Azathioprine and chlorambucil: mechanism of action and use in ...

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Carcinogenesis Due to their mutagenic properties, patients receiving alkylation therapy have been shown to have an increased risk in developing a second malignancy. Acute leukaemia is most frequently described as a second malignancy in humans, and usually develops within 1-4 years after drug exposure. 42 The phenomenon has not yet been documented in veterinary literature, possible due to the short treatment lengths in these species. Hypersensitivity reactions Anaphylaxis, urticaria and drug eruptions have been reported with chlorambucil use in humans. Reactions to topically applies alkylating agents may also sensitise to systemically administered compounds. 42 Miscellaneous Interstitial pneumonitis and pulmonary fibrosis have been reported in the human literature but not identified in veterinary medicine. Interestingly, a cumulative effect seems to be required as pulmonary fibrosis secondary to chlorambucil therapy has been noted after the discontinuation of therapy. Alkylating agents have a significant toxic effect on reproductive tissue leading to ovarian atrophy and aspermia. 42 As chlorambucil damages DNA at a fundamental level, it is also considered teratogenic. Alopecia a delayed regrowth of the hair coat has been reported in dogs, with Poodles and Kerry Blue Terrier more likely to be affected than other breeds. 22 As with azathioprine, the theoretical risk of opportunistic infections may be increased with long term immunosuppression, but little data exists in the human or veterinary literature on the prevalence of opportunistic infections associated with chlorambucil use. Contraindications and drug interactions Chlorambucil should not be used in patients with a known hypersensitivity to the drug. In addition dosage adjustments may need to be made in cases of renal or hepatic insufficiency. Use in pregnancy should be avoided unless the benefits clearly outweigh the risk. The principle concern for development of myelosuppression is concurrent use of antineoplasics, immunosuppressants (e.g. azathioprine, corticosterioids, cyclophophamide) and other bone marrow suppressive agents (e.g. chloramphenicol, flucytosine, amphotericin B, griseofulvin, colchicine). 43 Dosage and monitoring Chlorambucil (Leukeran®, GlaxoSmithKline) is available in a 2mg tablet. Doses range from 0.1- 0.2 mg/kg (dog and cat) administered orally every24-48 hours. Concurrent use of corticosteroids may be required in the induction phase, once clinical response is seen then maintenance on every other day dosing of chlorambucil has been reported. As with azathioprine, no formal guidelines exist for hematological or biochemical monitoring of chlorambucil in dermatology patients in exist. Baseline complete blood count (CBC) and serum biochemistry panels should be run prior to the initiation of therapy. The author then repeats the CBC at weekly intervals for the first 4 weeks of therapy, then fortnightly to 8 weeks of therapy, monthly to 16 weeks then every 3 months thereafter. Biochemical analysis is then only repeated if there is any evidence of gastrointestinal upset, inappetence, fever, malaise or icterus present. Ideally, urine culture and sensitivity should be performed prior to the initiation of therapy and then every 3 months. 53
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