Cladribine Tablets in the Treatment of Patients with Multiple Sclerosis: An Integrated Analysis of Infections in Association with Severe Lymphopenia

Background: The results from CLARITY, CLARITY Extension, ORACLE-MS, and ONWARD show that cladribine tablets given annually for 2 years in short-duration courses are efficacious across a broad spectrum of patients. Lymphopenia, a dose-related expected event related to cladribine's mechanism of action, has been well-characterized and consistently reported across studies with oral cladribine monotherapy.

Objectives: To assess the nature of infections observed in cladribine-treated patients, and to explore the association between severe lymphopenia and infections.

Methods: Integrated safety data that comprised specific populations was used to assess infection in association with cladribine treatment. The cohorts were: monotherapy oral (MO; 1555 patients exposed to cladribine), placebo-controlled double-blind (PDB; 1458 patients exposed to cladribine) and all exposed (All-E; 1976 patients exposed to cladribine). Adjusted adverse events incidences per 100 patient years (Adj-AE per 100PY) were calculated for the integrated analyses.

Results:

Across the trials, when cladribine was given as monotherapy at a cumulative dose of 3.5 mg/kg, no evidence of an increase in the incidence of severe infections in patients with decreased lymphocyte counts was observed, except for herpes zoster.

In All-E, herpes zoster was the most frequently reported herpetic infection, of note 90% (86/95) of these were non-severe. Severe herpes zoster occurred more frequently in the cladribine group than in the placebo group (PDB: 0.21 vs 0 Adj-AE per 100PY; All-E: 0.10 vs 0.04 Adj-AE per 100PY). All 9 severe events resolved. Overall, in patients exposed to cladribine in each cohort, the incidence of herpetic infections (reported as an adverse event of special interest) was higher in the period of treatment in which CTCAE Grade 3 or 4 lymphopenia occurred, compared to the time when the patients were not experiencing Grade 3 or 4 lymphopenia (MO 3.5 mg/kg dose had Adj-AE incidence per 100PY (95%CI) 2.16 (0.90-5.19) with lymphopenia, compared to 0.75 (0.50-1.12) without lymphopenia.

Conclusions: Herpes zoster was the only severe infection reported more frequently with cladribine across the clinical program; herpetic infections were reported more frequently in patients experiencing Grade 3 or 4 lymphopenia. Herpes zoster infection is an important identified risk for cladribine tablets, for which risk mitigation strategies are proposed.