Cladribine for the Effective Control of Multiple Sclerosis via Memory B Cell Depletion (S52.007)

Objective: To study the effect of cladribine therapy on the peripheral memory B cell compartment. We hypothesized that (i) cladribine preferentially depletes memory B cells to be consistent with other high-efficacy DMT, and (ii) adapted dosing would avoid severe lymphopenia. Background: Cladribine is a lymphocyte-depleting agent that inhibits relapsing MS. We developed a compassionate-use program using subcutaneous cladribine in people with MS (PwMS) ineligible for licensed disease modifying therapy (DMT). We adapted drug dosing to individual lymphocyte levels. Design/Methods: We obtained the regulatory submission of oral cladribine from the European Medicines Agency. PwMS consented to receive 60–70mg subcutaneous cladribine and have blood samples immunophenotyped. We extracted expression data of genes associated with cladribine activity from public databases. Results: 12 month efficacy of 3.5 mg/kg oral cladribine was associated with modest depletion of CD4+ (~40%)and CD8+ T cells (~20%). However, there was marked (~85%) depletion of CD19+ B cells. No grade 3 or 4 lymphocyte toxicities were observed in pwMS receiving personalized dose subcutaneous cladribine. Although the number of CD19+ B cells often recovered to normal, both class-switched (IgD−) and non-switched (IgD+) CD19+/CD27+ memory B cells remained significantly below normal limits at all time points analysed (1–12 months post-dosing). High deoxycytidine kinase (DCK) levels, which produce toxic phosphorylated cladribine moieties, were found in B compared to T cells, and in germinal centre B cells, which form memory B cells. High DCK coupled with low levels of adenosine deaminase (ADA) and low adenosine-active cytoplasmic 5′ nucleotidases, and the slow repopulation of memory B cells create a molecular mechanism for selective targeting of memory B cells. Conclusions: Cladribine selectively induces marked and long-lasting memory B cell depletion similar to alemtuzumab creating a central unifying mechanism of action for cladribine and other highly effective DMT. Personalized dosing based on individual lymphocyte response may de-risk the use of cladribine further. Study Supported by: N/A Disclosure: Dr. Ceronie has nothing to disclose. Dr. Dubuisson has nothing to disclose. Dr. Jacobs has nothing to disclose. Dr. Mao has nothing to disclose. Dr. Ammoscato has nothing to disclose. Dr. Lock has nothing to disclose. Dr. Longhurst has nothing to disclose. Dr. Giovannoni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Received compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Almirall, Atara Bio, Biogen, Sanofi-Genzyme, Genentech, GSK, Merck, Novartis. Dr. Giovannoni has received personal compensation in an editorial capacity for Elsevier as Editor of MSARDs. Dr. Giovannoni has received research support from Takeda. Dr. Baker has received compensation for serving on the Board of Directors of Canbex. Dr. Baker holds stock and/or stock options in Canbex, which sponsored research in which Dr. Baker was involved as an investigator. Dr. Baker has received research support from Sanofi-Genzyme. Dr. Schmierer has nothing to disclose.