Delaying ocrelizumab is a risk


I have been suggesting that ocrelizumab may behave like alemtuzumab and have some immune reconsitution therapy potential and may not need to be dosed every 6 months. However, I have always said what does the data say and that a proper trial should be done where people are randomised to standard dosing or extended dosing. However, the next thing is the real World data. COVID-19 made some people decide to delay treatment in an attempt to allow a better SARS-CoV-2 vaccine response. But if you do this what does it mean for retrun of disease activity? This is a real-life study and suggests that disease activity increases five times if you extend the dose….The data indicate that there a large range of increase so it may not be 5 times (maybe about the same) but it could be more (maybe 24 times). However, other studies have not suggested this and certainly have not seen a five times increase risk of disease activity and they have not indicated an increase, despite some studies being as big as the current study. However this related largely to the occurrence of MRI lesional activity compared to relapse. They say” EID (extended interval dosing = treatment gap over the standard dosing) was associated with an increased risk of MRI activity during the infusion interval observed, although it did not infuence the risk of relapse occurrence” However the follow-up was short.

However, hopefully will stimulate others to look at their data in the same way to see if it the same. However look at alemtuzumab and dose two, there are clearly some people that need a third dose because of disease activity and if we look at this group 25% show disease activity. We know that a previously high disease activity is a risk for future disease activity with many treatments.

I am sure that this is music to the manufacturer’s ears…that the implication that you need to be treated forever, but you have to ask can a delay of a month make such a big difference? As to contribute to the extended dosing interval you had only to delay dosing by 1 month or more. The standard interval dosing between start to finish was 10.3±3.6 months when they were aiming for 12 months and 15.1±2.5 months with the extended dosing, but about a average of 5 month difference between the two groups, but on average those taking the extending dosing had been diagnosed 3 years less but about twice as many people on the extended dosing had had COVID-19 vaccine

I have to ask what is the biology that could explain this? More antibody would have disappearred and a few more B cells would have appeared . Indeed higher levels of B cell depletion before the last dose was associated with less disease activity, but this was seen regardless of whether stnadard or extended interval dosing was used

I was all excited when I read the paper as it suggested travel in my thought direction…with a YES at the end of the sentence. However reading the paper suggests something different with a NO at the back end. However it teaches us to read the paper (it is open access) and not the title and teachs us to keep an open mind. However, it could suggest that a “watch and wait approved” may be a viable option as long as one monitors for MRI activity. This could stop the lesions manifesting disease activity as the inhibitoy effect is rapid after dosing as seen by blocking natalizumab associated rebound and through studies in trials.

I wonder if further randomised studies on extended dosing interval will every happen now:-(

Zanghì A, Avolio C, Signoriello E, Abbadessa G, Cellerino M, Ferraro D, Messina C, Barone S, Callari G, Tsantes E, Sola P, Valentino P, Granella F, Patti F, Lus G, Bonavita S, Inglese M, D’Amico E. Is It Time for Ocrelizumab Extended Interval Dosing in Relapsing Remitting MS? Evidence from An Italian Multicenter Experience During the COVID-19 Pandemic. Neurotherapeutics. 2022 Aug 29. doi: 10.1007/s13311-022-01289-6.

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.

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  • I guess we’ll have to find a balance between risks of long term B cell depletion and MS activity. I am doing EID based on repopulation off B cells and as soon as we see an increase we redose with ocrelizumab. It took 12 months last time and suspect it will take at least that long again. Even with the above information I’m going to stick to this approach until it either doesn’t work anymore or my neuro won’t continue with it. Are there other ongoing studies looking at EID and ocrelizumab or other CD20 depleting agent?

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