PT  - JOURNAL ARTICLE
AU  - David Baker
AU  - Samuel S. Herrod
AU  - Cesar Alvarez-Gonzalez
AU  - Lukasz Zalewski
AU  - Christo Albor
AU  - Klaus Schmierer
TI  - Both cladribine and alemtuzumab may effect MS via B-cell depletion
AID  - 10.1212/NXI.0000000000000360
DP  - 2017 Jul 01
TA  - Neurology - Neuroimmunology Neuroinflammation
PG  - e360
VI  - 4
IP  - 4
4099  - http://nn.neurology.org/content/4/4/e360.short
4100  - http://nn.neurology.org/content/4/4/e360.full
SO  - Neurol Neuroimmunol Neuroinflamm2017 Jul 01; 4
AB  - Objective: To understand the efficacy of cladribine (CLAD) treatment in 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 CLAD Tablets Treating Multiple Sclerosis Orally (CLARITY) (NCT00213135) cladribine and Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis, study one (CARE-MS I) (NCT00530348) alemtuzumab trials were obtained from the European Medicine Agency through Freedom of Information requests. Data were extracted and statistically analyzed.Results: Either dose of cladribine (3.5 mg/kg; 5.25 mg/kg) tested in CLARITY reduced the annualized 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 3.5 mg/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 redosing. However, alemtuzumab induced hyperrepopulation 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 that B-cell suppression could be the major direct mechanism of action.ALEM=alemtuzumab; ANOVA=analysis of variance; CARE-MS I=Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis, study one; CLAD=cladribine; CLARITY=CLAD Tablets Treating Multiple Sclerosis Orally; DMT=disease-modifying therapy; FOI=Freedom of Information; NK=natural killer; PDF=portable document format; pwRMS=people with relapsing MS; SAI=secondary B-cell autoimmunity