The Italian Multiple Sclerosis Register Experience With Cladribine: Impact on Relapses, PIRA, and Treatment Sequencing Strategies Evaluation.

Background and objectives: Cladribine is an immune reconstitution therapy approved for relapsing multiple sclerosis (RMS). This multicentric retrospective study of the Italian Multiple Sclerosis Register (RISM) aimed to assess the effect of cladribine on the annualized relapse rate (ARR) and progression independent of relapse activity (PIRA) phenomena, also evaluating the strategies of disease-modifying treatment (DMT) continuation after cladribine termination.

Methods: Patients with RMS treated with at least one cycle of cladribine recorded in RISM after 2018 were retrospectively included in the analysis. Patients previously treated with other DMTs were stratified into moderately and highly effective DMTs. Adjusted ARR and PIRA events were calculated in the overall cohort and stratified by age at cladribine start (<50 vs ≥ 50 years) and by previous DMT. ARRs were compared between groups using negative binomial models. PIRA was analyzed using the Ghosh-Lin Cox-type regression for the marginal mean. DMTs prescribed after cladribine cycles were analyzed.

Results: A total of 2,329 patients treated with cladribine were identified in RISM, with a median (IQR) age of 36.5 (29.2-45.2) years at treatment start. 1,488 patients (63.9%) received 2 courses of cladribine. ARR decreased (p < 0.0001) from 0.96 (95% CI 0.91-1.02) in the 2 years preceding cladribine start to 0.09 (0.08-0.11) during the 2 years after in the overall cohort. One hundred thirty-three PIRA events were reported during the noncladribine treatment period and 54 during cladribine therapy (HR 0.711, 95% CI 0.531-0.952, p = 0.0219) in the entire cohort. All the analyses stratified by age and previous treatment confirmed the significant reduction in PIRA events and the suppression of relapse activity. After cladribine, most DMTs prescribed were ocrelizumab, ofatumumab, and natalizumab. Eight patients re-treated with an additional cycle of cladribine were also identified.

Discussion: For patients with RMS, both naïve and switchers, as well as younger and older patients, cladribine is an effective treatment in reducing relapses and PIRA. Different therapeutic strategies after cladribine are currently reported.

Classification of evidence: This study provides Class IV evidence that for patients with relapsing multiple sclerosis, cladribine treatment is associated with a reduction in ARR and PIRA events.