The myelodysplastic syndromes

Published on 03/04/2015 by admin

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The myelodysplastic syndromes

The myelodysplastic syndromes (MDS) are a group of clonal disorders of the bone marrow. Their common feature is bone marrow failure as a result of ineffective haematopoiesis rather than reduced haematopoietic activity. A hypercellular marrow and peripheral blood cytopenia with characteristic dysplastic morphological abnormalities form the basis for diagnosis. In early disease there is increased apoptosis of marrow progenitors causing peripheral blood cytopenia but in later MDS there is actually decreased apoptosis with characteristic gene mutations, enhanced survival of myeloblasts and potential expansion of a leukaemic clone. Patients may develop frank acute myeloid leukaemia (AML; see p. 40). Increased marrow angiogenesis and autoimmunity also occur.

MDS is predominantly a disease of the elderly, although it may affect all ages. It can arise de novo or follow previous chemotherapy or radiotherapy for another malignancy. It seems to be increasing in incidence.

Classification

This is not straightforward. The French-American-British (FAB) classification divides MDS into five subtypes depending on morphological features and particularly the number of blood and marrow leukaemic blast cells. The more recent WHO system (Table 25.1) divides MDS into unilineage or multilineage dysplasia, refractory anaemia with ring sideroblasts and dysplasia with excess blasts. The FAB entity chronic myelomonocytic leukaemia (CMML) is now included in the overlap ‘MDS with myeloproliferative disorder’ category. It is likely that cytogenetic and molecular abnormalities will be increasingly incorporated into the classification; a current example is 5q− syndrome, a distinct subtype of MDS associated with a response to novel therapy and a good prognosis.

Clinical features

The diagnosis may follow a routine blood count in an asymptomatic patient. Where symptoms do occur they range from a mild anaemia to the consequences of severe marrow failure with profound anaemia, leucopenia and thrombocytopenia (Fig 25.1). Abnormal haematopoiesis can cause functional abnormalities of cells, and infection and haemorrhage may be more severe than would be predicted from the degree of cytopenia. Pronounced symptoms are predictably more common in the subtypes with increased blast cells. CMML, like the acute monocytic leukaemias, has specific features including splenomegaly (rare in other forms of MDS), skin infiltration and serous effusions.

Fig 25.1 Purpuric rash in myelodysplastic syndrome.
The patient was thrombocytopenic.

Diagnosis

The diagnosis of MDS depends on careful morphological examination of the blood film and bone marrow aspirate and trephine specimens (Fig 25.2). Common abnormalities include:

Fig 25.2 Myelodysplastic syndromes.
Morphological changes in the blood film and bone marrow aspirate. (a) Pseudo-Pelger neutrophil with bilobed nucleus. (b) Dysplastic megakaryocyte in the bone marrow. (c) Iron stain of the bone marrow showing ‘ring sideroblasts’.

Peripheral blood. Red cells – anisopoikilocytosis, macrocytosis. Neutrophils – hypogranulation, pseudo-Pelger forms. Platelets – giant forms.

Bone marrow. Erythroid cells – multinuclearity, nuclear budding, ring sideroblasts. Myeloid cells – hypogranularity, increased blast cells. Megakaryocytes – giant forms or micromegakaryocytes.

Where there are changes in all three lines the term ‘trilineage dysplasia’ is used. The bone marrow trephine biopsy usually confirms marrow hypercellularity, although fibrosis and even hypocellularity may occur.

Genetics

Around 50% of cases of MDS show cytogenetic abnormalities. Common changes include monosomy 7 or 7q−, trisomy 8, monosomy 5 or 5q−, and loss of the Y chromosome. The incidence of chromosome abnormalities increases with the severity of the disease and risk of leukaemic transformation.

Work is ongoing to better characterise the complex molecular basis of MDS. Mutations of genes encoding cell surface receptors (e.g. KIT), signal transduction proteins (e.g. RAS), transcription factors (e.g. AML1), epigenetic modifiers (e.g. MLL) and protein degradation pathways (e.g. CBL) have been identified.

Prognostic factors

The outcome is closely linked to the classification and the risk of transformation to leukaemia. The International Prognostic Scoring System (IPSS) – based on the number of blood cytopenias, percentage of bone marrow blasts and karyotype – is a simple prognostic tool which can be used to direct treatment (Table 25.2). Median survivals vary from 6 years in the low risk group to less than a year in patients at higher risk. Patients with low risk disease have an average period of 10 years before the onset of AML whereas for high risk patients this is only a few months.

Table 25.2

The International Prognostic Scoring System for Primary MDS

Int: Intermediate

¹ E.g. normal, del (5q).

² E.g. complex or chromosome 7 abnormalities.

Treatment

Supportive care

In patients with significant marrow failure, supportive care is crucial to ameliorate symptoms and prolong life. Regular blood transfusion is often necessary to control symptoms of anaemia, and haemorrhage is managed with platelet transfusions. Patients receiving multiple blood transfusions can benefit from iron chelation therapy. This may reduce not just iron overload but also transfusion dependency. Infections require swift intervention with broad-spectrum antibiotics.

Specific treatments

Treatment needs to be individualised according to the type of disease and age of the patient.

Low-risk MDS

In patients with low-risk MDS, the main goal of treatment is to improve cytopenias. Anaemia may respond to erythropoietin alone or combined with G-CSF. Immunosuppression with anti-thymocyte globulin (ALG) can give good results in younger patients with marrow hypocellularity. The immunomodulatory agent lenalidomide is particularly effective in patients with del (5q), often leading to resolution of anaemia and transfusion independence. After a long period when low-risk MDS patients received only supportive care, it is likely that many will now receive at least a trial of growth factors or a novel agent.

High-risk MDS

In high-risk MDS (e.g. RAEB; see Table 25.1), the primary aim is to prolong survival and delay transformation to AML. In younger patients, AML-type chemotherapy and allogeneic stem cell transplantation, the only potentially curative treatment, are possible options. The hypomethylating agent azacitidine has shown efficacy in higher risk subgroups with significantly prolonged survivals and delay of onset of AML. It is given subcutaneously as outpatient therapy and is generally well tolerated.

The myelodysplastic syndromes

MDS is a heterogeneous group of clonal disorders of the bone marrow; the abnormal clone differentiates ineffectively, leading to a hypercellular marrow and blood cytopenia.

MDS may affect all ages but is predominantly a disease of the elderly.

Diagnosis depends on the presence of characteristic morphological changes in the blood and marrow.

Classification into subtypes relies on bone marrow morphology and cytogenetics.

Prognosis is highly variable.

Supportive care remains crucial but growth factors and other specific therapeutic agents (e.g. lenalidomide, azacitidine) are increasingly used. Chemotherapy and stem cell transplantation may be considered in younger patients with high-risk disease

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