465.
5. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36(7):1703–1719.
6. Fenaux P, et al. Luspatercept in Patients with Lower-Risk Myelodysplastic Syndromes. N Engl J Med. 2020;382(2):140-151.
7. European Medicines Agency. Reblozyl (luspatercept): EPAR, product information. 2024.
8. Malcovati L, et al. Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet. Blood. 2013;122(17):2943-2964.
9. Hoffbrand AV, Higgs DR, Keeling DM, Mehta AB. Postgraduate Haematology. Wiley-Blackwell. 7th ed. 2016.
10. Greer JP, et al. Wintrobe’s Clinical Hematology. Wolters Kluwer. 14th ed. 2018.
11. Kaushansky K, et al. Williams Hematology. McGraw-Hill. 10th ed. 2021.
12. Arber DA, Orazi A, Hasserjian RP, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200–1228.
13. Bewersdorf JP, Zeidan AM. Evolving therapies for lower-risk myelodysplastic syndromes. Ann Hematol. 2020;99(4):677–692.
14. Platzbecker U, Santini V, Fenaux P, et al. Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;403(10423):249–260. doi:10.1016/S0140-6736(23)01724-5.
15. European Medicines Agency. Rytelo (imetelstat): EPAR and product information. 2025.