Relapses and lymphocyte counts before and after rescue therapy in the phase III, 96-week, double-blind, placebo-controlled CLARITY study of cladribine tablets for relapsing-remitting multiple sclerosis

BACKGROUND:Treatment with cladribine tablets demonstrated significant efficacy versus placebo and preferentially reduced peripheral lymphocyte counts in patients with relapsing–remitting multiple sclerosis (RRMS) in the CLARITY study. Here we explore the impact of interferon (IFN) beta-1a rescue therapy in CLARITY by examining relapses and lymphocyte counts before and after rescue in patients given such therapy. METHODS:Patients with RRMS were to receive 4 or 6 short courses of cladribine tablets (cumulative doses 3.5 or 5.25 mg/kg, respectively) or matching placebo over 96 weeks. Treatment courses (once-daily dosing for 4–5 days) were to begin at Day 1 and Weeks 5, 9, 13, 48 and 52. Rescue therapy with IFN beta-1a 44 mcg subcutaneously three times a week was permitted from Week 24 if patients experienced >1 relapse and/or a 3-month sustained increase in Expanded Disability Status Scale (EDSS) score of ≥1 point (1.5 points if baseline EDSS score was 0). Lymphopenia was graded according to the Common Terminology Criteria for Adverse Events (CTCAE). RESULTS:In the placebo, cladribine tablets 3.5 and 5.25 mg/kg groups, 27/437 (6.2%), 11/433 (2.5%) and 9/456 (2.0%) patients received rescue treatment, with mean time from first dose to rescue of 65.2, 65.3 and 66.0 weeks, respectively. Among the 20 cladribine-treated patients given IFN beta-1a rescue therapy, the numbers of relapses before rescue therapy were 0 (2 patients), 1 (5 patients), 2 (8 patients), 3 (4 patients) and 4 (1 patient); 19 patients had no relapse after rescue and one had 1 relapse after rescue. Grade 1–3 lymphopenia was seen in 15 cladribine-treated patients at the time of rescue. After starting rescue treatment, 3 patients had an increase in the severity of lymphopenia (from grade 0 to 1, from grade 1 to 2, and from grade 1 to 3), 11 had no change, and 6 had a decrease in severity of lymphopenia. In addition, 3 patients experienced 6 adverse events in the infections and infestations system organ class (all rated as mild or moderate in severity), beginning 0.5–5 months after the start of rescue treatment. CONCLUSIONS:Among patients who experienced relapses while receiving cladribine tablets in CLARITY, rescue treatment with IFN beta-1a prevented further relapses in all but one case. No clear pattern was observed in the incidence and severity of lymphopenia or infections among these patients, suggesting that IFN beta-1a could reasonably be given after discontinuing treatment with cladribine tablets.