Aplastic anaemia

Published on 03/04/2015 by admin

Filed under Hematology, Oncology and Palliative Medicine

Last modified 22/04/2025

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26

Aplastic anaemia

The term aplastic anaemia is a misnomer in that the disorder so described is characterised by a pancytopenia arising from failure of production of all the normal cells of peripheral blood. The underlying cause is a reduction in the number of pluripotential stem cells. This deficit may be exacerbated by an abnormality in the marrow microenvironment or an autoimmune reaction against the abnormal haematopoietic tissue.

Aplastic anaemia is rare (approximately 2–5 cases/million/year worldwide) and affects all ages. It must be emphasised that it is not a subtype of leukaemia. However, the disease’s presenting clinical characteristics, the management problems of marrow failure (including fulminating septicaemia and haemorrhage) and the possible evolution to a clonal marrow disorder dictate its inclusion in this section.

Classification and aetiology

Aplastic anaemia (AA) may be part of a congenital syndrome, be secondary to well-defined insults to the bone marrow, or arise apparently spontaneously with no identifiable cause. A simple classification is shown in Table 26.1. The most common congenital disorder is Fanconi’s anaemia. Affected children suffer from defective DNA repair and the aplasia often coexists with skeletal deformities, skin pigmentation (Fig 26.1) and renal abnormalities. To date, fifteen genes (termed FANC) have been identified. Dyskeratosis congenita, another form of constitutional aplasia, is distinguished by a later onset, nail dystrophy, leukoplakia of mucosal surfaces and a high incidence of epithelial tumours. There is defective telomere maintenance and patients usually have very short telomeres. This is also observed in 10–15% of patients with acquired AA.

Table 26.1

Classification of aplastic anaemia

1. Idiopathic AA  
2. Congenital AA Fanconi’s anaemia
  Dyskeratosis congenita
3. Secondary AA Drugs – idiosyncratic or dose-related
  Chemicals
  Ionising radiation
  Infection

Infections known to predispose to AA include viral hepatitis and parvovirus infection. Exposure to chemicals, drugs and radiation can damage stem cells. Drugs may depress haematopoiesis idiosyncratically or predictably (Table 26.2). In roughly two-thirds of patients, no cause is apparent and AA is termed ‘idiopathic’. Improved haematopoiesis following immunosuppression (see below) suggests that in at least some cases the abnormal stem cell compartment is further compromised by poorly defined immune phenomena.

Table 26.2

Drugs associated with aplastic anaemia1

Predictable Cytotoxic agents
Idiosyncratic Chloramphenicol
  Sulfonamides
  Phenylbutazone
  Indometacin
  Gold salts
  Penicillamine
  Carbamazepine
  Phenytoin
  Carbimazole

1This is a selective list of more commonly implicated agents.

Diagnosis

There are really two questions. Is the pancytopenia due to aplastic anaemia? Is this idiopathic AA or aplasia secondary to an identifiable cause (Table 26.3)?

A reasonable sequence of investigations is as follows:

2 Bone marrow aspirate and trephine

This is the key diagnostic test. The marrow aspirate can be highly suggestive of aplasia with grossly hypocellular particles but a trephine biopsy is necessary to confirm the diagnosis and quantify the degree of hypocellularity (Fig 26.2). Aplasia may be patchy and if the trephine is surprisingly cellular in the context of the blood count, then further samples should be obtained. In practice the only likely confusion is with hypocellular myelodysplastic syndrome (see p. 50) or an atypical presentation of acute leukaemia, the latter particularly in childhood.

Measurement of severity

This is crucial as the severity defined from peripheral blood and bone marrow measurements predicts the response to treatment and survival (Table 26.4). The median survival of untreated severe AA is 3–6 months with only 20% of patients surviving longer than 1 year.

Management

Restoring normal haematopoiesis

There are two major options: immunosuppression and stem cell transplantation.

Immunosuppression

AA is thought to be at least in part an autoimmune disease and immunosuppressive agents provide worthwhile responses and prolonged survival in 60–80% of patients with 5-year survival around 75%. Responses are poorer in younger patients and in severe aplastic anaemia (SAA). The best regimen is a combination of antithymocyte globulin (ATG) and ciclosporin. Both drugs are potentially toxic – ATG can produce pyrexia, rashes and hypotension while ciclosporin may cause nephrotoxicity and hypertension. Complete or partial responses to immunosuppressive treatment can take several months. Other immunosuppressive drugs which may be considered include cyclophosphamide and the anti-CD52 monoclonal antibody alemtuzumab. As further discussed below, there is concern that immunosuppression may stimulate haematopoiesis but not necessarily cure the disease.

Immunosuppression or SCT?

Younger patients (less than 30 years) with SAA and a matched sibling donor should be transplanted. In VSAA (see Table 26.4) in this age group, the lack of a family donor should prompt a search for an HLA-matched unrelated donor. In patients 30–40 years with SAA, sibling SCT and immunosuppression produce similar survivals over 2–5 years. However, a significant proportion of patients receiving immunosuppression alone, approximately 25% at 10 years, evolve to clonal marrow diseases such as paroxysmal nocturnal haemoglobinuria, myelodysplastic syndrome and acute myeloid leukaemia. Thus in this group matched sibling SCT probably gives a better long-term prognosis. In older patients with SAA, and patients with non-severe AA, immunosuppression is generally the treatment of choice.

Growth factors

Growth factors cannot rectify the stem cell defect and are therefore not routinely used in AA. G-CSF may be useful in severe infection.