Myelodysplastic Syndromes (MDS) are bone marrow disorders where the body’s blood-forming tissue malfunctions. This condition disrupts the production of healthy, mature blood cells, leading to deficits in circulating red cells, white cells, or platelets. MDS is classified as a type of cancer, originating in the hematopoietic stem cells within the bone marrow. The severity of the disease largely depends on the extent of the bone marrow damage and guides the appropriate course of management.
Defining Myelodysplastic Syndromes
MDS is fundamentally a clonal disorder, originating from a single, damaged hematopoietic stem cell that reproduces abnormally. These dysfunctional stem cells lead to ineffective hematopoiesis, the process of blood cell formation within the bone marrow. The cells produced are defective and frequently die prematurely, resulting in low counts of mature cells in the peripheral blood.
This failure of maturation is termed dysplasia, referring to the abnormal appearance and development of blood cell precursors. Dysplasia can affect the erythroid (red cells), myeloid (white cells), or megakaryocytic (platelets) lineages. The resulting deficiencies in peripheral blood counts are called cytopenias, such as anemia, neutropenia, or thrombocytopenia.
MDS ranges from slow-progressing to aggressive diseases. A concern is its potential to transform into Acute Myeloid Leukemia (AML), a rapidly progressing blood cancer. This progression is determined by the number of immature, abnormal white cells, known as blasts, present in the bone marrow and blood. If blasts reach 20% or more, the diagnosis changes from MDS to AML.
The World Health Organization (WHO) provides the standard classification system for MDS. This system groups disorders based on the specific type of cytopenia, the degree of dysplasia, and the percentage of blasts observed. The WHO classification standardizes diagnosis and reflects that MDS is a collection of distinct disorders.
Identifying the Causes and Risk Factors
The cause of Myelodysplastic Syndromes is unknown in the majority of cases, classified as primary or de novo MDS, where the genetic mutation appears spontaneously. A smaller proportion of cases are secondary or therapy-related MDS, linked to prior exposure to a known agent.
Advanced age is the most influential risk factor, with the median age at diagnosis typically around 70 years. The increasing incidence suggests that the accumulation of genetic damage over a lifetime contributes to the condition.
Environmental exposures are also linked to elevated risk. Long-term exposure to chemicals like benzene, a solvent, is a recognized risk factor. Furthermore, previous cancer treatments, specifically chemotherapy agents (alkylating agents or topoisomerase II inhibitors) and high-dose radiation therapy, can damage bone marrow stem cells, leading to secondary MDS years later.
Diagnosis and Classification of MDS
Diagnosis begins when a routine Complete Blood Count (CBC) reveals persistent cytopenias, especially anemia. A peripheral blood smear is examined for abnormal cell shapes, a sign of dysplasia. The definitive diagnosis relies on a bone marrow aspiration and biopsy to collect tissue samples.
The biopsy allows pathologists to assess marrow cellularity, the degree of dysplasia (requiring at least 10% abnormality in at least one cell line), and the percentage of blasts. Cytogenetic analysis identifies specific chromosomal abnormalities that influence prognosis. A finding of less than 20% blasts confirms MDS rather than AML.
The severity of the disease is stratified using the Revised International Prognostic Scoring System (IPSS-R). This weighted scoring tool predicts the patient’s likelihood of progressing to AML and their overall survival outlook. The IPSS-R calculates a score based on five factors: the percentage of blasts, the depth of the cytopenias, and the type of cytogenetic abnormalities present.
The total IPSS-R score places patients into one of five risk categories: Very Low, Low, Intermediate, High, or Very High. This stratification guides subsequent treatment decisions. Low-risk patients are managed with supportive measures, while high-risk categories require disease-modifying therapies due to the increased risk of leukemia transformation.
Management and Treatment Options
Treatment for MDS is individualized based on the IPSS-R risk category. For Very Low or Low-risk patients, the primary goal is supportive care focused on managing symptoms caused by low blood counts. This often involves regular red blood cell or platelet transfusions to address severe anemia or bleeding risk.
Anemia management frequently includes Erythropoiesis-Stimulating Agents (ESAs) to encourage red blood cell production. Patients with the isolated deletion of chromosome 5q (del(5q)) may respond well to immunomodulatory drugs like lenalidomide, which can reduce transfusion dependence. Other agents, such as luspatercept, are approved for low-risk patients who have ring sideroblasts.
For individuals with High or Very High-risk MDS, the goal shifts toward disease modification to slow progression to AML and prolong survival. Hypomethylating Agents (HMAs), such as azacitidine and decitabine, are the standard non-transplant options. These drugs alter DNA structure in cancer cells, encouraging them to mature or undergo programmed cell death.
The only potentially curative treatment for MDS is Allogeneic Hematopoietic Stem Cell Transplantation (HSCT), or a bone marrow transplant. This procedure replaces the patient’s diseased stem cells with healthy ones from a donor. Due to the intensity and associated risks, HSCT is generally reserved for younger, medically fit patients with higher-risk disease.