Myelodysplastic Syndrome

Bone marrow aspirate demonstrating dysplastic erythroid and myeloid precursors with abnormal nuclear segmentation, characteristic of Myelodysplastic Syndrome (MDS).

Myelodysplastic Syndrome (MDS) is a clonal bone marrow failure disorder characterized by ineffective hematopoiesis, persistent cytopenias, and a variable risk of progression to acute myeloid leukemia (AML). This group of hematologic neoplasms arises when hematopoietic stem cells acquire genetic or epigenetic mutations that impair normal blood cell maturation across one or more lineages—erythroid, granulocytic, or megakaryocytic. The resulting dysplasia leads to abnormal cell morphology, poor marrow output, and peripheral cytopenias such as anemia, neutropenia, and thrombocytopenia. Because of its potential to transform into AML, MDS is often regarded as a preleukemic condition requiring careful diagnostic evaluation and risk-stratified management.

Myelodysplastic syndromes are classified as clonal stem cell disorders that cause ineffective blood cell production and varying degrees of cytopenia. According to World Health Organization (WHO) classification and the International Consensus Classification (ICC), MDS encompasses a spectrum ranging from low-risk disease with isolated cytopenia to high-risk subtypes with increased blasts and complex cytogenetic abnormalities. Modern molecular profiling has identified recurrent mutations in genes such as SF3B1, TET2, ASXL1, TP53, and RUNX1, which have prognostic and therapeutic significance.

MDS primarily affects older adults (over 65 years), although younger individuals can also develop the condition. Early stages are driven by increased apoptosis (programmed cell death), while advanced stages show accumulating mutations and clonal evolution, leading to expansion of leukemic blasts and potential progression to AML. Although the bone marrow is typically hypercellular, a hypocellular variant (hypoplastic MDS) may mimic aplastic anemia. Accurate diagnosis requires bone marrow biopsy, cytogenetic and molecular testing, and risk assessment using the Revised International Prognostic Scoring System (IPSS-R) or the newer IPSS-M.

Early diagnosis and individualised, risk-adapted therapy—including hypomethylating agents, lenalidomide, luspatercept, and allogeneic stem cell transplantation—can improve outcomes, reduce transfusion dependence, and delay progression to acute leukemia.

Aetiology:

With a few exceptions, the exact causes of MDS are unknown.

Some evidence suggests that certain people are born with a tendency to develop MDS. This tendency can be thought of as a switch that is triggered by an external factor. If the external factor cannot be identified, then the disease is referred to as “primary MDS”.

Radiation and chemotherapy for cancer are among the known triggers for the development of MDS. Patients who take chemotherapy drugs or who receive radiation therapy for potentially curable cancers, such as breast or testicular cancers, Hodgkin’s disease and non-Hodgkin’s lymphoma, are at risk of developing MDS for up to 10 years following treatment.

Myelodysplastic syndrome that develops after use of cancer chemotherapy or radiation is called “secondary MDS” and is usually associated with multiple chromosome abnormalities in cells in the bone marrow. This type of MDS often develops rapidly into AML.

Long term exposure to certain environmental or industrial chemicals, such as benzene, can also trigger MDS.

While alcohol consumed on a daily basis may lower red blood cell and platelet counts, alcohol does not cause MDS.

There is insufficient data available to determine if smoking increases the risk of developing MDS. However, it is known that the risk of developing AML is 1.6 times greater for smokers than for non-smokers.

MDS is not inherited. In fact, it is a very rare occasion when family members, including siblings, are diagnosed with MDS.

Cytogenetically, patients with MDS or AML fall into three groups:

•Normal karyotype
•Balanced chromosomal abnormality causing the generation of fusion oncogenes
•Complex karyotypes (usually >3 abnormalities)

Comparison of cytogenetic abnormalities in therapy-related MDS and therapy-related AML, highlighting chromosome 5/7 abnormalities, balanced translocations, and the prevalence of complex karyotypes.

Clinical features:

Symptoms tend to reflect the most affected cell line and may include pallor, weakness, and fatigue (anemia); fever and infections (neutropenia); and increased bruising, petechiae, epistaxis, and mucosal bleeding (thrombocytopenia).

In addition to reduced numbers of blood cells, the mature blood cells circulating in the blood may not function properly because of dysplasia.

Extramedullary hematopoiesis may occur, leading to hepatomegaly and splenomegaly.

Myelofibrosis is occasionally present at diagnosis or may develop during the course of MDS.

Symptoms may also be referable to other underlying disorders; e.g. in elderly patients with preexisting cardiovascular disorders, anemia from MDS may exacerbate anginal pain.

Diagnosis:

The presence of dysplastic changes in the peripheral blood smear and trilineage dysplasia and hypercellular marrow in the absence of vitamin deficiency is diagnostic of MDS. The presence of typical chromosomal abnormalities supports the diagnosis and contributes to determining the prognosis of MDS.

Myelodysplastic syndrome is suspected in patients (especially the elderly) with refractory anemia, leucopenia, or thrombocytopenia. Cytopenias secondary to congenital disorders, vitamin deficiencies, or drug adverse effects must be ruled out.

Some degree of thrombocytopenia is usual; on peripheral smear, platelets vary in size, and some appear hypogranular. Abnormalities such as giant hypogranular platelets and megakaryocyte fragments are present.

The WBC count may be normal, increased, or decreased. Neutrophil cytoplasmic granularity is abnormal, with anisocytosis and variable numbers of granules. Granulation abnormalities vary from an absence of granules to abnormal distribution inside the cytoplasm (Döhle bodies).

Peripheral smear demonstrating a neutrophil containing Döhle bodies—pale blue cytoplasmic inclusions associated with inflammation, infection, and myelodysplastic syndrome.

Eosinophils also may have abnormal granularity. Pseudo Pelger-Huët cells (hyposegmented neutrophils) may be seen. Monocytosis is characteristic of the chronic myelomonocytic leukemia (CMML) subgroup, and immature myeloid cells may occur in the less well differentiated subgroups.

Peripheral smear demonstrating Pseudo Pelger–Huët cells—bilobed, hyposegmented neutrophils commonly associated with myelodysplastic syndromes and other marrow disorders.

The cytogenetic pattern is usually abnormal, with one or more clonal cytogenetic abnormalities often involving chromosomes 5 or 7.

In most cases, bone marrow changes include hypercellularity with trilineage dysplastic changes. A small number of patients may have a hypocellular marrow. This often overlaps with aplastic anemia. Increased marrow fibrosis may be confused with other myeloproliferative disorders. Dysplastic changes in RBC lineage (dyserythropoiesis) are characteristic. In the absence of vitamin B12 or folate deficiencies, the bone marrow usually exhibits asynchronous maturation of nuclei and cytoplasm similar to that described in megaloblastic anemias.

• Other changes include binuclearity or multinuclearity in the erythroid cell precursor cells and the presence of ringed sideroblasts (iron accumulation in the mitochondria). Refractory anemia with ringed sideroblasts (RARS) is one of the MDS types in the French-American-British (FAB) Cooperative Group classification system.

Bone marrow aspirate demonstrating ring sideroblasts—erythroid precursors with perinuclear iron granules stained by Prussian blue, characteristic of MDS-RARS.

Bone marrow aspirate demonstrating dyserythropoiesis with multinucleated erythroid precursors, nuclear irregularities, and abnormal chromatin patterns, consistent with Myelodysplastic Syndrome.

Morphologic features of dyserythropoiesis demonstrating nuclear irregularities, budding, and aberrant chromatin patterns typical of Myelodysplastic Syndrome.

• Dysplastic changes in white blood cell (WBC) lineage (dysmyelopoiesis) involve myeloid hyperplasia with an increased number of myeloblasts and an expanded myelocyte and metamyelocyte population (midstage bulge). This separates it from acute leukemia (absence of mid stage).

Peripheral smear demonstrating features of dysmyelopoiesis, including hypogranular neutrophils and abnormal nuclear morphology, consistent with Myelodysplastic Syndrome.

Peripheral smear demonstrating features of dysmyelopoiesis, including hypogranular neutrophils and abnormal nuclear morphology, consistent with Myelodysplastic Syndrome.

• In the FAB classification, the percentage of myeloblasts separates RA (< 5%), RAEB (5-20%), RAEB in transformation (>20, < 30%), and acute myeloid leukemia (AML; >30%). The 2008 update of the WHO classification considers single-lineage dysplasia as a valid criterion for diagnosis of MDS, and Refractory cytopenia with multilineage dysplasia (RCMD) became an official entity in that classification. In 2004, WHO revised the percentage of blasts that defines AML from 30% to 20%; thus, the RAEB in transformation entity has become officially AML.

Summary table showing Myelodysplastic Syndrome subtypes with corresponding bone marrow criteria and median survival, including refractory anemia, ring sideroblasts, excess blasts, and CMML.

• Morphologic abnormalities are evident in nuclear-cytoplasm dissociation in maturation and when the pseudo–Pelger forms are also present in bone marrow.

• Dysthrombopoiesis in the platelet production cell lineage consists of micromegakaryocytes (dwarf forms) with poor nuclei lobulation and giant platelets budding off from their cytoplasm.

Bone marrow aspirate demonstrating micromegakaryocytes—small dysplastic megakaryocytic forms with hypolobated nuclei, a classic morphologic feature of Myelodysplastic Syndrome.

Cytogenetic studies of the bone marrow cells indicate mutations into clonal cell lines, with abnormal chromosomes in 48-64% in different series. With higher-resolution techniques (e.g. FISH), some practitioners claim a 79% rate of chromosomal abnormalities in patients with primary MDS.

Chromosomal abnormalities are clonal and include 5q-, monosomy 7 (-7) or 7q-, trisomy 8 (+8), and numerous other less frequent abnormalities. Multiple combinations may be present; this indicates a very poor prognosis. A single abnormality, except those involving chromosome 7, usually indicates a good prognosis and survival.

Deletion 5q is a rare form of Myelodysplastic Syndrome (MDS). For many people, it can remain stable for many years causing few symptoms. For others, it may progress rapidly into a different subtype of MDS or transform into acute leukemia. Refractory anemia is very common in Del 5(q) MDS.

Chronic Myelomonocytic Leukemia (CMML):

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes and myeloproliferative neoplasms, with an inherent risk for leukemic transformation (~15% over 3-5 years). Diagnosis is based on the presence of sustained (>3 months) peripheral blood monocytosis (≥1 x 10⁹/L; monocytes ≥10%), usually with accompanying bone marrow dysplasia. Clonal cytogenetic abnormalities occur in ~ 30% of patients, while >90% have somatic gene mutations. Mutations involving TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%), and the oncogenic RAS pathway (~30%) are frequent, while the presence of ASXL1 and DNMT3A mutations and the absence of TET2 mutations negatively impact overall survival.

Peripheral smear demonstrating features of CMML, including persistent monocytosis and dysplastic monocytes with abnormal nuclear morphology and granularity.

Staging:

• Low risk
• Intermediate – 1 risk (Int-1)
• Intermediate – 2 risk (Int-2)
• High risk

Besa EC. Myelodysplastic syndromes (refractory anemia): A perspective of the biologic, clinical, and therapeutic issues. Med Clin North Am. 1992;76(3):599–617.

Bejar R, Steensma DP. Recent developments in myelodysplastic syndromes. Blood. 2014;124(18):2793–2803.

Emmanuel C Besa, MD. Myelodysplastic Syndrome: Background, Pathophysiology, Etiology. Medscape. Accessed September 2016. https://emedicine.medscape.com/article/207347-overview

Germing U, Kobbe G, Haas R, Gattermann N. Myelodysplastic syndromes: diagnosis, prognosis, and treatment. Dtsch Arztebl Int. 2013;110(46):783–790.

Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997;89(6):2079–2088.

Greenberg PL, et al. Revised International Prognostic Scoring System (IPSS-R) for Myelodysplastic Syndromes. Blood. 2012;120(12):2454–2465. doi:10.1182/blood-2012-03-420489

Haase D. Cytogenetic and molecular genetic pathways in the evolution of myelodysplastic syndromes. Haematologica. 2020;105(6):1456–1468. doi:10.3324/haematol.2019.232116

Khoury JD, et al. The 2022 WHO Classification of Myeloid Neoplasms and Acute Leukemias: Key updates and diagnostic principles. Blood. 2022;140(11):1200–1228. doi:10.1182/blood.2022015850

List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med. 2006;355(14):1456–1465.

List A, Kurtin S, Roe DJ, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005;352(6):549–557.

Michael E Rytting, MD. Myelodysplastic Syndrome – Hematology and Oncology – Merck Manuals Professional Edition. Accessed October 2014. https://www.merckmanuals.com/professional/hematology-and-oncology/leukemias/myelodysplastic-syndrome

National Cancer Institute (NCI). Myelodysplastic Syndromes Treatment (PDQ®) – Health Professional Version. https://www.cancer.gov/types/myeloproliferative/hp/myelodysplastic-treatment-pdq

National Institutes of Health (NIH) / MedlinePlus. Myelodysplastic Syndromes (MDS). https://medlineplus.gov/myelodysplasticsyndromes.html

National Organization for Rare Disorders (NORD). Myelodysplastic Syndromes – Overview and Management. https://rarediseases.org/rare-diseases/myelodysplastic-syndromes

Patnaik MM, Tefferi A. Chronic Myelomonocytic Leukemia: 2022 Update on Diagnosis, Risk Stratification and Management. Am J Hematol. 2022. doi:10.1002/ajh.26455

Patnaik MM, Tefferi A. Chronic Myelomonocytic Leukemia (CMML). Medscape. Updated 2024. https://emedicine.medscape.com/article/198320-overview

Savona MR, et al. Chronic myelomonocytic leukemia: 2023 update on diagnosis, prognosis, and treatment. Blood Rev. 2023;58:101015. doi:10.1016/j.blre.2023.101015

Silverman LR, Demakos EP, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: A study of the Cancer and Leukemia Group B. J Clin Oncol. 2002;20(10):2429–2440.

Keywords:

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Myelodysplastic Syndrome (MDS) – Causes, Diagnosis & Treatments | Ask Hematologist

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Explore myelodysplastic syndrome (MDS): bone marrow failure, genetic mutations, risk of AML, and treatment strategies explained by Dr Moustafa Abdou.

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Dr Moustafa Abdou

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askhematologist.com

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