The Myelodysplastic Syndromes

Introduction

• The myelodysplastic syndromes (MDS) are a group of clonal haemopoietic disorders. They are characterized by:

• Ineffective haemopoiesis resulting in peripheral blood cytope- nias of all three lineages, but especially anaemia

• Increased risk (30%) of transformation to acute myeloid leukaemia

• MDS is mainly a disease of the elderly, with a median age at diag- nosis of 60–75 years. It does, however, affect younger adults also. MDS is rare in children, and is associated with genetic disorders such as Fanconi’s anaemia.

Aetiology and pathogenesis

The myelodysplastic syndromes (MDS) are classified into two major groups, primary (or de novo) and secondary. Primary refers to the majority of cases, where the cause is unknown.

Secondary cases, when there is an identifiable cause for its develop- ment, comprise 10–20% of all MDS. There is a recognized association between exposure to occupational chemicals, especially benzene, and the subsequent development of MDS. More frequently, previous chemotherapy or radiotherapy may lead to MDS, and this is termed therapy-related MDS. High-dose chemotherapy before autologous bone marrow or peripheral blood stem cell transplantation, along with radiotherapy, is associated with the development of MDS, usually 4–7 years later. Exposure to alkylating agents, such as melphalan and cyclophosphamide, is also linked to subsequent MDS.

Compared to primary cases, therapy-related MDS is characterized by

• more severe cytopenias

• occurrence at a younger age

• a higher rate of transformation to acute leukaemia

• more clonal chromosomal abnormalities

• a generally poorer prognosis.

The initial steps in the pathogenesis of MDS involve DNA damage to a pluripotent stem cell. This leads to the development of a myelodysplastic clone, which has a growth advantage over other haemopoietic cells. There is increased cellular proliferation within the bone marrow, resulting in a hypercellular marrow. However, these cells do not differentiate properly and there is an increased rate of apoptosis (programmed cell death). This means that, despite the hypercellular marrow, fewer mature cells exit the marrow into the peripheral blood, resulting in peripheral blood cytopenias. T-cell- mediated destruction of marrow elements results in a hypocellular marrow in the minority of cases.

Recently, much attention has focused on the extra addition of methyl groups to many genes involved in cell cycle regulation. It ap- pears that hypermethylation of many genes results in their silencing, particularly tumour suppressor genes, contributing to uncontrolled proliferation of the abnormal clone (Fig. 8.1).

Diagnosis

The diagnosis should be suspected in an elderly person with unexplained anaemia, usually macrocytic, with normal haematinic levels. It should also be suspected in cases of anaemia with involvement of the other lineages, namely thrombocytopenia and neutropenia. Referral to a haematologist is indicated if MDS is suspected. It is important to assess the patient when he or she is otherwise well, as acute illnesses may give an erroneous impression of bone marrow function.

Symptoms

Many patients may be asymptomatic and have a full blood count performed for incidental reasons. Other patients may have symptoms of bone marrow failure. These include symptoms from anaemia (short- ness of breath, chest pain, fatigue), from thrombocytopenia (bruising,

Figure 8.1   Pathogenesis of myelodysplastic syndromes

bleeding) or from neutropenia (infections). Physical findings are often minimal, but may include pallor, purpura and rarely splenomegaly.

Investigations

The blood count and the blood film are vital in the diagnosis of MDS. It is very important to diagnose and correct B12 or folate deficiency before considering the diagnosis of MDS. Dysplastic features found in the peripheral blood and bone marrow are summarized in Table 8.1, although this list is not exhaustive.

However, to diagnose MDS confidently, a bone marrow aspirate and trephine biopsy are necessary. Many patients with suspected myelodysplasia will be very elderly with significant comorbidities, and may not require intervention, and therefore an invasive proce-

Figure 8.2   Pseudo-Pelger neutrophil (left) with a dysplastic neutrophil

(right).

Figure 8.3   Ringed sideroblasts

dure may not be necessary. However, all patients requiring regular therapy, including transfusion, should have the diagnosis confirmed with a bone marrow examination. It should be noted that dysplasia is not specific to MDS, and may be seen in other disorders, such as alcohol excess and cytotoxic therapy. It has therefore been suggested that at least 10% of the cells in a lineage should be dysplastic before that lineage is considered to be dysplastic.

Cytogenetics also gives important information. The presence of the same cytogenetic abnormality in multiple cells in the marrow

Figure 8.4   Dysplastic megakaryocytes with separated nuclei

gives more weight to the notion that the abnormality has arisen from a clonal disorder such as myelodysplasia. Cytogenetics is also very important in risk stratification, which has important impli- cations on prognosis (see below). Notably, loss of the long arm of chromosome 5 (5q−) is found typically in middle aged women, and is associated with a long survival and a low risk of transformation to acute myeloid leukaemia (AML). Tissue typing is needed if stem cell transplantation is considered, especially in younger patients.

morphology. It is also important to note that there is a new entity in the WHO classification, namely, MDS associated with isolated 5q−. This is to recognize its excellent median survival, 116 monthsin one series.

Prognosis

As seen from the above classification, survival can range from months to many years. If a patient has poor risk disease, aggressive manage- ment may be offered to them, if appropriate. However, patients with good risk disease will not benefit from aggressive management. Therefore, in 1997, the International Prognostic Scoring System (IPSS) was proposed to risk stratify patients with myelodysplasia. This uses the percentage of bone marrow blasts, the bone marrow karyotype and the number of cytopenias to create an overall score value (Table 8.3). Each score value corresponds to a specific risk group (Table 8.4).

The median survival decreases as the risk group rises from low to high for any given age. For any given risk group, the survival decreases as age increases. Assessment of the IPSS score is therefore important when making management decisions.

Management

In determining the most appropriate management for a given patient, many factors need to be taken into account. These include the patient’s age, comorbidities and the severity of their myelodysplasia, as assessed by the IPSS. The availability of a suitable donor for a possible stem cell transplant is also important. Management options include:

1. No active treatment: watch and wait. This may be suitable for patients with mild cytopenias.

2. Supportive care, including transfusion of red cells and platelets, is the mainstay of management of most patients with myelodysplasia. This should take into account patients’ symptoms rather than an absolute threshold for transfusion, as well as other comorbid conditions such as chronic cardiorespiratory disease. Iron overload will result from multiple transfusions, and iron chelation therapy should be considered for patients who need regular transfusions but who have a good prognosis, such as those with pure

refractory anaemia or isolated 5q− abnormality. This should be considered after the patient has received approximately 25 units of red cells, which is the equivalent of 5 g of iron.

3. It may be possible to reduce transfusion requirements for some patients using erythropoietin injections, with or without granulocyte colony stimulating factor (GCSF). The combination of the two may be particularly effective in refractory anaemia with ringed sideroblasts (RARS).

4. Some 50% of patients with hypoplastic MDS respond to immunosuppression with antilymphocyte globulin (ALG).

5. The investigational drug lenalidomide, a thalidomide analogue, has been shown to reduce or even obviate the need for transfusion in some patients with low risk disease. The effects of lenalidomide were particularly marked in patients with the 5q− syndrome, with 75% of patients achieving complete cytogenetic remission.

6. Hypermethylation of genes involved in cell cycle regulation results in silencing of many genes, especially tumour suppressor genes. DNA methyltransferase inhibitors (hypomethylating agents) can normalize methylating patterns of these genes and may restore differentiation of the abnormal clone. The first drug in this class to be evaluated was azacitidine, shortly followed by decitabine. Azacitidine has been shown to reduce the risk of transformation to leukaemia and improve survival, compared to supportive care alone. Further trials are currently underway.

7. Low-dose cytarabine chemotherapy has been used in high risk MDS with response rates of 15–20%, but this is associated with considerable toxicity. Although elderly patients tolerate intensive chemotherapy poorly, younger patients with high risk MDS are candidates for AML-type chemotherapy (as per Medical Research Council AML trials). Complete response rates of about 50% can be expected, and patients achieving remission can be considered for a stem cell transplant.

8. Stem cell transplantation remains the only curative treatment for MDS. Patients < 65 years old with high risk disease should be considered for a stem cell transplant. Many factors should be considered, especially the availability of a matched donor and the patient’s other comorbid disorders. If a sibling donor is not available, a search for a matched unrelated donor can be initiated. Reduced intensity transplants are less myelosuppressive than standard full intensity transplants, and attempt to harness a ‘graft versus leukaemia’ effect to eradicate the malignant clone. This results in a reduction in transplant-related mortality and therefore enables patients who otherwise would not be eligible, either on the grounds of age or comorbidity, to receive a transplant