Myelodysplastic Syndrome

A group of disorders characterised by bone marrow failure/ineffective haematopoiesis, or clonal proliferation of an abnormal haematopoietic stem cell — with a high risk of conversion to AML. Cause is unknown; risk factors include benzene/radiation/ chemotherapeutic exposure, increasing age, and chromosomal abnormalities. Blood count abnormalities depend on the subtype: anaemia (most common), neutropenia, thrombocytopenia.

Therapy-related MDS (after chemotherapy, typically alkylating agents, 2–7 years post-exposure) carries a worse prognosis than de novo disease — commonly associated with monosomy 5, monosomy 7, or complex cytogenetics, and transforms to AML in around 55% of cases vs ~30% for de novo MDS.

Subtypes

• Refractory anaemia: anaemia with reticulocytopenia; normal/hypercellular marrow with erythroid hyperplasia and dyserythropoiesis; blasts ≤5% of nucleated marrow cells.
• Refractory anaemia with ringed sideroblasts: as above, but ringed sideroblasts >15% of nucleated marrow cells.
• Refractory cytopenia with multilineage dysplasia: cytopenia not restricted to red cells; prominent dysplasia of white cell precursors and megakaryocytes.
• …with ringed sideroblasts: as above, with ringed sideroblasts >15%.
• Refractory anaemia with excess blasts (RAEB): cytopenia of ≥2 cell lines with morphological abnormalities; hypercellular marrow with dyserythropoiesis/ dysgranulopoiesis; blasts 5–9% (RAEB-I) or 10–19% (RAEB-II).
• MDS, unclassified: doesn’t fall into a defined category.
• MDS with isolated del(5q): typically severe anaemia and thrombocytosis, with deletion of the long arm of chromosome 5.
• CMML and JMML: mixed myelodysplastic/myeloproliferative neoplasms — absolute monocytosis (>1000/mcL) with a significant increase in marrow monocyte precursors.
• Chronic neutrophilic leukaemia: neutrophilia without the Philadelphia chromosome/ BCR-ABL1 fusion gene.

Demographics: incidence ~4.9 per 100,000 (~20,500 new US cases/year); rises with age — most cases occur after 65, highest incidence (58 per 100,000) over 80. More common in men and White individuals.

History

Signs/symptoms relate to the affected cell line: anaemia (pallor, weakness, fatigue), neutropenia (infections, fevers), thrombocytopenia (easy bruising, bleeding gums, heavy menstrual bleeding, epistaxis).

Examination

Splenomegaly and hepatomegaly are not uncommon (extramedullary haematopoiesis).

Investigations

FBC: usually reduced counts in the affected line(s) — anaemia, leukopenia, thrombocytopenia, or (paradoxically) monocytosis. Peripheral smear. Bone marrow biopsy is required for diagnosis and provides prognostic information — myeloblasts must be <20% of bone marrow cells (≥20% indicates AML instead).

Management

Treatment is generally reserved for symptomatic patients, later in the disease course — asymptomatic low-risk disease gets no survival benefit from early treatment.

• Supportive: transfusions for anaemia, G-CSF for neutropenia.
• Erythropoiesis-stimulating agents (ESA) reduce anaemia severity in 15–20% of patients (non-transfusion-dependent, serum EPO <500 mIU/mL); adding G-CSF raises the erythroid response rate to near 40% in refractory anaemia with ringed sideroblasts. ESA ± G-CSF does not improve survival or reduce AML transformation risk.
• Luspatercept — for anaemia in very low- to intermediate-risk MDS with ringed sideroblasts, either ESA-naive or after ESA failure.
• Azacitidine prolongs overall survival versus supportive care/conventional chemotherapy alone; median survival on azacitidine across all MDS subgroups is 21 months. Continue for as long as the patient benefits (minimum 4–6 cycles).
• Decitabine/cedazuridine — oral option for intermediate-/high-risk MDS or CMML.

Current risk stratification uses the Revised International Prognostic Scoring System (IPSS-R) to guide treatment intensity — cytogenetics, blast percentage, and degree of cytopenia (Hb <8 g/dL, platelets <50 x10⁹/L, ANC <0.8 x10⁹/L) each worsen prognosis.

Prognosis: median survival ranges from 0.8 years (highest-risk group) to ~8 years (lowest-risk group). 10–30% transform to AML.