Myelodysplastic Syndromes

Introduction

Myelodysplastic syndromes are clonal disorders of the haematopoietic stem cell in which blood cell precursors mature abnormally (dysplasia) and are destroyed within the marrow before release, or are released as poorly functioning cells - a state of ineffective haematopoiesis. The result is one or more peripheral blood cytopenias despite a bone marrow that is often normo- or hypercellular.¹

MDS matters clinically for two reasons: it causes significant morbidity through the cytopenias themselves, and it is a pre-leukaemic state, with a variable but ever-present risk of transformation to acute myeloid leukaemia (AML).

Aetiology

• Primary (de novo) MDS - the majority of cases, with no identifiable prior cause, strongly associated with increasing age
• Secondary (therapy-related) MDS - following previous cytotoxic chemotherapy (particularly alkylating agents and topoisomerase II inhibitors) or radiotherapy, typically presenting years after treatment and carrying a worse prognosis and higher-risk cytogenetics than de novo disease
• Rare predisposing conditions include prior exposure to benzene and other marrow toxins, and certain inherited bone marrow failure syndromes

Clinical features

Onset is typically insidious, and many cases are picked up incidentally on a routine blood count in an older patient. Symptoms reflect whichever cell line is most affected:

• Anaemia - the commonest presentation; fatigue, dyspnoea, pallor
• Neutropenia - recurrent or unusual infections
• Thrombocytopenia - easy bruising, petechiae, mucosal bleeding
• Some patients have more than one cytopenia at presentation; a minority have only an isolated abnormality (e.g. macrocytosis) noted incidentally
• Hepatosplenomegaly and lymphadenopathy are not typical of MDS and should prompt consideration of an alternative or overlapping diagnosis

Investigations

Full blood count and blood film

Cytopenias affecting one or more lineages, often with a macrocytosis even in the absence of B12/folate deficiency. The blood film may show dysplastic features:

• Hypogranular or hyposegmented neutrophils ("pseudo-Pelger-Huet" cells, with a bilobed rather than multi-lobed nucleus)
• Giant or agranular platelets
• Basophilic stippling, and circulating blasts in higher-risk disease

Bone marrow examination - the key diagnostic test

Bone marrow aspirate and trephine biopsy is required for diagnosis, showing dysplastic changes across one or more of the erythroid, myeloid and megakaryocytic lineages, and allows the blast percentage to be counted (which distinguishes MDS, where blasts are <20%, from acute leukaemia, where they are ≥20%).¹

Perls' (Prussian blue) staining identifies ring sideroblasts - erythroid precursors with iron-laden mitochondria forming a ring around the nucleus - which define specific MDS subtypes (MDS with ring sideroblasts) and reflect defective haem synthesis.

Cytogenetics

Essential for both diagnosis and prognosis. Common abnormalities include deletions of chromosome 5q, 7q and 20q, monosomy 7, and complex karyotypes (which carry a particularly poor prognosis). The isolated 5q- deletion defines a distinct, favourable-risk subtype.

Excluding mimics

B12 and folate levels, copper level, and HIV testing should be checked, since severe deficiency states and HIV can cause dysplastic changes that mimic MDS but are reversible with treatment of the underlying cause.

Risk stratification and classification

The Revised International Prognostic Scoring System (IPSS-R) combines the degree of cytopenia, bone marrow blast percentage, and cytogenetic risk group to stratify patients into very low, low, intermediate, high and very high risk categories, which directly guides management intensity and estimates median survival and risk of progression to AML.²

The WHO classification subdivides MDS by the number of dysplastic lineages, blast percentage, and specific genetic features (e.g. MDS with ring sideroblasts, MDS with isolated del(5q)), refining prognosis further.

Differential diagnosis

• Severe B12 or folate deficiency - causes megaloblastic, dysplastic-appearing changes that resolve with replacement; always exclude before diagnosing MDS
• Aplastic anaemia - hypocellular marrow without dysplasia, rather than the normo/hypercellular dysplastic marrow of MDS
• Acute myeloid leukaemia - distinguished by a bone marrow blast count of 20% or more
• Other causes of cytopenia - hypersplenism, marrow infiltration, drug effect, HIV
• Myeloproliferative/myelodysplastic overlap syndromes (e.g. chronic myelomonocytic leukaemia), which combine proliferative and dysplastic features

Management

Lower-risk disease

• Supportive care - blood and platelet transfusion as needed, with iron chelation if transfusion becomes frequent
• Erythropoiesis-stimulating agents for anaemia in selected patients with a low endogenous EPO level
• Lenalidomide - particularly effective in MDS with isolated del(5q), often achieving transfusion independence
• Growth factors (G-CSF) used judiciously for severe, symptomatic neutropenia

Higher-risk disease

• Hypomethylating agents (azacitidine) - standard first-line therapy for higher-risk MDS not proceeding straight to transplant, improving survival and delaying progression to AML³
• Allogeneic haematopoietic stem cell transplant - the only curative option, reserved for fit patients (fitness matters more than chronological age alone) with higher-risk disease and a suitable donor
• Clinical trial enrolment where available, given the rapidly evolving treatment landscape

Complications

• Transformation to acute myeloid leukaemia - the central long-term risk, with likelihood determined by IPSS-R risk group
• Infection, from neutropenia and also from qualitative neutrophil dysfunction even when the count is preserved
• Bleeding, from thrombocytopenia and qualitative platelet dysfunction
• Transfusion-related iron overload in transfusion-dependent patients
• Reduced quality of life from chronic fatigue and repeated hospital visits for monitoring and transfusion

Red flags

Prognosis

Prognosis in MDS is highly variable and driven predominantly by IPSS-R risk category: very low-risk disease can have a median survival exceeding 8 years with a low risk of AML transformation, while very high-risk disease carries a median survival of under a year without transplant and a high likelihood of progression to AML.²

Allogeneic stem cell transplant remains the only treatment that offers cure, but is limited by patient fitness, donor availability and the risks of the procedure itself, so most patients are managed with a combination of supportive care and disease-modifying therapy aimed at controlling cytopenias and delaying progression rather than cure.