key: cord-0951125-ufl6d8ld
authors: Rieckmann, Peter; Centonze, Diego; Giovannoni, Gavin; Hua, Le H.; Oreja-Guevara, Celia; Selchen, Daniel; Sørensen, Per Soelberg; Vermersch, Patrick; Wiendl, Heinz; Salloukh, Hashem; Yamout, Bassem
title: Expert opinion on COVID-19 vaccination and the use of cladribine tablets in clinical practice
date: 2021-12-07
journal: Ther Adv Neurol Disord
DOI: 10.1177/17562864211058298
sha: fa139304fdbddce59b824c018e231adbeab0414c
doc_id: 951125
cord_uid: ufl6d8ld

BACKGROUND: Gaps in current evidence and guidance leave clinicians with unanswered questions on the use of cladribine tablets for the treatment of multiple sclerosis (MS) in the era of the COVID-19 pandemic, in particular relating to COVID-19 vaccination. OBJECTIVE: We describe a consensus-based program led by international MS experts with the aim of supplementing current guidelines and treatment labels by providing timely recommendations relating to COVID-19 vaccination and the use of cladribine tablets in clinical practice. METHODS: A steering committee (SC) of 10 international MS experts identified 7 clinical questions to answer concerning the use of cladribine tablets and COVID-19 vaccination, which addressed issues relating to patient selection, timing and efficacy, and safety. Clinical recommendations to address each question were drafted using available evidence combined with expert opinion from the SC. An extended faculty of 28 MS experts, representing 19 countries, in addition to the 10 SC members, voted on the recommendations. Consensus on recommendations was achieved when ⩾75% of respondents expressed an agreement score of 7–9, on a 9-point scale. RESULTS: Consensus was achieved on all 13 recommendations. Clinical recommendations are provided on whether all patients with MS receiving cladribine tablets should be vaccinated against COVID-19, and whether they should be prioritized; the timing of vaccination around dosing of cladribine tablets (i.e. before and after a treatment course); and the safety of COVID-19 vaccination for these patients. CONCLUSION: These expert recommendations provide timely guidance on COVID-19 vaccination in patients receiving cladribine tablets, which is relevant to everyday clinical practice.

The COVID-19 pandemic has represented a global public-health emergency, which has affected both acute and ongoing medical care. Multiple sclerosis (MS) is a lifelong, progressive disease that requires regular management and treatment. MS, including the relapsing forms of MS, in which the patient experiences periods of stability in between episodes of new or worsening symptoms, is typically treated by disease-modifying therapies (DMTs) such as cladribine tablets (Mavenclad®; Merck Europe B.V., The Netherlands). Many DMTs, including cladribine tablets, affect immune response, and this is the rationale used to treat an autoimmune disease such as MS. The effect of DMTs on immune cells may increase the risk of infections as well as impair vaccine response. The provision of health and social-care services for MS has been significantly affected by the COVID-19 pandemic, leading to treatment delays and interruptions to rehabilitation services. In some parts of the world, this has affected the health and wellbeing of people with MS, including the risk of disease progression. [1] [2] [3] [4] At the time of writing, there have not been any efficacious therapies for the treatment of SARS-CoV-2 infection. 5 Vaccination against COVID-19 remains the most efficient way to protect the global population, including people with MS. Approved vaccines have demonstrated high effectiveness and acceptable safety, yet hesitation to be vaccinated against COVID-19 remains a challenge in some people with MS. 6, 7 All DMTs used in the treatment of MS lack vaccine-specific studies for SARS-CoV-2 due to its novel nature, although vaccine studies exist for other pathogens. This raises practical difficulties related to timing of vaccination relative to MS treatment, given treatment modulation of the immune system. Stopping or delaying treatment can potentially result in disease rebound. In addition, and given that MS is an autoimmune disease, there is always a theoretical concern for the effect of vaccination on MS disease status.

Cladribine tablets are a short-course, oral DMT for use in MS, approved by the European Medicines Agency and the United States Food and Drug Administration (FDA), as well as other regulatory authorities around the world. [8] [9] [10] [11] Cladribine is a deoxyadenosine analogue that selectively reduces B and T lymphocytes and is thought to interrupt the cascade of immune events central to the pathogenesis of MS. 9 Common adverse reactions reported in MS patients who receive cladribine tablets at the recommended cumulative dose of 3.5 mg/kg body weight over 2 years in clinical studies included oral herpes, herpes zoster, rash, alopecia, and decrease in neutrophils count, while lymphopenia was very common. Local and global medical societies have issued national and international guidance on the use of DMTs for MS during the COVID-19 pandemic and on COVID-19 vaccination in patients receiving DMTs. [12] [13] [14] [15] [16] [17] These guidelines and position statements, however, leave gaps and unanswered questions, and more specific guidance for everyday clinical practice is required; these guidelines and position statements are summarized in Supplementary Table S1.   To improve the care provided to people with MS  treated with cladribine tablets during the ongoing  global pandemic, a consensus-based program was  developed to address unanswered questions relating to patient selection for COVID-19 vaccination, vaccine timing, efficacy, and safety. The objective of the program was to provide timely, consensus-based, practical recommendations relating to COVID-19 vaccination in MS patients receiving cladribine tablets.

The consensus program, based on a modified Delphi methodology, took place between February and May 2021; the process is outlined in Figure 1 . The methodology was used previously for a consensus paper on the use of cladribine tablets in clinical practice. 18 

In total, 13 recommendations were drafted by the SC for voting. Consensus was achieved on all 13 of these recommendations, with 12 recommendations achieving consensus in the range of 90-100% and one recommendation achieving consensus in the range of 80-90%. All but two EF members voted on all questions. These abstentions were due to technical issues with the online platform. Therefore, the number of experts voting on each recommendation was either 36 or 38. A summary of the available evidence for each question is given below, and the clinical recommendations for each question provided in Tables  1-3 . For those recommendations where some faculty members voted 6 or less, their reasons for doing so are listed in Supplementary Tables  S2-S4 . nationwide mass vaccination in Israel suggests that the BNT162b2 mRNA vaccine is effective for a wide range of COVID-19-related outcomes, including symptomatic COVID-19, hospitalization, severe disease, and death. 6 While the majority of people with MS are not thought to be at a greater risk of COVID-19 disease than the general population, certain exceptions to this exist. In general, older age, male sex, higher Expanded Disability Status Scale (EDSS), longer MS duration, presence of comorbidities, progressive MS course, recent methylprednisolone use, or therapy with an anti-CD20 agent were all risk factors for a more severe COVID-19 disease course. 29, 30 Similar findings were also observed in a large cohort analysis of 12 data sources from 28 countries (n = 2340 patients). 31 Limited data are available on outcomes from SARS-CoV-2-infected MS patients on cladribine tablets. However, analysis of the first 272 cases of COVID-19 (confirmed or suspected) reported to the Merck Global Patient Safety Database (as of 15 January 2021) indicate that people with MS receiving cladribine tablets are generally not at greater risk of serious disease and a more-severe outcome with COVID-19 compared with the general population and other patients with MS who acquired COVID-19. 32 Clinical recommendations to address question 1 are provided in Table 1 . 34 The clinical recommendation to address question 2 is provided in Table 1 . 

CR13: There is currently no available evidence to indicate that vaccination against COVID-19 will lead to an MS relapse or permanent disease worsening Transient worsening of MS symptoms may occur as a result of COVID-19 vaccination (e.g. in the setting of fever), but this should not be confused with worsening of disease The overall benefits of vaccination outweigh transient worsening of MS symptoms (N = 15) demonstrated that seroprotective antibody levels against varicella zoster and seasonal influenza were maintained or increased for at least 6 months (time of follow-up) independent of lymphocyte counts and irrespective of vaccine timing relative to dosing with cladribine tablets. 36 In the ongoing CLOCK-MS study (NCT03963375), a small subset of enrolled patients who had received treatment with cladribine tablets and planned to receive the influenza vaccine as part of standard care were enrolled in the vaccine substudy. 35 Initial findings (N = 4) show seroprotective influenza antibody levels at 4 weeks post-vaccination in MS patients taking cladribine tablets, independent of lymphocyte counts (including two patients -one with grade 1 and one with grade 2 lymphopenia -at the time of vaccination). 35 Recently updated findings from 272 reported cases of COVID-19 among cladribine tablets recipients found no greater risk of serious and severe outcomes compared to the general population, with a total of 15% (40/272) of patients experiencing a severe course of COVID-19. 32 Data on immune cell responses following treatment with cladribine tablets may have relevance to the timing of vaccinations. Cladribine tablets preferentially reduce cells of the adaptive immune system, while leaving the innate immune system relatively spared.

There is a preferential reduction in lymphocyte subpopulations, followed by lymphocyte count recovery (immune reconstitution). The lowest absolute lymphocyte counts occurred approximately 2-3 months after the start of each treatment course and were lower with each additional treatment course. The majority of cladribine tablet-treated patients in the phase III trials experienced grade 1 or 2 lymphopenia; grade 3 lymphopenia was observed in approximately 25% of patients, and <1% of patients experienced grade 4 lymphopenia at any time over 2 years of treatment. In patients receiving cladribine tablets, no increase in opportunistic infections was shown. 37 Recent data from the MAGNIFY-MS biomarker study showed rapid repopulation of naïve B-cells and the sparing of immunoglobulin G up to 1 year after cladribine tablet treatment. 36 Clinical recommendations to address question 3 are provided in Table 2 .

In the context of vaccination timing, it is important to understand the unique posology of cladribine tablets. The recommended cumulative dose of cladribine tablets is 3.5 mg/kg body weight over 2 years, administered as one treatment course of 1.75 mg/kg per year. Each treatment course consists of 2 treatment weeks: one at the beginning of the first month and one at the beginning of the second month of the respective treatment year. Each treatment week consists of 4 or 5 days on which a patient receives 10 or 20 mg (one or two tablets) as a single daily dose, depending on bodyweight. After completing two treatment courses, no further cladribine treatment is required in Years 3 and 4. 38 The current label for cladribine tablets states that treatment should not be initiated within 4-6 weeks after vaccination with live or attenuated live vaccines, but none of the approved COVID-19 vaccines contain live or attenuated live virus. 38 There are few data regarding timing of vaccinations before starting cladribine tablets. In the small retrospective MAGNIFY-MS analysis, three patients received vaccination against varicella-zoster virus (VZV) before treatment with cladribine tablets. Seroprotective VZV titers were maintained over 6 months post-initiation with cladribine tablets, despite lymphocyte count reduction. 36 Clinical recommendations to address question 4 are provided in Table 2 . There are no controlled clinical studies specifically investigating vaccine responses in people with MS receiving cladribine tablets. There are data from the small number of patients in the MAGNIFY-MS and CLOCK-MS trials, described earlier. 35, 36 A positive COVID-19 serology test was reported for 17/17 patients with MS receiving cladribine tablets, but the timing around infection and dosing with cladribine tablets in these patients is unknown. 32 As described earlier, data on the immune-cell responses following treatment with cladribine tablets may have relevance to the timing of vaccinations. 37 The National Multiple Sclerosis Society recently advised that currently available limited data do not suggest that timing of the vaccine in relation to cladribine tablets dosing is likely to make a significant difference in vaccine response, 16 while other national guidelines suggest to wait around 3 months before administering the vaccine. 15 vaccines, compared to the general population', and that these types of vaccine 'are not likely to trigger an MS relapse or to worsen chronic MS symptoms'. 12 The clinical recommendation to address question 7 is provided in Table 3 .

The clinical recommendations described here provide practical advice on COVID-19 vaccination for people with MS treated with cladribine tablets. The complete faculty of 38 MS experts from 19 countries voted on the recommendations, lending a quality and strength to their relevance. All but one recommendation achieved 90-100% consensus among the faculty.

The recommendation achieving the lowest level of consensus was around the timing of vaccination in patients receiving cladribine tablets: CR10 'If already undergoing a course of cladribine tablets, people with MS should receive COVID-19 vaccination when available and offered, regardless of lymphocyte counts or timing of the subsequent dose'. The reasons of some faculty members for not strongly agreeing with this statement are provided in Supplementary Table 3 . Three of the EF experts commented that the timing of vaccination would depend on the level of lymphocytes or reconstitution. This is a topic of debate in the MS community because most DMTs reduce immune cells, including lymphocytes. Nevertheless, it is important to note that this recommendation still met the criteria for consensus. At present, there is no absolute total lymphocyte count that predicts an antibody response to a vaccine or, for that matter, the outcome of COVID-19 infection. 33, [39] [40] [41] [42] Reasons for this are complex and may relate to the fact that circulating lymphocytes represent only 2-3% of the total lymphocyte pool and do not reflect differences within the T-cell pool; for example, comparing the potential naïve and responsive T cells. 43, 44 In addition, functional factors, such as immunosenescence, are not reflected in the total lymphocyte counts. 44, 45 Other relevant factors that predict an antibody response are relevant to the lymph node or secondary lymphoid organ function, in particular the integrity and functioning of germinal centers. 44, 46 An important topic of discussion among the SC members was whether to include the need for a COVID-19 antibody titer measurement following vaccination. The decision was not to recommend such measurements. It is the opinion of the SC members that there could be some level of protection after COVID-19 vaccination in the absence of a robust humoral B-cell response, mediated by T cells, but these responses are more difficult to measure and standardize. In general, age is an important factor related to antibody production. In people with MS, older patients were at a greater risk of serious COVID-19, including those without comorbidities. [29] [30] [31] 33 Finally, another complicating factor is the need to standardize testing, since different test assays may report different antibody response results. 47, 48 One of the weaknesses of the consensus was the limited availability of data; that is, specific studies looking at SARS-CoV-2 antibody responses or COVID-19 vaccination in patients with MS. Large, controlled trials on vaccination are needed, particularly with respect to people with MS on DMTs. In the time since voting took place, new journals.sagepub.com/home/tan 9 evidence has been published in these areas. [49] [50] [51] Published data from these new studies lend support to at least some of the recommendations described here.

The efficacy of humoral response to the BNT162b2 COVID-19 vaccine was assessed in 125 people with MS; of these, 23 were receiving treatment with cladribine tablets (median time from last treatment dose to vaccination was 7.1 months). All patients treated with cladribine tablets were efficiently vaccinated and developed a protective SARS-CoV-2 antibody titer, even with vaccination as early as 4.4 months after the last treatment dose. 50 It is reassuring to see that people with MS receiving cladribine tablets mounted good immune responses to COVID-19 vaccination, but it is important to note that the sample size in this study was small, and additional trials with a larger number of patients are needed. It should be noted that, at the time of this consensus exercise, no data on the clinical effectiveness of the COVID-19 vaccines were available from people with MS, whether treated with DMTs or not.

Further recently published data of interest regarding efficacy includes analysis of SARS-CoV-2 antibodies in a large cohort of MS patients from Amsterdam. 51 Of 546 patients, 64 (11.7%) were positive for SARS-CoV-2 antibodies. Within this cohort, 74.2% of patients were receiving DMTs, and SARS-CoV-2 antibodies were less prevalent in patients using injectable drugs and in patients treated with ocrelizumab. 51 The safety of the BNT162b2 COVID-19 vaccine was assessed in a cohort of adults with MS: 555 patients received the first dose and 435 received the second dose, of which 414 (74.6%) and 326 (74.9%) were being treated with immunomodulatory drugs, respectively. The most commonly reported adverse events were local pain at the injection site, fatigue, headaches, muscle or joint pain, and flu-like symptoms manifested as fever, chills, or a combination of both. No increased risk of relapse activity was noted over a median follow-up of 20 and 38 days after first and second vaccine doses, respectively. The rate of patients with acute relapse was 2.1% and 1.6% following the first and second doses, respectively, which is similar to the rate in non-vaccinating patients during the corresponding period. 49 It is encouraging that in this study, people with MS did not incur more frequent or severe adverse events in response to COVID-19 vaccination compared with the general population, but additional studies with more patients are required.

Further recent evidence that may be of interest is outlined in Supplementary Table S5 .

These consensus-based recommendations represent the opinions and perspectives of a group of international experts within the field of MS. A thorough review of the literature was performed, and the experts carefully considered recent research when formulating their responses. The responses to the questions posed in this expert opinion program are expected to cover the most significant and regularly addressed aspects of COVID-19 vaccination for patients with MS taking cladribine tablets.

These recommendations were developed to provide timely guidance in the absence of much published data on COVID-19 vaccination in people with MS receiving cladribine tablets, and to reflect the knowledge, evidence, and opinion in 2021. Updates to these recommendations will be made as new evidence emerges. This expert opinion is expected to be a concise and thorough resource for medical professionals, with the aim of assisting them in making informed decisions regarding COVID-19 vaccinations in this group of patients to improve their standard of care. 

Biogen Idec, Bayer Schering Pharma, Boehringer-Ingelheim, Sanofi-Aventis, Genzyme, Novartis, Teva Pharmaceutical Industries, and Serono Symposia International Foundation

Sanofi-Genzyme, and Teva. He is also the principal investigator in clinical trials for Bayer Schering

His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec

Ironwood, and Novartis; and has received research support unrelated to this study from Biogen Idec

Novartis, Teva, MedDay Pharmaceuticals, and GSK; on steering committees or independent data monitoring boards in trials sponsored by Merck KGaA (Darmstadt, Germany), Teva, GSK, and Novartis; and has received speaker honoraria from Biogen Idec

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All authors attended two steering committee meetings, reviewed the literature and outputs of the extended faculty voting, and contributed equally to the development and refinement of the programme questions and consensus recommendations. Peter Rieckmann and Bassem Yamout shared chair duties, and led the presentation and discussion of data.

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: P.R.