Both cladribine and alemtuzumab may effect multiple sclerosis via B cell depletion
Neurology: Neuroimmunology and Neuroinflammation
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OBJECTIVE. To understand the efficacy of cladribine treatment in multiple sclerosis (MS) through analysis of lymphocyte subsets collected, but not reported, in the pivotal phase III trials of cladribine and alemtuzumab induction-therapies. METHODS. The regulatory submissions of the CLARITY (NCT00213135) cladribine and CARE-MS I (NCT00530348) alemtuzumab trials were obtained from the European Medicine Agency through Freedom of Information requests. Data was extracted and statistically analysed. RESULTS. Either dose of cladribine (3.5mg/kg; 5.25mg/kg) tested in CLARITY reduced the annualised relapse rate to 0.16-0.18 over 96 weeks, and both doses were similarly effective in reducing the risk of MRI lesions and disability. Surprisingly, however, T cell depletion was rather modest. Cladribine 3.5mg/kg depleted CD4+ cells by 40-45% and CD8+ cells by 15-30%, whereas alemtuzumab suppressed CD4+ cells by 70-95% and CD8+ cells by 47-55%. However, either dose of cladribine induced 70-90% CD19+ B cell depletion, similar to alemtuzumab (90%). CD19+ cells slowly repopulated to 15-25% of baseline before cladribine re-dosing. However, alemtuzumab induced hyper-repopulation of CD19+ B cells 6-12 months after infusion, which probably forms the substrate for B cell autoimmunities associated with alemtuzumab. CONCLUSIONS. Cladribine induced only modest depletion of T cells, which may not be consistent with a marked influence on MS, based on previous CD4+ T cell depletion studies. The therapeutic drug response relationship with Cladribine is more consistent with lasting B cell depletion and, coupled with the success seen with monoclonal CD20+ depletion, suggests B cell suppression could be the major direct mechanism of action.
AuthorsBAKER, D; SCHMIERER, K; Herrod, S; Alvarez Gonzalez, C; Zalewski, L; Albor, C
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