The treatment of aplastic anaemia depends first on providing total support for the patient while awaiting bone marrow recovery and, second, on attempts to accelerate that recovery. It should be emphasized that support and encouragement may be required for months or years before some sort of remission occurs and that disappointment and anxiety bedevil the management of aplastic anaemia. Patients, relatives and staff all need help in maintaining morale.

Support for the aplastic anaemia patient

This consists of providing blood product support and protecting patients from infection by isolating them from sources of infection as far as possible and in the use of antibiotics, both prophylactic and therapeutic.

Blood product support is mainly with packed red cells and platelet transfusions, to maintain a safe blood count. Patients are usually transfused with packed cells as required; in non-bleeding patients this is about 1 unit per week, given as three or four units every 3 or 4 weeks. Prophylactic platelet transfusions should be given when the platelet count is < 10 X 109/L (or < 20 X 109/L in the presence of fever), rather than giving platelets only in response to bleeding. Prediction of bleeding is difficult in an individual patient. Fatal haemorrhage, usually cerebral, is more common in patients who have < 10 X 109/L platelets, retinal haemorrhages, buccal haemorrhages or rapidly spreading purpura. However, cerebral haemorrhage may be the first major bleed in patients who have none of these other bleeding manifestations. A proportion of patients will become sensitized to platelet transfusions if random donors are used. Those who are sensitized will have to receive HLA-matched platelets. Family members should be avoided unless bone marrow transplantation has been ruled out as treatment. Platelets given twice per week are usually sufficient to prevent bleeding.

Antibiotics may be used prophylactically, particularly in patients with severe neutropenia (< 0.2 X 109/L). These patients may acquire infection from the gastrointestinal tract (particularly aerobic pathogens) or from the upper respiratory passages. Good mouth care with chlorhexidine mouthwash is of benefit. Patients should be in reverse-barrier isolation while in hospital. Measures to decrease potential intestinal pathogens include the use of non-absorbable antibiotics and antifungal agents, and the provision of low-bacterial food. When fever or signs of infection develop, fevers should be treated immediately in severely neutropenic patients, that is, with the prompt administration of broad-spectrum intravenous antibiotics, particularly those active against Gram-negative organisms. Treatment should be started after taking appropriate samples for microbiology but before the results are available. The antibiotics should be continued until at least 72 h of normal temperature has been achieved, but, unfortunately, in the severely neutro-penic patient, infection is rarely eradicated and all too frequently fever returns after stopping the therapy.

Staphylococcus epidermidis is a common cause of bacteraemia in patients who have a central line in place. If fever in the neu-tropenic patient does not resolve within 24 h, vancomycin or teicoplanin (or other antibiotic active against S. epidermidis) should be added to the Gram-negative antibiotic regimen. Failure of the fever to resolve after this in the absence of a positive blood culture suggests the possibility of a fungal infection and intravenous amphotericin should be added early to the regimen. Granulocyte colony-stimulating factor (G-CSF) may raise the neutrophil count and improve their function, and may have a role to play in the eradication of infection in aplastic patients, although no formal trials have been conducted. G-CSF tends to have the weakest effect in the most severely aplastic patients.

Restoration of marrow activity

Spontaneous remission of aplastic anaemia may occur, but this may not happen for several months or even years and the majority of patients with SAA die from the complications of neutro-penia or thrombocytopenia before this can occur. Bone marrow transplantation is a therapeutic option open to younger patients who have an HLA-matched sibling donor and is discussed in detail below.

Immunosuppressive therapy

Immunosuppressive therapy with ALG and/or cyclosporin has proved to be effective in increasing the remission rate in aplastic anaemia. There is no role for the use of corticosteroids in the treatment of aplastic anaemia, other than a short course when used with ALG to help prevent serum sickness. Coticosteroids are ineffective in the treatment of aplastic anaemia; they encourage bacterial and fungal colonization and can precipitate serious gastrointestinal haemorrhage in the presence of severe thrombocytopenia.

Antilymphocyte globulin

The use of ALG in the treatment of aplastic anaemia was pioneered by George Mathe and his colleagues in Paris in the 1960s and developed by Bruno Speck in Basle. The benefit of ALG in promoting marrow recovery in aplastic anaemia was later confirmed in randomized trials conducted in the USA.

Preparations. Antilymphocyte globulin is available from a number of commercial companies. The antihuman lymphocyte globulin is raised either in horses or in rabbits. A variety of immunogens are used in the preparation of the spectrum of polyclonal antibodies, which make up the various preparations of ALG. In many preparations, the immunogen is a thymocyte-derived cell line or thymocytes obtained from thymuses removed during cardiac surgery in children. These preparations are usually called antithymocyte globulin (ATG). The main combinations used in the preparation of ALG or ATG and the range of antibodies obtained are shown in Table 13.4. During preparation, unwanted antihuman antibodies are removed by absorption with specific tissues, but most preparations still have some anti-platelet activity. Although, clearly, there is not biological equivalence between preparations, no proper comparative studies have been carried out to identify essential characteristics or antibody components. Most preparations have been developed for the prevention of graft rejection in cardiac or renal transplants, but it is not evident that the same antibody profile is needed for the treatment of aplastic anaemia.

Administration. Antilymphocyte globulin is a highly immuno-suppressive drug. It should be prescribed only by physicians familiar with using the drug. It must be given only as an inpatient therapy, and patients should be nursed in isolation facilities with reverse-barrier nursing. Prophylactic antibiotics

Table 13.4 Antilymphocyte (ALG) and antithymocyte globulin (ATG) preparations. Variations in animal origin, immunogens and antibody content.

Animal Immunogens used

Range of antibodies from different preparations

Table 13.4 Antilymphocyte (ALG) and antithymocyte globulin (ATG) preparations. Variations in animal origin, immunogens and antibody content.

Animal Immunogens used

Range of antibodies from different preparations

Horse Lymphocytes

CD3 (< 0.03-0.58)


CD5 (0-12.2)

Lymphocytes + thymocytes

CD11a (3.15-20.3)

T lymphoblasts

CD18 (18.7-269)

B lymphoblasts

CD45 (0.16-4.01)



Rabbit T lymphoblasts


and antifungal therapy should be used routinely. It is sclerosing to veins and should be given through a central line. A test dose of the preparation should be given before starting the full dosage, to test for anaphylaxis. A test dose (10 mg in 100 mL of saline) intravenously over half an hour must be given beforehand. Providing that the patient does not show evidence of anaphylaxis to the test dose, the full dose may be administered, starting on the same day as the test dose. Because of the anti-platelet activity of ALG, platelets should be given before and after the infusion, although not during the administration of the ALG. The full dose is given over 12-18 h.

Reactions are common. Fever, rigors, rashes, hypotension or hypertension are usual on the first day of treatment but become less troublesome as the therapy continues. These effects can usually be ameliorated by slowing the rate of infusion and giving corticosteroids, antihistamine (e.g. Piriton®) and pethidine. Although the test should exclude patients with anaphylaxis, pulmonary haemorrhage and capillary leak have been seen occasionally during the first day of administration of the full dose.

The treatment schedule is by no means established on the basis of clinical trials. The original European trials used administration of ALG daily for 5 days. This is the most widely followed regimen, but other schedules have been described, so far without any clear superiority over the 5-day course. The dosage varies from preparation to preparation, and the instructions of the manufacturers should be followed.

Serum sickness. Serum sickness occurs in about three-quarters of the patients given ALG. Some 7-10 days after its administration, fever, rash and severe joint pains may appear. Proteinuria may be seen, but frank renal failure has not yet been reported. The syndrome is self-limiting, but symptoms may respond to corticosteroids, requiring high doses for about 7 days. Prophylactic prednisolone (1 mg/kg per day) should be given to

Time period







1460 2190 2920 Days after treatment

IS, survival at 3 years 52% (45-60%) 61% (45-60%) 71% (45-60%) 75% (45-60%) 80% (45-60%) 85% (45-60%)

3650 43S0

Figure 13.2 Response survival of patients with aplastic anaemia treated with immunosuppressive therapy (ALG with or without cyclosporin). Data from EBMTR SAA working party showing improved survival with time (with permission).

help prevent or ameliorate serum sickness. Ideally, patients should be kept under observation as an inpatient until the risk of serum sickness is over; this is usually 2-3 weeks from the start of ALG treatment.

Response. Response to ALG is delayed, with improvement in marrow function rarely being seen before 6 weeks. Approximately 50% of patients respond by 3 months and up to 67% by 6 months (Figure 13.2). Patients with severe aplastic anaemia respond less well than non-severe patients, particularly if the neutrophil count is < 0.2 X 109/L. Age does not seem to be a factor in response.

Further treatment. If there is no response to ALG after 46 months, a second course may be tried, either rabbit ATG if horse ALG has been used in the first instance, or a second course of horse ALG. In responding patients, the marrow does not usually return entirely to normal and some degree of cytopenia may persist for several years, although the patient may not require transfusion support.

Relapse occurs in 25 -40% of responders over 10 years. Relapse does not always indicate a return to transfusion dependence but may herald the development of PNH, myelodysplastic

syndrome or acute myeloid leukaemia (AML). Even when a stable recovery has been observed, patients treated with immunosuppression should be followed regularly for many years with screening for PNH and cytogenetic studies.


Cyclosporin has been used both with ALG and alone in the treatment of aplastic anaemia. When used immediately following ALG, cyclosporin accelerates recovery in blood counts without significantly improving overall survival. However, the combination of cyclosporin with ALG results in improved failure-free survival, meaning that fewer patients require a second course of ALG for non-response or relapse, compared with ALG alone, and the combination delays the onset of relapse after ALG. A significant proportion of patients are dependent on continued cyclosporin long-term after ALG. For patients with NSAA, the use of cyclosporin alone is associated with a significantly lower response rate and failure-free survival than the combination of ALG and cyclosporin. Nevertheless, cyclosporin may be used on its own if there are contraindications to using ALG in a particular patient. An appropriate starting dose of cyclosporin is 5 mg/kg per day in divided doses, the dose being adjusted according to blood pressure, renal function tests and blood levels of the drug.

Haemopoietic growth factors

Circulating levels of haemopoietic growth factors are markedly elevated in most patients with aplastic anaemia. They should not be used on their own in newly diagnosed patients in the mistaken belief that they may cure the disease. G-CSF will raise the neutrophil count in patients with aplastic anaemia, although the smallest benefit is seen in those with the most severely affected marrow. One study from Europe showed that G-CSF given after a course of ALG and cyclosporin appears to reduce the risk of severe infections after ALG, but does not improve the response rate and survival. Other growth factors, including erythropoietin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin 3 (IL-3), IL-6 and stem cell factor have proved to be largely ineffective and/or toxic to patients with aplastic anaemia. Trials with thrombopoietin in aplastic anaemia have not been reported, but it is not yet known whether it will be effective in the presence of already high plasma levels of the growth factor in aplastic anaemia, and there is potential concern about the development of anti-thrombopoietin antibodies.


Historically androgens, or anabolic steroids, were the first specific form of therapy used in aplastic anaemia. They have a temporary benefit in the management of Fanconi anaemia and appeared to be effective in some cases of acquired aplastic anaemia, with some patients being androgen dependent. A European trial demonstrated that the addition of oxymetholone to ALG resulted in improved response compared with ALG

alone, although their use has diminished since the introduction of cyclosporin to immunosuppressive protocols for treatment of aplastic anaemia. The androgens are usually given in high doses (for example, oxymetholone 2.5 mg/kg per day), starting after the period of serum sickness. Side-effects include virilization (and so are often unacceptable to female patients), pro-static enlargement, salt retention and hepatotoxicity, including the development of peliosis hepatitis and/or hepatocellular carcinoma after prolonged usage. If there is no response after 6 months, the androgens should be stopped. If there is a response, androgens should be slowly reduced, first to an alternate day therapy and then increasing the interval between doses.

Other treatments

The use of high-dose cyclophosphamide without stem cell support has been advocated as an alternative treatment for aplastic anaemia on account of its highly immunosuppressive qualities and the observation that autologous haematological recovery may occur following graft rejection after allogeneic bone marrow transplantation (BMT) in aplastic anaemia patients. Its use in this manner is generally not recommended, however, because of the perhaps predictably prolonged delayed neutrophil and platelet recovery and high risk of serious infective, particularly fungal, infections that are often fatal when the drug is administered at high doses without stem cell support. Furthermore, its use does not prevent the later onset of clonal disorders such as PNH or myelodysplasia. Mycophenolate mofetil is an im-munosuppressive drug that inhibits proliferation of B and T lymphocytes and has been used in refractory aplastic anaemia in a recent European pilot study but found to be ineffective.

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