Does dosing frequency of anti‐CD20 therapies blunt vaccine responses and increase COVID‐19 susceptibility in patients with multiple sclerosis?

Word that the National Institute for Health and Care Research (NIHR), working with the National Health Services (NHS) of the United Kingdom, has launched the Efficacy and Mechanism evaluation (EME) programme to ‘investigate optimizing treatment duration with immunomodulators to reduce overtreatment’ is welcome news. According to the EME statement, ‘the issue of risk-benefit analysis is particularly complex for those treatments associated with serious adverse events or side-effects’. The programme's rationale is that the optimal dose and duration of treatment are unclear. On this side of the Atlantic, one hopes that similar initiatives would be undertaken in the United States. The goal, beyond financial persuasions, is to evaluate if one of the factors linked to prolonged B-cell depletion and blunted vaccine responses or severe COVID-19 infections is the dosing frequency of anti-CD20 therapies. Drugs that impact naïve CD20 B-cell populations from returning to pre-infusion levels before the next dose is administered need closer scrutiny. Interestingly, incomplete depletion of circulating B cells may be enough to achieve clinical efficacy,1 and this may be pivotal in individualizing therapy. Anti-CD20 therapies in multiple sclerosis (MS) have evolved into first line therapies following their FDA approval in 2017, but dosing intervals do not follow B-cell repopulation kinetics or guide clinicians with redosing schedules. Redosing is not based on any measurable metric such as CD19 cell counts (the de facto surrogate cell marker for CD20 B cells) but follows a fixed, predetermined and universalized dosing interval. Whether a fixed timed-dosing interval impacts vaccine responsiveness and severity of infections has never been explored, but probably needs to be, given that B-cell repopulation times vary widely.1 Most importantly, the impact of a fixed timed-dosing interval on vaccine responsiveness or severity of COVID-19 infections has not been studied. B-cell depletion should not necessarily expose patients to severe SARS-CoV-2 infection since innate and CD8 T-cell responses are not influenced by B-cell depletion,2 a fact based on recovery of patients on anti-CD20 therapy. Long-term use of anti-CD20 therapies, however, may need closer evaluation because of risk of serious and opportunistic infections, including impaired immune responsiveness to vaccines.3 To mitigate risk, modified3 or extended4 dosing has been studied but has not been universalized or approved by the European or US drug agencies for clinical use. Mitigating the risk of anti-CD20 therapies includes limiting their use in older patients, severely disabled and in those using immunosuppressive therapies concomitantly. Some have utilized the concept of personalized CD19 B-cell counts5 to direct dosing schedules during the COVID-19 pandemic in an observational setting. In a phase 2b double-blind study that provides class 1 evidence, the maximum dose–response effect on anti-CD20 cells was seen at ≥30 mg S.C. ofatumumab/12 weeks1 (Kesimpta, Novartis). At this dosing (Figure 1), B-cell reconstitution ranged from 85 to 777days (323.4 days, or 46.1 weeks approximately, mean). Since ofatumumab, FDA-approved in August 2020, for MS, is dosed at 20 mg S.C./4 weeks; are we not administering the drug at double the dose, regardless of the duration of treatment? The pharmacokinetic data for IV form of ofatumumab, (Arzerra), used in chronic lymphocytic leukaemia shows that the drug clearance decreases significantly as compared to its subsequent clearance after the first infusion. This is attributed to its clearance by both a target-independent and a B-cell-mediated route. The initial dosing for IV ofatumumab is 300 mg/kg followed by seven weekly and four monthly infusions of 2000 mg/kg per dose. The Cmax was 40% higher, and area under curve (AUC) was 60% higher after the 8th infusion than after the 4th infusion. This points to decreased drug clearance when B-cell populations are depleted and may contribute to blunted responsiveness to vaccines and increased severity to infections. Additionally, B-cell repopulation kinetics display both high inter-and intraindividual variance, with no significant variation in the same individual. The degree of B-cell depletion varies between individuals even for the same dose, suggesting that individual factors are important in determining depletion, a finding that is ripe for individualized therapy. A higher body mass index (BMI) may be associated with faster repopulation rates.6 In studies that investigated the depletion of CD20-expressing B cells in solid tissues, depletion is significant but not complete, with bone marrow and spleen being more easily depleted than lymph nodes.7 Age, male sex, cardiovascular comorbidities, neurological disability and anti-CD20 therapies contribute to severity of COVID-19 infection in patients with MS,8 but a dosing interval question has never been explored. Depletion of B cells is not only linked to the total drug dose administered and distribution in various tissues but also B-cell intrinsic and microenvironment factors influencing recruitment of effector mechanisms and antigen and effector modulation. Among patients with vasculitis, systemic lupus erythematosus (SLE) or rheumatoid arthritis treated with anti-CD20 drugs, safety concerns with severe COVID-19 infections have also been observed. Depletion of B cells produced by a fixed dosing interval regardless of CD19 cell counts in the peripheral blood has significant clinical importance because of long-term safety risks. To guide therapeutic decisions linked to treatment intervals and follow-up therapy, tracking monthly CD19 cell counts in blood might be a simple option that has never been explored. Additionally, continuous depletion of B cells is not required for clinical benefit either—the MIRROR study1 drives home this point. The most logical option is to personalize the dosing regimen. B cells that repopulate have a different immunological profile. The first wave of repopulating B cells are immature B cells (CD38high, IgD+, CD10+, CD24high), and the immunoglobulin receptors are not yet somatically mutated.9 Additionally, the number of naive B cells increase, and they predominate in the peripheral blood B-cell pool. CD27 + memory B cells show a slow and delayed repopulation, but their numbers stay significantly reduced (<50%) compared to baseline.5 Repopulation occurs mainly with naïve B cells and transitional B cells similar to that seen after bone marrow transplantation. Reappearing B cells showed activation of CD25 and CD69 and expressed higher levels of costimulatory CD40 and CD86 markers10. One course of treatment with rituximab, the original CD20 depleting drug, was followed by B-cell repopulation of the peripheral blood starting usually within 6–9 months—but it can take several months or even years for total B-cell numbers recover to pretreatment levels. The odds ratio for seroconversion to SARS COV2 in persons using anti-CD20 therapies, compared to no disease-modifying therapy was 0.03 (95% confidence interval, CI = 0.01–0.06, p < 0.001) indicating a substantially lower likelihood of developing antibodies following vaccination.11 An adjusted odds ratio of 4.44 for severity following anti-CD20 therapies was independently associated with a more severe COVID-19 course in patients with MS.12 While anti-CD20 therapies impact serological responses, they do not necessarily eliminate T-cell-mediated responses to vaccination. How certain are we that anti-CD20 therapy dosing schedules that do not follow B-cell kinetics are not responsible for poor vaccine responsiveness or severity of COVID-19 infections? A quantitative metric to study COVID-19 severity or vaccine responsiveness must be done to evaluate the effect of individualized dosing schedules compared to a standard regimen because (1) repopulation of B cells shows high intra- and interindividual variance and B-cell depletion may be dependent in part on BMI; the clearance of anti-CD20 drugs depends on the existence of B-cell populations during subsequent dosing(s) and baseline B-cell CD19 cell counts probably influence repopulation kinetics; (2) naïve B cells are the predominant cell type in repopulated cells; (3) there is an increased risk of infections associated with current dosing schedules of anti-CD20 drugs; and (4) anti-CD20 dosing must follow CD20 expression in B cells in every patient. While anti-CD20 drugs may not influence innate and CD8 T cell responses, the effect of prolonged suppression of the humoral responses following by a fixed dosing schedule needs to be revisited. No prospective study has compared a scheduled, fixed dosing regimen of anti-CD20 medications to a ‘test’ group whose dosing is based on following CD19 cell counts at periodic intervals to study if vaccine effectiveness and COVID 19 infection rates can be improved. The twin aims of the EME programme, to optimize treatment duration with immunomodulators and to address overtreatment are precisely what the treatment landscape with anti-CD20 drug's needs. Clinicians require specific guidelines for anti-CD20 dosing intervals based on periodic testing of CD19 cell counts to minimize the side-effects of immunomodulator use in MS and to reduce costs of individual therapy, while maintaining efficacy.