Both cladribine and alemtuzumab may effect MS via B-cell depletion

Abstract

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.

The efficacy of cladribine tablets in CIS patients retrospectively assigned the diagnosis of MS using modern criteria: Results from the ORACLE-MS study

“…However, an analysis of the effect of the two cladribine doses on lymphocyte subsets showed that while there is no dose effect on B lymphocytes, there is a greater effect on T lymphocytes seen with the 5.25 mg/kg than with the 3.5 mg/kg dose. 16 Potentially, alterations of the relative B to T cell counts, or the proportions of lymphocyte subsets, may be important for dose-related effects, but this hypothesis requires further study. Nevertheless, based on the benefit:risk ratio seen with the lower dose, on 23 June 2017, the European Medicines Agency's Committee for Medicinal Products for Human Use recommended granting marketing approval for the use of cladribine tablets at the dose of 3.5 mg/kg as a treatment for relapsing forms of MS with approval granted by the European Commission on 25 August 2017.…”

Cladribine: mechanisms and mysteries in multiple sclerosis

“…First, cladribine also depletes various innate immune cells including NK cells and monocytes, although to a lesser extent than lymphocytes 50 52. In the CLARITY dataset, cladribine led to rapid depletion of CD56 + NK cells consistent with their DCK expression52 (figure 2). Second, cladribine penetrates the CNS and may deplete CNS-resident immune cells in vivo.…”

“…Immunophenotyping of 309 CLARITY participants revealed that cladribine administration leads to rapid, profound and long-lasting lymphocyte depletion 52. The mean number of lymphocytes reached a nadir with the end of the second cycle and was sustained throughout the study period.…”

Actualidad en el papel de la Cladribina en el tratamiento de la Esclerosis Múltiple tipo brote-remisión

“…Se observa además que la cladibrina causa una marcada y duradera depleción preferencial de células tipo B con el marcador de superficie CD19, las cuales luego de un año de tratamiento aún no habían vuelto a niveles basales. En la actualidad no existe información objetiva sobre influencia de la cladibrina en células B de memoria, sin embargo la efectividad de esta droga suprimiendo la actividad en la esclerosis múltiple podría indicar efectivamente acción del fármaco sobre estas poblaciones 16 .…”