Effect of Previous Disease-Modifying Therapy on Treatment Effectiveness for Patients Treated With Ocrelizumab

Abstract

Background and ObjectivesB cell–depleting antibodies were proven as effective strategy for the treatment of relapsing multiple sclerosis (RMS). The monoclonal antibody ocrelizumab was approved in 2017 in the United States and in 2018 in the European Union, but despite proven efficacy in randomized, controlled clinical trials, its effectiveness in the real-world setting remains to be fully elucidated. In particular, most study patients were treatment naive or switched from injectable therapies, whereas oral substances or monoclonal antibodies made up >1% of previous treatments.MethodsWe evaluated ocrelizumab-treated patients with RMS enrolled in the prospective cohorts at the University Hospitals Duesseldorf and Essen, Germany. Epidemiologic data at baseline were compared, and Cox proportional hazard models were applied to evaluate outcomes.ResultsTwo hundred eighty patients were included (median age: 37 years, 35% male patients). Compared with using ocrelizumab as a first-line treatment, its use as a third-line therapy increased hazard ratios (HRs) for relapse and disability progression, whereas differences between first- vs second-line and second- vs third-line remained smaller. We stratified patients according to their last previous disease-modifying treatment and here identified fingolimod (FTY) (45 patients, median age 40 years, 33% male patients) as a relevant risk factor for ongoing relapse activity despite 2nd-line (HR: 3.417 [1.007–11.600]) or 3rd-line (HR: 5.903 [2.489–13.999]) ocrelizumab treatment, disability worsening (2nd line: HR: 3.571 [1.013–12.589]; 3rd line: HR: 4.502 [1.728–11.729]), and occurrence of new/enlarging MRI lesions (2nd line: HR: 1.939 [0.604–6.228]; 3rd line: HR: 4.627 [1.982–10.802]). Effects were persistent throughout the whole follow-up. Neither peripheral B-cell repopulation nor immunoglobulin G levels were associated with rekindling disease activity.DiscussionOur prospectively collected observational data suggest suboptimal effectiveness of ocrelizumab in patients switching from FTY compared with those switching from other substances or having been treatment naive. These findings support previous studies indicating abated effectiveness of immune cell–depleting therapies following FTY treatment in patients with RMS.Classification of EvidenceThis study provides Class IV evidence that for patients with RMS, previous treatment with FTY compared with previous treatment with other immunomodulating therapies decreases the effectiveness of ocrelizumab.

Effect of Prior Treatment With Fingolimod on Early and Late Response to Rituximab/Ocrelizumab in Patients With Multiple Sclerosis

“…Especially, we found no pejorative evolution of disease in patients who previously received fingolimod, as recently suggested. 7 The large sample of patients switching from fingolimod we included (108 vs 38 in the Pfeuffer et al study) and the longer follow-up (3.5 vs 2.3 years) could explain in part the discrepancy with the previous study. In addition, the longer washout period of patients switching from fingolimod in the study by Pfeuffer et al (48 vs 27 days in our study) might explain why some patients in the previous study showed persistent disease reactivation beyond 6 months.…”

“… 1 - 8 However, real-life studies noted that the risk of disease activity after switching to BCDT may be unequal depending on the prior DMT. 4 - 7 , 9 , 10 …”

“…One recent study of the potential effect of previous DMT on the response to BCDT beyond 6 months suggested that the effectiveness of BCDT was diminished in patients who previously received fingolimod. 7 This point is of major importance for clinical practice, with implications for counseling and monitoring, because this reduced effectiveness beyond 6 months could not be prevented by any action such as shortening the washout period. Indeed, the authors hypothesized that this long-term reduced effectiveness of BCDT with previous fingolimod treatment could be inherent to a long-lasting effect of fingolimod on the immune system.…”

“…However, because these results were obtained in a limited number of patients, they should be replicated. 7 …”

“…Finally, we focused on the period beyond 6 months to test whether prior treatment with fingolimod has a long-term effect on the effectiveness of BCDT that could be related to a potential inherent effect of a sequestrating agent, as recently suggested. 7 …”