Should anti-CD20 be used as an immune reconstitution therapy?

In light of the changes in disease-modifying treatment (DMT) practice during the COVID-19 pandemic, the “Controversies in Multiple Sclerosis” section of the April edition of Multiple Sclerosis Journal explores whether 6-monthly intervals between anti-CD20 infusions should be maintained or extended. Van Kempen et al. ¹ argue in favor and question the efficacy of extended interval dosing as the majority of the studies which have looked at extending infusion intervals are retrospective with short follow-up. On the contrary, Rolfes and Meuth ² argue that the immunosuppressive effect of anti-CD20 extends beyond the 6-monthly intervals and that extending infusion intervals may offer an opportunity to reduce frequency of infusion and limit consequences of long-term immune suppression. However, both parties do not discuss a very valid third option, namely to use anti-CD20 as an immune reconstitution therapy (IRT). This would imply that anti-CD20 is administered for a limited number of infusion cycles followed by a treatment-free period during which disease recurrence is monitored by clinical and radiological biomarkers. We argue that exploitation of anti-CD20 treatment as an IRT could result in important benefits for people with multiple sclerosis (pwMS) treated with this therapy.

First, there is evidence that using anti-CD20 as an IRT could provide a better balance between risks and benefits. In an analysis of the ocrelizumab (OCR) phase-2 extension trial, it became clear that the annualized relapse rate (ARR) remained low during the drug-free 18-month follow-up period after 3 or 4 treatment cycles in 101 individuals. ³ Moreover, the ARR was comparable to the ARR reported in the 5-year follow-up open-label extension study of pwMS on 6-monthly infusions. ⁴ During the treatment-free anti-CD20 period, no new T1-gadolinium-enhancing or T2-lesions were detected, and there were less adverse events and infection as during the treated period. ³ In 26 pwMS, the phase-1 (RTX) rituximab extension study also reported a maintained anti-inflammatory benefit 12 months after the last infusion. ⁵ Of note, two other multiple sclerosis (MS) DMTs are currently used as an IRT in routine clinical practice (i.e. alemtuzumab and cladribine). Pivotal trials of cladribine and alemtuzumab showed long-lasting clinical efficacy in controlling relapses after two cycles of treatment with a 1-year interval^6–8 which was similar to OCR in a network meta-analysis of the phase III trials. ⁹ Importantly, the therapeutic effect of cladribine and alemtuzumab is deemed to be related to their shared and profound effect on B cell counts as previous CD4⁺ depletion studies have been ineffective in controlling MS disease activity.^10,11 Along this line, the persistent and long-term depletion of memory B cells has been put forward as a key mechanism of action driving long-term efficacy of IRTs.^12,13

Second, chronic B-cell depletion renders pwMS more susceptible for common and severe infections compared to other DMTs. In a pre-COVID-19 nationwide Swedish cohort, RTX-treated pwMS exhibited the highest rate of serious infections compared to other DMTs (hazard ratio (HR), 1.70; 95% confidence interval (CI), 1.11–2.61). ¹⁴ This is especially relevant for the most vulnerable individuals who have urinary tract dysfunction or swallowing difficulties.^15,16 Observational cohorts during the COVID-19 pandemic have shown a more than twofold higher incidence of severe infections and intensive care unit (ICU) admissions in OCR compared to other DMTs.^17,18 One of the anti-CD20 specific risk factors for severe infections might be the occurrence of IgG deficiency which was present in 7.1% of pwMS after 6 years of treatment. ¹⁹ In addition, anti-CD20 treatment interferes with adequate IgG antibody response to vaccines.^20,21 This observation has been highlighted during the COVID-19 pandemic. Several investigators showed that anti-CD20 therapy significantly reduced in most pwMS anti-SARS-CoV-2 spike and receptor-binding domain-specific antibodies and memory B-cell responses.^22,23 No data exist on vaccine efficacy when consistently extending anti-CD20 infusion intervals, but in several studies, there is a correlation with time to last OCR infusion.^22,24 In contrast, most pwMS treated with anti-CD20 mAb generated antigen-specific CD4⁺ and CD8⁺ T-cell responses following vaccination.^22,23 These observations indicate that chronic anti-CD20 allows virus elimination but disturbs the immunological memory and thus prevention of repeat infection in people infected in the past or after vaccination.

In summary, there is no observational or mechanistic evidence that continued infusions would be necessary to control MS inflammation. Therefore, we argue that the use of anti-CD20 treatment as an IRT should be investigated. We acknowledge that there is no real-time biomarker available for MS disease recurrence, but this is equally true for pwMS treated with cladribine and alemtuzumab. Although confirmation is needed in standardized trials, post hoc analyses of the phase-3 OCR data have suggested that lower body mass index (BMI) and thus a higher exposure to anti-CD20 could be associated with slower disability progression. ²⁵ This observation is perfectly compatible with an IRT strategy in which anti-CD20 infusions are BMI-adjusted for three or four cycles.