It’s a bittersweet fact that wars spark big leaps in science, and this has unfortunately also been true for our fight against the COVID-19 pandemic. When it comes to treating MS, susceptibility to common infections and ability to mount vaccine responses have become important themes among neurologists. Furthermore, pwMS prefer drugs that do not require regular hospital or phlebotomist visits. One of the DMT’s at the frontline during this pandemic has definitely been anti-CD20 treatment. For decades, the standard interval between anti-CD20 infusions (I.e. ocrelizumab, rituximab) has been 24 weeks. This was based on the practice in pivotal clinical trials that tested their efficacy against placebo, but was swiftly overruled by the viral enemy troops.
Several journals recently published articles in which the standard interval between anti-CD20 infusions has been delayed because of COVID-19. In Germany, the delay between infusions was arbitrary and dichotomised in more or less than 4 weeks. This lead to a median delay in infusions of 8 weeks. In The Netherlands, reinfusion of ocrelizumab was done when B cells showed minimal signs of repopulation (≥ 10 cells/microliter; lower limit of normal in healthy controls 100 cells/microliter). This approach resulted in a median redosing interval of 34 weeks which is a 2.5 month extension compared to the standard interval. Follow-up periods in both studies were relatively short: 3 months in Germany, and 11 months in The Netherlands. During this period, no meaningful differences in frequency of relapses, disability progression and MRI markers were seen.
Implementing B-cell guided reinfusion schemes in clinical practice essentially means that you buy a new carton of milk when the previous one is empty. Your first infusion depletes your B cells and you are reinfused when B cells go up again. An obvious example of good housekeeping! Adopting this strategy means that 8 anti-CD20 infusions in 5 years will suffice compared to our current practice of 12 infusions. The price of a rituximab vial is around 1500 euro whereas ocrelizumab is priced about 6000 euro (depending on national Pharma contracts). This saves health insurance companies a lot of money, and means that funds can be invested elsewhere.
However, it’s important to realise this is only the first step in rationalising MS treatment with anti-CD20. There is a slight but consistent increased infection risk with chronic anti-CD20, and vaccination responses are at least partially blunted. It is unclear whether extended-interval dosing will solve this problem. The cut-off of 10 B cells/microliter for reinfusion is still very stringent, implying it is unlikely going to impact on the hypogammaglobulinemia (I.e. low IgM and IgG antibody levels) that occurs with longstanding anti-CD20 use. Similarly, the positive impact of this redosing strategy on vaccination responses need to be seen. Anyway, timing of vaccination under anti-CD20 will remain a hassle in clinical practice. Overall, also when we use B-cell guided reinfusion protocols, pwMS will be chronically immune suppressed.
Therefore, we need to ask ourselves whether chronic immune suppression is necessary, and whether aggressive induction therapy with for example four B-cell guided anti-CD20 infusions followed by watchful waiting (similar to cladribine/alemtuzumab/aHSCT) or a mild first-line immune suppressant (such as Tecfidera) would be a valid alternative strategy. We know that absolute B cell counts are not a good surrogate of re-emergent disease activity in MS and there is evidence that pwMS on anti-CD20 remain stable long beyond B cell repopulation rates. Let’s hope future research brings us a peaceful revolution!
Disclaimer: Please note that the opinions expressed here are those of dr. Ide Smets and do not necessarily reflect the position of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust.
Mult Scler. 2021 Jul 9;13524585211028833.
Zoë Ygj van Lierop 1, Alyssa A Toorop 1, Wouter Jc van Ballegoij 2, Tom Bg Olde Dubbelink 3, Eva Mm Strijbis 1, Brigit A de Jong 1, Bob W van Oosten 1, Bastiaan Moraal 4, Charlotte E Teunissen 5, Bernard Mj Uitdehaag 1, Joep Killestein 1, Zoé LE van Kempen 1Affiliations expand
PMID: 34240631, DOI: 10.1177/13524585211028833
In this observational study, 159 patients with multiple sclerosis received personalized dosing of ocrelizumab incentivized by the COVID-19 pandemic. Re-dosing was scheduled when CD19 B-cell count was ⩾10 cells/µL (starting 24 weeks after the previous dose, repeated 4-weekly). Median interval until re-dosing or last B-cell count was 34 [30-38] weeks. No clinical relapses were reported and a minority of patients showed Expanded Disability Status Scale (EDSS) progression. Monthly serum neurofilament light levels remained stable during extended intervals. Two (1.9%) of 107 patients with a follow-up magnetic resonance imaging (MRI) scan showed radiological disease activity. Personalized dosing of ocrelizumab could significantly extend intervals with low short-term disease activity incidence, encouraging future research on long-term safety and efficacy.
Neurol Neuroimmunol Neuroinflamm. 2021 Jul 14;8(5):e1035.
Leoni Rolfes 1 , Marc Pawlitzki 1 , Steffen Pfeuffer 1 , Christopher Nelke 1 , Anke Lux 1 , Refik Pul 1 , Christoph Kleinschnitz 1 , Konstanze Kleinschnitz 1 , Rebeca Rogall 1 , Katrin Pape 1 , Stefan Bittner 1 , Frauke Zipp 1 , Clemens Warnke 1 , Yasemin Goereci 1 , Michael Schroeter 1 , Jens Ingwersen 1 , Orhan Aktas 1 , Luisa Klotz 1 , Tobias Ruck 1 , Heinz Wiendl 1 , Sven G Meuth 2
PMID: 34261812 DOI: 10.1212/NXI.0000000000001035
Objective: To evaluate the clinical consequences of extended interval dosing (EID) of ocrelizumab in relapsing-remitting multiple sclerosis (RRMS) during the coronavirus disease 2019 (COVID-19) pandemic.
Methods: In our retrospective, multicenter cohort study, we compared patients with RRMS on EID (defined as ≥4-week delay of dose interval) with a control group on standard interval dosing (SID) at the same period (January to December 2020).
Results: Three hundred eighteen patients with RRMS were longitudinally evaluated in 5 German centers. One hundred sixteen patients received ocrelizumab on EID (median delay [interquartile range 8.68 [5.09-13.07] weeks). Three months after the last ocrelizumab infusion, 182 (90.1%) patients following SID and 105 (90.5%) EID patients remained relapse free (p = 0.903). Three-month confirmed progression of disability was observed in 18 SID patients (8.9%) and 11 EID patients (9.5%, p = 0.433). MRI progression was documented in 9 SID patients (4.5%) and 8 EID patients (6.9%) at 3-month follow-up (p = 0.232). Multivariate logistic regression showed no association between treatment regimen and no evidence of disease activity status at follow-up (OR: 1.266 [95% CI: 0.695-2.305]; p = 0.441). Clinical stability was accompanied by persistent peripheral CD19+ B-cell depletion in both groups (SID vs EID: 82.6% vs 83.3%, p = 0.463). Disease activity in our cohort was not associated with CD19+ B-cell repopulation.
Conclusion: Our data support EID of ocrelizumab as potential risk mitigation strategy in times of the COVID-19 pandemic.