Reducing issues with CD20 depletion


What is the optimum dose and dosing schedule for ocrelizumab?

We don’t know because the manufacturers haven’t done the studies, but rituximab it seems that we can reduce the dose. A common dose was 1000mg and it was reduced to 500mg. Efficacy was maintained and impotant it reduced the loss of circulating antibodies. This is important as the loss of such antibodies was associated with 6 times more infections.

Could this be done with ocrelizumab?

Disanto G, Ripellino P, Riccitelli GC, et al. De-escalating rituximab dose results in stability of clinical, radiological, and serum neurofilament levels in multiple sclerosis [published online ahead of print, 2020 Aug 25]. Mult Scler. 2020;1352458520952036. doi:10.1177/1352458520952036

Background: Phase II and observational studies support the use of rituximab in multiple sclerosis. Standard protocols are lacking, but studies suggest comparable efficacy between low- and high-dose regimens.

Objective: To evaluate effectiveness and safety of de-escalating rituximab dose from 1000 to 500 mg/6 months in multiple sclerosis.

Methods: Patients were switched from rituximab 1000 to 500 mg/6 months and prospectively followed for 12 months. Relapses, disability, occurrence of brain/spinal magnetic resonance imaging (MRI) lesions, serum neurofilament light chain (NfL), CD19+ B cell, and IgG concentrations were analyzed.

Results: Fifty-nine patients were included (37 relapsing-remitting, 22 secondary progressive). No relapses occurred, with no difference in expanded disability status scale (EDSS) between baseline (4 (2.5-4.5) and 12 months (3.5 (2.5-5.5) p = 0.284). Overall, three new T2 lesions appeared during follow-up. NfL concentration was stable between baseline (7.9 (5.9-45.2) pg/mL) and 12 months (9.1 (5.9-21.3) pg/mL, p = 0.120). IgG concentrations decreased with greater rituximab load (coefficient = -0.439, p = 0.041). IgG deficient patients had greater risk of infections (OR = 6.27, 95% CI = 1.71-22.9, p = 0.005).

Conclusion: De-escalating rituximab dose from 1000 to 500 mg/6 months is safe, results in clinical and radiological stability, and does not affect serum NfL over 12 months. Rituximab load negatively influences IgG concentrations, and IgG deficient patients are at higher risk of infections.

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  • But how does this mesh with the finding that lower weight improves outcomes on Ocrevus?

    It seems like the answer is a significantly higher dose for a couple rounds (to fully clear out the CD20 b-cells from every nook and cranny) followed by no or small doses at an extended interval.

    • Lower weight means a relatively higher amount of antibody and this seem to be associated with less progression, perhaps because it allows more antibody to get into the brain.

      However based on the Roche data this lower weight had no influence on relapsing disease and this report is about relapsing MS. As you say the first dose clears the B cells and then in subsequent doses there are few B cells to clear and so on second cycle the dose is relatively bigger it is also given as a 600mg dose rather thant two lots of 300mg 2 weeks apart for the first cycle.

  • Hi MD – didn’t the phase 2 OPERA trial results look at this and show there was not a significant increased risk of relapse with extended dosing of ocrelizumab?

  • Still a bit confused. I thought we were starting to think we need higher doses here to stop the “smouldering” disease and really stop progression. This study seems to say that a lower dose may keep relapses at bay, but from prior discussions, not do anything for the real disease. What do you think is really the best course of action? More or less? I’m on Rituxan, I’m IgG deficient from it, I can’t fight sinus infections so I get monthly IVIG as a result, so I have a very vested interest on this exact subject! I convinced my neuro to switch me to just one dose of 1000mg Rituxan every six months (dropping a 2nd dose of 1000mg 2 weeks later) but I don’t think I am seeing any difference. Just had a scan a few days ago so I’ll let you know what that says!

    PS I am not an neuro

    • The smouldering disease is not relapsing disease lower doses can keep relapses at bay because they are caused by the immune system entering the brain. The smouldering MS is in the brain and antibodies are about 99% excluded from the brain and so cant influence what goes on. The idea of higher dose is that more antibody gets and so it may have an impact on smouldering MS…I am not convinced that is the answer I would say less frequuent anti CD20 and add a other agents into the mix
      p.s. I am not a neuro. After the first double dose I dont understand why you would persist with the double dose there is nothing to deplete after the first double dose

          • Maybe research one with antiviral aspects…..when used after an anti-CD20 DMT, an agent with anti-viral aspects might help keep the bad b-cell at bay. Plus, added benefit, it might also help with the sinus infections.

            Outside of MS, I found my sinus infections subsided after I got my deviated septum fixed. Sinus infections are horrible, not that MS is any better. I hope you find some relief.

          • We have sort of done this alreay, when ProfK started his compassionate cladribine programme he used to give a course of famcilcovir to stop viral infections….I think the dose was initially abit high….maybe he can say what the effect was in these individuals…maybe time for another audit:-)

            Sinus infections and MS sends a cold shiver down my spine…At MS meetings there is a a bit of of an MS nutter from South Africa region, and its not ProfG, who gets up and tells us that sinusitis is the cause of MS after every talk and gets this in even if the talk has no links to sinusitus…by the end of the day you are ready to bat-him, but he also used to preace that a certain infection was the cause of MS and mad cow….more like mad scientist

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