Are we over dosing with anti-CD20? Evidence based on rituximab

A

People with stable MS who were treated with rituximab and then watched remained stable. This should come as nothing new for the general reader but in case you are new to the blog read on

Maarouf A, Rico A, Boutiere C, et al. Extending rituximab dosing intervals in patients with MS during the COVID-19 pandemic and beyond?. Neurol Neuroimmunol Neuroinflamm. 2020;7(5):e825. Published 2020 Jun 25. doi:10.1212/NXI.0000000000000825

Objective: To evaluate disease activity in patients with relapsing-remitting MS (RRMS) receiving rituximab with an extended dosing interval.

Methods: In the context of COVID-19 pandemic, this was an interim analysis of an ongoing prospective observational study of patients who were stable on rituximab for at least 6 months and who had a planned extended dosing interval of 24 months. Only data for patients with active RRMS before rituximab were analyzed.

Results: Among 177 patients receiving rituximab, 33 had RRMS and MRI activity before rituximab and at least 8 months of follow-up after the last infusion. The mean (SD) age was 40 (14) years, 25 were females, the mean disease duration was 10 (6.8) years, the mean annual relapse rate (ARR) before rituximab was 1.7 (1.3), and the median Expanded Disability Status Scale (EDSS) score before rituximab was 4.5 (1-7). Before extended dosing, when rituximab was infused every 6 months, the mean (SD) ARR decreased to 0.04 (0.1) (p < 0.0001) and the EDSS score to 4 (0-7) (p = 0.04). At the time of this analysis, the median follow-up since the last infusion was 11 (8-31) months. No patient showed relapse or disability progression. In total, 30 patients had at least 1 MRI performed since the last infusion (median time between the last MRI and the last infusion 10 [8-31] months). No MRI showed activity. The CD19+ cell proportion was >1% for 10 of 25 patients at the last count (median time 8 [6-25] months).

Conclusions: An extended dosing interval for rituximab for patients with stable MS during the COVID-19 pandemic may be associated with a low risk of disease activity.

This may be important because long- term B cell depletion is not without problems. This is becomming recognised

‘Fatal underhanded chronic enterovirus infection associated with anti-CD20 monotherapy for central nervous system demyelinating disease’ Radu TanasescuBruno Gran Mult Scler 2020 https://doi.org/10.1177/1352458520933541 “The case also highlights the uncertainties over long-term use of anti-CD20 therapies and the need to monitor B-cell populations (total CD19+ or memory CD19+/CD27+ B cells) or immunoglobulins, to guide interval dosing”. 

So even more of a reason why the ADIOS (extended dosing interval) studies need to be done. I have made the case that this may mean that you can have a drug free pregnancy. When I suggested this the reviewer said this was abit off topic, but this is relevant as the antibody can cross the placenta and deplete the B cells in the unborn

Dysfunctional Immune System Reconstitution After Rituximab Exposure In Utero.Clark R, Lindsey D, Whiteway S, Mikita C, Lieuw K.J Pediatr Hematol Oncol. 2020 Jun 23. doi: 10.1097/MPH.0000000000001871. Online ahead of print.PMID: 32590421

Rituximab is an antibody that binds to B-lymphocytes and is increasingly used during pregnancy. As an immunoglobulin G, it will transfer across the placenta. Previous case reports describe a diversity of clinical presentations in neonates (babies) born following rituximab exposure in utero (in the womb). Our case is of an infant with severe neutropenia and prolonged profound hypogammaglobulinemia (low antibody levels) and class-switching B cell defect (memory cell deficit) after in utero rituximab exposure.

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MouseDoctor

5 comments

  • I may be wrong but wasn’t there a study or theory that higher dosing can push more anti-cd20 into the brain which results in a better outcome? Any thoughts on balancing those two things?

  • In the context of extended dosing to allow for B cells to come back up to >4% (or similar “normal” level) to help protect against COVID19, is there a risk of ADA emerging making anti-CD20 therapy less effective for future infusions? Thinking of Ocrelizumab in particular.

    • Yes, but only early on, i.e. interrupting after 1st and 2nd doses. The latter is known for rituximab, but not for ocrelizumab. It is likely that it will be less of a problem with ocrelizumab as it is more humanised than rituximab.

  • Strangely enough, I had delayed my Rituximab treatment during covid but had
    B cells tested every few weeks. At month 8 since the last dose (2 months past the day I was due. My last dose was a single 1000mg dose), my B cells test continued to turn up as 0. The very next day, I had odd tingling and weakness in my hands, which I hadn’t experienced in years after being on Rituximab. It continued for about a week – up until I was able to get in the chair for the next Rituxan dose, and then went away a day or two later. I wasn’t able to get an MRI at the time (covid..) to fully confirm, but I’m pretty convinced it was a relapse. As someone who needs monthly IVIG due to Rituxan, we were trying to push the limits and had felt pretty good that 0 B cells meant a very low chance of a relapse, but seems like it backfired. I haven’t been able to make much sense of it I’m kind of at a loss on next steps.. it would be great to be vaccine ready and ease off the Rituxan for a few months but the risk could be infinite. I’m getting IVIG but still have a 2 year long sinus infection.

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