Ocrelizumab extended-interval dosing in multiple sclerosis during SARS-CoV-2 pandemic: a real-world experience.

BACKGROUND AND PURPOSE: During the COVID-19 pandemic, ocrelizumab administration was frequently postponed because of a lack of safety information and to favour vaccination. The clinical implications of ocrelizumab administration delay in multiple sclerosis (MS) patients were assessed. METHODS: Relapsing (RMS) and primary progressive (PPMS) MS patients receiving ocrelizumab for at least 6 months at our centre were retrospectively classified, according to the possible occurrence of a delay (≥4 weeks) in treatment administration. Patients were categorized in the extended-interval dosing (EID) group in the presence of at least one delayed infusion; otherwise they were considered as part of the standard interval dosing (SID) cohort. MS history, magnetic resonance imaging examinations and B-cell counts were also retrospectively collected and analysed. RESULTS: A total of 213 RMS and 61 PPMS patients were enrolled; 115 RMS and 29 PPMS patients had been treated according to the SID regimen, whilst 98 RMS and 32 PPMS patients were included in the EID cohort. Average follow-up after delay was 1.28 ± 0.7 years in the EID cohort. In RMS, comparing SID and EID patients, no differences were found considering the occurrence of clinical relapses (9.6% vs. 16.3%, p = 0.338), magnetic resonance imaging activity (9.8% vs. 14.1%, p = 0.374) or disability progression (11.3% vs. 18.4%, p = 0.103). Similar findings were observed in PPMS patients. In the pooled EID group, treatment delay correlated with CD19-positive relative (r = 0.530, p < 0.001) and absolute (r = 0.491, p < 0.001) cell counts, without implications on disease activity. CONCLUSIONS: Sporadic ocrelizumab administration delay granted sustained treatment efficacy in our cohort. Prospective data should be obtained to confirm these observations and set up systematic extended-interval regimens.

Natalizumab wearing-off symptoms: effect of extend interval dosing during Sars-CoV-2 pandemic.

BACKGROUND: Many patients treated with Natalizumab experience wearing-off symptoms (WoS) towards the end of the administration cycle. During the pandemic we advised and asked patients undergoing treatment with Natalizumab if they wanted to be shifted from a standard interval dosing (StID of 4 weeks) to an extended interval dosing (ExID of 5-6 weeks), regardless of their JCV index. Our main objective was to study prevalence and incidence of WoS when ExID was adopted. METHODS: We enrolled 86 patients, from May 2020 to January 2021, evaluated at baseline and during a 6 months follow-up with a survey focused on WoS, Fatigue Severity Scale (FSS), Expanded Disability Status Scale (EDSS) and MRI. RESULTS: Among the 86 patients, 32 (37.2%) reported WoS. Most common one was fatigue (93.7%). Mean EDSS was higher in the group reporting WoS (3.8 WoS vs 3.1 non-WoS, p < 0.05). Sphincterial function was the EDSS item that significantly differed between the WoS group and the non-WoS group (1.4 WoS vs 0.6 non-WoS, p < 0.001). WoS correlate with the FSS scale (p < 0.001). CONCLUSION: Adopting an extended interval dosing does not result in significantly different occurrence of WoS between the ExID and the StID populations, in our cohort of patients. Interestingly, there is a strong correlation between WoS and a higher EDSS and FSS. Safety and efficacy of Natalizumab with ExID are relatively preserved in our study.

Is It Time for Ocrelizumab Extended Interval Dosing in Relapsing Remitting MS? Evidence from An Italian Multicenter Experience During the COVID-19 Pandemic.

In the COVID-19 pandemic era, safety concerns have been raised regarding the risk of severe infection following administration of ocrelizumab (OCR), a B-cell-depleting therapy. We enrolled all relapsing remitting multiple sclerosis (RRMS) patients who received maintenance doses of OCR from January 2020 to June 2021. Data were extracted in December 2021. Standard interval dosing (SID) was defined as a regular maintenance interval of OCR infusion every 6 months, whereas extended interval dosing (EID) was defined as an OCR infusion delay of at least 4 weeks. Three infusions were considered in defining SID vs. EID (infusions A, B, and C). Infusion A was the last infusion before January 2020. The primary study outcome was a comparison of disease activity during the A-C interval, which was defined as either clinical (new relapses) or radiological (new lesions on T1-gadolinium or T2-weighted magnetic resonance imaging (MRI) sequences). Second, we aimed to assess confirmed disability progression (CDP). A total cohort of 278 patients (174 on SID and 104 on EID) was enrolled. Patients who received OCR on EID had a longer disease duration and a higher rate of vaccination against severe acute respiratory syndrome-coronavirus 2 (p < 0.05). EID was associated with an increased risk of MRI activity during the A-C interval (OR 5.373, 95% CI 1.203-24.001, p = 0.028). Being on SID or EID did not influence CDP (V-Cramer 0.47, p = 0.342). EID seemed to be associated with a higher risk of MRI activity in our cohort. EID needs to be carefully considered for OCR-treated patients.

The wearing-off phenomenon of ocrelizumab in patients with multiple sclerosis.

BACKGROUND: Patients with multiple sclerosis (MS) who are treated with monoclonal antibodies frequently report an increase of MS-related symptoms prior to the next dose known as the wearing-off phenomenon. The objective of this study was to assess the prevalence and predicting factors of the wearing-off phenomenon in patients with MS using ocrelizumab. METHODS: This was a prospective cohort study in patients with MS receiving ocrelizumab ≥1 year. Most participants received B-cell guided personalized extended interval dosing to limit ocrelizumab exposure and hospital visits during the COVID-19 pandemic (cut-off ≥ 10 cells/µL). Participants completed questionnaires during ocrelizumab infusion and 2 weeks thereafter. Demographics, clinical and radiological characteristics, CD19 B-cell counts, and serum neurofilament light (sNfL) levels were collected. Data were analyzed using logistic regression analyses. RESULTS: Seventy-one (61%) out of 117 participants reported the wearing-off phenomenon during ocrelizumab treatment. The most frequently reported symptoms were fatigue, cognitive disability and sensory symptoms. Wearing-off symptoms started < 1 week (11%), 1-4 weeks (49%) or more than 4 weeks (37%) before ocrelizumab infusion. Fifty participants (43%) reported a current wearing-off phenomenon at the first questionnaire. Higher body mass index (threshold BMI ≥ 25) increased the odds of reporting a current wearing-off phenomenon (OR 2.70, 95% CI 1.26 to 5.80, p = .011). Infusion interval, EDSS score, MRI disease activity, clinical relapses, CD19 B-cell counts, and sNfL levels were no predictors. Disappearance of the wearing-off phenomenon occurred in the first week after ocrelizumab infusion in most participants. Participants with a current wearing-off phenomenon significantly improved in self-reported physical and psychological functioning after ocrelizumab infusion. Reporting the wearing-off phenomenon did not influence treatment satisfaction. Forty of 109 participants (37%) reported post-infusion symptoms, such as fatigue, flu-like symptoms or walking difficulties. These post-infusion symptoms started directly or in the first week after ocrelizumab infusion and disappeared within 2 weeks. CONCLUSIONS: The wearing-off phenomenon is reported by more than half of patients with MS using ocrelizumab. Only BMI was identified as a predicting factor. The wearing-off phenomenon was not elicited by extending infusion intervals or higher B-cell counts. The wearing-off phenomenon of ocrelizumab therefore does not seem to reflect suboptimal control of MS disease activity.

Wearing-off symptoms during standard and extended natalizumab dosing intervals: Experiences from the COVID-19 pandemic.

Natalizumab effectively prevents disease activity in relapsing-remitting multiple sclerosis, but many treated patients report subjective wearing-off symptoms at the end of the 4-week interval between infusions. Extended interval dosing (EID) is a promising strategy to mitigate the risk of natalizumab-associated progressive multifocal leukoencephalopathy, but it is unknown whether EID affects wearing-off symptoms. In this observational study, we evaluated if prevalence or intensity of wearing-off symptoms changed when natalizumab dosing intervals were extended from 4 to 6 weeks in 30 treated patients during the outbreak of COVID-19 in Norway. New or increased wearing-off symptoms during EID were reported by 50%. Symptom increase was more frequent among patients with pre-existing wearing-off symptoms during standard dosing compared to patients without such pre-existing symptoms [p = 0.0005]. Our observations support the need to study the effect of EID on wearing-off symptoms in randomized controlled trials.

COVID-19 occurring during Natalizumab treatment: a case report in a patient with extended interval dosing approach.

BACKGROUND: The novel Coronavirus SARS-CoV-2, which was identified after a recent outbreak in Wuhan, China, in December 2019, has generated a global pandemic impacting over 200 countries around the world. Recent reports suggest that ACE2, which is the target protein to invade the host, has a ubiquitous presence in human organs, including lung parenchyma, gastrointestinal tract, nasal mucosa, renal and urinary tract, airway epithelia, lymphoid tissues, reproductive organs, vascular endothelium and neurons. In this scenario, neurologists are particularly involved into considering even more specific therapeutic strategies according to the available data during the pandemic. In particular, MS patients are usually receiving disease-modifying therapies (DMTs) with immunosuppressant or immunomodulatory effects, which increase the risk of infections and morbidity, compared with the general population. Development of PML or other serious opportunistic infections during treatment with natalizumab forces to consider whether de-risking strategies are needed in this particular context and how to manage a high-efficacy treatment. METHODS: In this paper we report on a patient treated with natalizumab for relapsing MS who developed COVID-19 and recovered in a few days without complications. RESULTS: After recovery natalizumab has been administered in the window of the extended interval dosing (EID), without reporting any worsening or new symptoms. DISCUSSION: This case supports the opportunity to avoid discontinuing or delaying the retreatment over 8 weeks in patients recovered from a recent COVID-19.