Myelodysplastic Syndrome

Myelodysplastic syndrome (MDS) refers to a heterogeneous group of clonal haematological malignancies characterised by ineffective blood cell production within the bone marrow. In this condition, haematopoietic stem cells fail to mature properly, resulting in the formation of abnormal and dysfunctional blood cells. Consequently, patients develop varying degrees of cytopenias, including anaemia, neutropenia, and thrombocytopenia. MDS primarily affects older adults and displays a broad clinical spectrum, ranging from indolent disease to aggressive forms that may progress to acute myeloid leukaemia (AML).

Background and Definition

MDS is classified as a cancer of the bone marrow and blood, arising from acquired genetic and epigenetic abnormalities in haematopoietic stem cells. These abnormalities disrupt normal differentiation and maturation pathways, leading to dysplastic changes in one or more blood cell lineages. The disease was first recognised in the early twentieth century, but the term “myelodysplastic syndrome” was formally adopted in 1976 to reflect its underlying pathological features.
The defining hallmark of MDS is ineffective haematopoiesis, meaning that although the bone marrow is often normocellular or hypercellular, it fails to produce adequate numbers of functional blood cells. This paradox explains why patients may have a cellular marrow yet exhibit low peripheral blood counts.

Epidemiology

MDS is relatively uncommon but increases markedly with age. Approximately seven per 100,000 individuals are affected, with around four new cases per 100,000 people diagnosed annually. The typical age of onset is approximately 70 years, making it predominantly a disease of the elderly. It is rare in children, though paediatric cases are often associated with inherited genetic syndromes.
Men are affected slightly more frequently than women. The incidence is higher in populations with prior exposure to cytotoxic therapies or environmental toxins, reflecting the role of DNA damage in disease pathogenesis.

Causes and Risk Factors

In many cases, MDS develops without an identifiable cause and is described as primary or de novo MDS. However, several risk factors have been clearly associated with disease development.
Previous exposure to chemotherapy, particularly alkylating agents such as melphalan, cyclophosphamide, busulfan, and chlorambucil, significantly increases the risk. Radiation therapy, whether therapeutic or accidental, is another well-established risk factor. Therapy-related MDS typically develops several years after exposure and often carries a poorer prognosis.
Environmental and occupational exposures also contribute. Contact with benzene, xylene, pesticides, tobacco smoke, and heavy metals such as mercury or lead has been linked to myelodysplasia. Certain occupational groups, including petroleum industry workers, demonstrate a slightly increased incidence. Historical exposures, such as Agent Orange in Vietnam veterans and radiation exposure in atomic bomb survivors, have also been associated with later development of MDS.
Genetic susceptibility plays an important role, particularly in children. Individuals with Down syndrome have an increased risk, as do those with inherited bone marrow failure syndromes such as Fanconi anaemia. Specific genetic conditions, including GATA2 deficiency and SAMD9 or SAMD9L syndromes, account for a significant proportion of paediatric MDS cases.

Pathophysiology

MDS originates from mutations within haematopoietic stem cells, leading to clonal expansion of abnormal cell populations. These mutations impair cellular differentiation and are associated with increased levels of programmed cell death (apoptosis) within the bone marrow. As a result, many developing blood cells die before reaching full maturity.
Secondary MDS may arise as a late complication of cancer therapy. Distinct cytogenetic patterns are often observed depending on the causative agent. For example, MDS following alkylating agent exposure frequently demonstrates deletions of chromosomes 5 or 7 and has a latency period of three to seven years. In contrast, MDS associated with topoisomerase II inhibitors develops more rapidly and may involve specific chromosomal translocations, such as those affecting chromosome band 11q23.
As the disease progresses, an increasing proportion of immature precursor cells, known as blasts, may accumulate in the bone marrow or peripheral blood. When blast counts exceed defined thresholds, transformation to AML is said to have occurred. Despite this risk, much of the morbidity and mortality in MDS arises from persistent cytopenias rather than leukaemic transformation.

Clinical Features and Signs

Early in the disease course, many individuals are asymptomatic, and abnormalities are often detected incidentally during routine blood tests. When symptoms do occur, they are typically related to deficiencies in specific blood cell types.
Anaemia is the most common and often the earliest manifestation. Patients may experience chronic fatigue, weakness, pallor, shortness of breath, and reduced exercise tolerance. Neutropenia leads to increased susceptibility to infections, which may be recurrent or severe. Thrombocytopenia results in easy bruising, bleeding, petechiae, purpura, and prolonged bleeding from minor injuries.
Systemic symptoms such as fever, weight loss, or splenomegaly are uncommon in pure MDS and may suggest an overlap disorder, such as a myelodysplastic–myeloproliferative neoplasm. Physical examination is often unremarkable, although hepatomegaly or splenomegaly may rarely be present.

Diagnosis and Classification

Diagnosis is based on a combination of peripheral blood findings, bone marrow examination, and cytogenetic analysis. Typical laboratory findings include one or more cytopenias, with morphological abnormalities such as abnormal nuclear shape, irregular cell size, and defective granulation.
Bone marrow biopsy reveals dysplasia in one or more cell lineages and allows quantification of blast cells. Cytogenetic studies identify chromosomal abnormalities, which are critical for classification and prognostication.
MDS is classified into distinct subtypes based on morphological features, blast percentage, and genetic changes. These classifications help guide treatment decisions and predict disease behaviour.

Genetics and Molecular Abnormalities

Genetic and epigenetic alterations are central to MDS pathogenesis. Abnormal DNA methylation patterns disrupt the regulation of genes involved in cell proliferation and differentiation. This understanding has led to the development of hypomethylating agents as targeted therapies.
Chromosomal abnormalities are common and include deletions, translocations, and changes in chromosome number. One well-characterised entity is the 5q syndrome, associated with deletion of the long arm of chromosome 5. This subtype has distinctive clinical features and responds particularly well to specific drug therapy.
Accumulating evidence also suggests that defects in DNA repair mechanisms and mitochondrial dysfunction contribute to disease development, particularly in older individuals. Increased oxidative DNA damage and impaired repair pathways have been demonstrated in many patients.

Treatment and Management

Management strategies depend on disease severity, patient age, comorbidities, and prognostic risk category. Treatment options range from supportive care to potentially curative therapies.
Supportive care forms the foundation of management for many patients. This includes red blood cell and platelet transfusions, erythropoiesis-stimulating agents to reduce transfusion dependence, and antibiotics for infection management. Long-term transfusion therapy may lead to iron overload, requiring chelation therapy.
Drug therapies include immunomodulatory agents, hypomethylating agents such as azacitidine and decitabine, and immunosuppressive treatments like antithymocyte globulin. Lenalidomide is particularly effective in patients with the 5q deletion.
The only curative treatment for MDS is allogeneic haematopoietic stem cell transplantation. This approach is generally reserved for younger, fit patients due to its associated risks. In selected individuals, chemotherapy followed by stem cell transplantation from a suitable donor can result in long-term remission or cure.