Risk of multiple sclerosis relapses when switching from fingolimod to cell-depleting agents: the role of washout duration

Ferraro, Diana; Iaffaldano, Pietro; Guerra, Tommaso; Inglese, Matilde; Capobianco, Marco; Morra, Vincenzo Brescia; Zaffaroni, Mauro; Mirabella, Massimiliano; Lus, Giacomo; Patti, Francesco; Cavalla, Paola; Cellerino, Maria; Malucchi, Simona; Pisano, Elisabetta; Vitetta, Francesca; Paolicelli, Damiano; Sola, Patrizia; Trojano, María

doi:10.1007/s00415-021-10708-1

Cited by 5 publications

(6 citation statements)

References 21 publications

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“…In contrast, impairment in disease control in patients switching from FTY to ocrelizumab was persistent during follow-up and thus far beyond the previously reported timespans. Whereas the abovementioned publications repeatedly identified the duration of washout as a risk factor for disease reactivation and/or disability worsening, 17 , 19 and were restricted to rather short follow-up, we here document impaired effectiveness of ocrelizumab in patients switching from FTY even after rebaselining to month 6 of ocrelizumab treatment.…”

Section: Discussioncontrasting

confidence: 43%

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

Pfeuffer

Rolfes

Ingwersen

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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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.

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Section: Discussioncontrasting

confidence: 43%

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

Pfeuffer

Rolfes

Ingwersen

et al. 2023

Neurol Neuroimmunol Neuroinflamm

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“…On the other hand, and in line with aspects presented above, a longer washout period could lead to recovery from lymphopenia before initiation of cell-depleting agents, which may limit the risk of therapies being ineffective. Interestingly, a recent study by Ferraro et al [49] in this journal showed that extending the washout period prior to commencing cell-depleting agents does not positively affect outcome parameters in the long term. In this study, the risk of relapse increased with the washout duration when switching from fingolimod to a lymphocyte-depleting agent (including cladribine, alemtuzumab, rituximab and ocrelizumab) during the 22 months of follow-up.…”

Section: Possible Mechanisms Of Compromised Efficacy and Resulting Management Considerationsmentioning

confidence: 95%

Neurological update: treatment escalation in multiple sclerosis patients refractory to fingolimod—potentials and risks of subsequent highly active agents

et al. 2022

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A critical issue in the management of relapsing MS (RMS) is the discontinuation of disease-modifying treatments (DMT) due to lack of efficacy, intolerability or impending risks. With new therapeutic agents introduced into the treatment of RMS, immediate- and long-term consequences of sequential drug use, as well as the effect of the sequence in which the drugs are given, are unclear but may affect efficacy, adverse events, and long-term immunocompetence. In the absence of clinical studies specifically addressing these concerns, observations from clinical practice are of particular value in guiding current management algorithms. Prompted by a study published by Ferraro et al. in this journal, we set out to provide an overview of the published real-world evidence on the effectiveness and safety of switching from fingolimod to another DMT in patients with active RMS. Seventeen publications reporting relevant information were identified. The literature suggests that immune cell depletion induced by alemtuzumab or ocrelizumab is associated with an increased risk of relapse and worsening disability in patients switching from fingolimod compared to patients switching from other therapeutic agents. However, the evidence reported for natalizumab and cladribine is inconclusive. While shortening of the washout period may limit early disease reactivation after fingolimod discontinuation, there is no strong evidence that the duration of the washout period or the absolute lymphocyte count at baseline are predictors of attenuated long-term efficacy. Further real-world studies are required to better understand outcomes among patients who are under-represented in controlled trials.

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“…Previous studies clearly demonstrated that MS disease reactivation is frequent and could be acute after fingolimod withdrawal. 14 - 16 Recent studies specifically assessed the switch from fingolimod to BCDT 4 - 6 , 17 and found a long washout period in patients switching from fingolimod to BCDT associated with risk of relapse. Zhong et al 6 reported a higher risk of relapse within the first 3 months of OCR for patients switching from fingolimod with a mean washout period of 48.5 days than for patients who previously received another DMT.…”

Section: Discussionmentioning

confidence: 99%

“… 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 …”

Section: Introductionmentioning

confidence: 99%

“…These real-life studies mostly focused on the effect of previous DMT on the effectiveness of BCDT during the first months after the switch. 4 - 6 They found increased risk of disease reactivation during the first months of treatment in patients who previously received fingolimod, particularly those with a long washout period. However, the studies did not clearly determine the washout period duration for which the risk increased when switching.…”

Section: Introductionmentioning

confidence: 99%

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

Graille-Avy,

Boutiere,

Rigollet

et al. 2024

Neurol Neuroimmunol Neuroinflamm

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Background and Objectives Real-life studies noted that the risk of disease activity in multiple sclerosis (MS) after switching to rituximab (RTX) or ocrelizumab (OCR) may be unequal depending on prior disease-modifying therapy (DMT), with a higher risk associated with fingolimod (FING). Methods We performed a retrospective analysis of a structured prospective data collection including all consecutive patients with relapsing MS who were prescribed RTX/OCR in the MS center of Marseille. Cox proportional hazards models were applied to clinical and MRI outcomes. Results We included 321 patients with a median (interquartile range [IQR]) follow-up of 3.5 years (1.5–5) after RTX/OCR initiation. At the first RTX/OCR infusion, the mean (SD) age of patients was 37 (10) years, and the median (IQR) disease duration was 8 years (3–15): 68 patients did not receive treatment before RTX/OCR and 108 switched from FING, 47 from low efficacy therapy, and 98 from natalizumab. For statistical analysis, the group “FING” was divided into “short-FING” and “long-FING” groups according to the median value of the group's washout period (27 days). On Cox proportional hazards analysis, for only the “long-FING” group, the risk of relapse within the first 6 months of RTX/OCR was increased as compared with patients without previous DMT (hazard ratio [HR]: 8.78; 95% CI 1.72–44.86; p < 0.01). Previous DMT and washout period duration of FING had no effect on B-cell levels at 6 months. Beyond the first 6 months of RTX/OCR, age <40 years was associated with increased risk of relapse (HR: 3.93; 95% CI 1.30–11.89; p = 0.01), male sex with increased risk of new T2 lesions (HR: 2.26; 95% CI 1.08–4.74; p = 0.03), and EDSS ≥2 with increased risk of disability accumulation (HR: 3.01; 95% CI 1.34–6.74; p < 0.01). Previous DMT had no effect on the effectiveness of RTX/OCR beyond 6 months after initiation. Discussion For patients switching from FING to RTX/OCR, the risk of disease reactivation within the first 6 months of treatment was increased as compared with patients with other DMT or no previous DMT only when the washout period exceeded 26 days. Neither FING nor other previous DMT reduced the effectiveness of RTX/OCR beyond the first 6 months of treatment.

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Risk of multiple sclerosis relapses when switching from fingolimod to cell-depleting agents: the role of washout duration

Cited by 5 publications

References 21 publications

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

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

Neurological update: treatment escalation in multiple sclerosis patients refractory to fingolimod—potentials and risks of subsequent highly active agents

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

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