title: Cladribine: a review of its use in multiple sclerosis.
abstract: Cladribine is a deaminase-resistant deoxyadenosine analogue that selectively reduces lymphocyte counts. The drug is an effective therapy for selected haematological malignancies and is being tested in patients with multiple sclerosis (MS), in whom the antilymphocytic effects of the drug may reduce the autoimmune destruction of myelin. With activity against resting and dividing cells that express high deoxycytidine kinase activity, cladribine causes prolonged, profound suppression of lymphocyte counts. Subcutaneous cladribine is 100% bioavailable and has no local tissue toxicity. Dosages used in clinical trials in patients with MS are in the range of 0.05 to 0.07 mg/kg/day subcutaneously for 5 days each month for 2 to 6 months. Temporary improvement or no change in neurological functioning and improvements in CNS lesions detected by gadolinium-enhanced magnetic resonance imaging (MRI) have been seen after cladribine use in patients with chronic progressive (CPMS) and relapsing-remitting (RRMS) forms of MS. In a randomised double-blind study of 24 pairs of patients, improvement or stabilisation of CPMS for approximately 2 years was observed in cladribine-treated patients, whereas the disease progressed in placebo recipients. Another study of 159 patients found no progression in either the treated or placebo control group. In both studies, marked improvements were seen in gadolinium-enhanced CNS lesions. Cladribine-associated improvements in neurological functioning were also seen in some patients with RRMS in one study, which also noted a reduction in the frequency and severity of relapses. In this and a separate RRMS study, cladribine resulted in the regression of CNS lesions on MRI. Bone marrow suppression is the main dose-related toxicity; in patients with MS, use of low total cladribine dosages appears to limit myelosuppression. Although thrombocytopenia is of concern with higher-dose regimens (i.e. 2.8 mg/kg total dose) in patients with MS, granulocyte counts and haemoglobin levels appear to be largely unaltered. Cladribine treatment is also associated with culture- negative fever and a risk of infections in patients with haematological malignancies.
  
  
  CONCLUSIONS
  Further study of cladribine is needed to confirm present results in wider numbers of patients treated or followed up for longer durations, define optimum treatment and retreatment schedules for the drug and compare it with other agents. Nonetheless, cladribine therapy appears to have the potential to slow the progression of MS, reduce CNS lesions in patients with either the chronic progressive or relapsing-remitting forms of the disease and improve neurological functioning in some of these patients.
authors.affiliation: Adis International Limited, Auckland, New Zealand. demail@adis.co.nz
authors.forename: H D
authors.initials: HD
authors.lastname: Langtry
authors.forename: H M
authors.initials: HM
authors.lastname: Lamb