Effects of cladribine on intrathecal and peripheral B and plasma cells.

Abstract

Introduction: Cladribine is a deoxyadenosine analogue that can penetrate the blood-brain barrier. It is used to treat multiple sclerosis (MS). However, the mechanistic understanding of the effect of this highly effective therapy on B cells and plasma cells in the central nervous system compartment is limited. The CLADRIPLAS study examined the effect of cladribine on peripheral and intrathecal B and plasma cell biology in people with MS.

Methods: Thirty-eight people with progressive MS ineligible for- or rejecting- treatment with licenced therapies were recruited and supplied a baseline lumbar puncture. Those exhibiting gadolinium-enhancing or new/enlarging T2 magnetic resonance imaging lesions and/or elevated neurofilament levels were offered subcutaneous cladribine (Litak®). Seven people were eligible; one person died before treatment, and only five completed the first year of treatment. Twenty-two ineligible people were willing to provide a repeat lumbar puncture twelve months later.

Results: The CLADRIPLAS study found no evidence of a difference in the odds of a positive cerebrospinal fluid oligoclonal band (cOCB) result between the cladribine-treated and untreated group. This is probably explained by microarray and in vitro studies, which demonstrated that plasmablasts and notably long-lived plasma cells are relatively resistant to the cytotoxic effect of cladribine compared to memory B cells at physiological concentrations. This was consistent with the loss of intracellular deoxycytidine kinase during antibody-secreting cell differentiation.

Conclusion: CLADRIPLAS indicates that cOCB are not rapidly eliminated in most people with MS. This may be explained by the relative lack of direct cytotoxic action of cladribine on long-lived plasma cells.