<figure><img src="image_1.png" /></figure>

## Review article

# Expert opinion on the long-term use of cladribine tablets for multiple sclerosis: Systematic literature review of real-world evidence

<figure><img src="image_2.png" /></figure>

Celia Oreja-Guevara<sup>a,b</sup>, Wallace Brownlee<sup>c</sup>, Elisabeth G. Celius<sup>d,e</sup>, Diego Centonze<sup>f,g</sup>,
Gavin Giovannoni<sup>h</sup>, Suzanne Hodgkinson<sup>i</sup>, Christoph Kleinschnitz<sup>j</sup>, Eva Kubala Havrdova<sup>k</sup>,
Melinda Magyari<sup>l</sup>, Daniel Selchen<sup>m</sup>, Patrick Vermersch<sup>n</sup>, Heinz Wiendl<sup>o</sup>,
Bart Van Wijmeersch<sup>p</sup>, Hashem Salloukh<sup>q</sup>, Bassem Yamout<sup>r,s,*</sup>

## ARTICLE INFO

### Keywords:

Relapsing multiple sclerosis

Cladribine tablets

Disease-modifying therapy

Expert opinion

Systematic literature review

Real-world evidence

## ABSTRACT

**Background:** Treatment with cladribine tablets (CladT), an immune reconstitution therapy for relapsing multiple sclerosis (RMS), involves two short courses of treatment in Year 1 and Year 2. Most patients achieve sustained efficacy with CladT, but a small proportion may experience new disease activity (DA). Following completion of the indicated dose, physicians may have questions relating to the long-term management of these patients. Since the EU approval of CladT over 5 years ago, real-world evidence (RWE) is increasing and may provide some insights and guidance for clinical practice. We describe a systematic literature review (SLR) of RWE and provide expert opinions relating to six questions regarding the long-term use of CladT.

**Methods:** Pertinent clinical questions were developed by a steering committee (SC) of 14 international multiple sclerosis (MS) experts regarding breakthrough DA in Year 1, new DA after 2 years or more of treatment, long-term management of stable patients, and whether additional courses of CladT may be required or safe. An SLR was performed in EMBASE and PubMed using the population, intervention, comparators, outcomes, study design (PICOS) framework to identify relevant studies within the last 15 years. Searches of key congress proceedings for the last 2–3 years were also performed. Following review of the results and RWE, the SC drafted and agreed on expert opinion statements for each question.

**Results:** A total of 35 publications reporting RWE for CladT were included in this review. In the real world, breakthrough DA in Year 1 is of low incidence (1.1–21.9%) but can occur, particularly in patients switching from anti-lymphocyte trafficking agents. In most patients, this DA did not lead to treatment discontinuation. Reported rates of DA after the full therapeutic effect of CladT has been achieved (end of Year 2, 3 or 4) range from 12.0 to

<footnote><sup>a</sup> Neurology, Hospital Clínico San Carlos, IdISSC, Madrid, Spain</footnote>

<footnote><sup>b</sup> Department of Medicine, Faculty of Medicine, Universidad Complutense de Madrid, Spain</footnote>

<footnote><sup>c</sup> Queen Square MS Centre, National Hospital for Neurology and Neurosurgery, London, United Kingdom</footnote>

<footnote><sup>d</sup> Department of Neurology, Oslo University Hospital, Oslo, Norway</footnote>

<footnote><sup>e</sup> Institute of Clinical Medicine, University of Oslo, Oslo, Norway</footnote>

<footnote><sup>f</sup> Department of Systems Medicine, Tor Vergata University, Rome, Italy</footnote>

<footnote><sup>g</sup> Unit of Neurology, IRCCS Neuromed, Pozzilli (IS), Italy</footnote>

<footnote><sup>h</sup> Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom</footnote>

<footnote><sup>i</sup> Department of Neurology, Liverpool Hospital, and UNSW Sydney, New South Wales, Australia</footnote>

<footnote><sup>j</sup> Department of Neurology and Center for Translational and Behavioural Neurosciences (C-TNBS), University Hospital Essen, Essen, Germany</footnote>

<footnote><sup>k</sup> Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic</footnote>

<footnote><sup>l</sup> Department of Neurology, Danish Multiple Sclerosis Center, Copenhagen University Hospital, Rigshospitalet, Denmark</footnote>

<footnote><sup>m</sup> Division of Neurology, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada</footnote>

<footnote><sup>n</sup> Univ. Lille, Inserm U1172, CHU Lille, FHU Precise, Lille, France</footnote>

<footnote><sup>o</sup> Department of Neurology, Institute of Translational Neurology, University of Münster, Münster, Germany</footnote>

<footnote><sup>p</sup> University MS Centre, Hasselt-Pelt, Hasselt University, Belgium</footnote>

<footnote><sup>q</sup> Ares Trading SA, Eysins, Switzerland (An Affiliate of Merck KGaA)</footnote>

<footnote><sup>r</sup> Neurology Institute, Harley Street Medical Center, Abu Dhabi, UAE</footnote>

<footnote><sup>s</sup> American University of Beirut, Lebanon</footnote>

<footnote>* Corresponding author at: Neurology Institute, Harley Street Medical Center, Abu Dhabi, UAE.
E-mail address: yamoutba@gmail.com (B. Yamout).</footnote>
18.7% in the few studies identified. No RWE was identified to support management decisions for stable patients in Year 5 or later. Views among the group were also diverse on this question and voting on expert opinion statements was required. Only two studies reported the administration of additional courses of CladT, but detailed safety outcomes were not provided.

**Conclusions:** RWE for the long-term use of CladT in the treatment of RMS is increasing, however, gaps in knowledge remain. Where possible, the RWE identified through the SLR informed expert statements, but, where RWE is still lacking, these were based solely on experiences and opinion, providing some guidance on topics and questions that occur in daily clinical practice. More real-world studies with longer-term follow-up periods are needed and highly anticipated.

### Non-standard abbreviations

<table><tr><td>AAN</td><td>American academy of neurology</td></tr><tr><td>ACTRIMS</td><td>Americas committee for treatment and research in multiple sclerosis</td></tr><tr><td>AE</td><td>adverse events</td></tr><tr><td>ARR</td><td>annualised relapse rate</td></tr><tr><td>CladT</td><td>cladribine tablets</td></tr><tr><td>CONy</td><td>Controversies in Neurology</td></tr><tr><td>DA</td><td>disease activity</td></tr><tr><td>DMT</td><td>disease modifying therapy</td></tr><tr><td>EAN</td><td>European Academy of Neurology</td></tr><tr><td>ECTRIMS</td><td>European Committee for Treatment and Research in Multiple Sclerosis</td></tr><tr><td>EDSS</td><td>expanded disability status scale</td></tr><tr><td>EU</td><td>European Union</td></tr><tr><td>Gd<sup>+</sup></td><td>gadolinium-enhancing</td></tr><tr><td>HCP</td><td>healthcare professional</td></tr><tr><td>IRT</td><td>immune reconstitution therapy</td></tr><tr><td>MENACTRIMS</td><td>Middle East North Africa Committee for Research and Treatment in Multiple Sclerosis</td></tr><tr><td>MS</td><td>multiple sclerosis</td></tr><tr><td>NEDA</td><td>no evidence of DA</td></tr><tr><td>NfL</td><td>neurofilament light chain</td></tr><tr><td>PICOS</td><td>Population, Intervention, Comparators, Outcomes, Study design</td></tr><tr><td>PPMS</td><td>primary progressive MS</td></tr><tr><td>PRO</td><td>patient reported outcomes</td></tr><tr><td>RMS</td><td>relapsing MS</td></tr><tr><td>RWE</td><td>real-world evidence</td></tr><tr><td>Q</td><td>question</td></tr><tr><td>SC</td><td>steering committee</td></tr><tr><td>SLR</td><td>systematic literature review</td></tr><tr><td>SPMS</td><td>secondary progressive MS</td></tr><tr><td>UAE</td><td>United Arab Emirates</td></tr><tr><td>WCN</td><td>World Congress of Neurology</td></tr></table>

## 1. Introduction

Cladribine tablets (CladT) are approved in Europe for the treatment of adults with highly active relapsing multiple sclerosis (RMS), as defined by clinical and imaging features (Merck, 2022). They are a short-course immune reconstitution therapy (IRT), in which patients require only two treatment courses (cumulative dose of 3.5 mg/kg body weight over 2 years, given as one treatment course of 1.75 mg/kg per year). Each treatment course comprises two treatment weeks, one at the beginning of the first month and one at the beginning of the second month, in each treatment year. Following completion of two treatment courses, no further treatment with CladT is required in Years 3 and 4 (Merck, 2022).

Cladribine selectively targets B and T lymphocytes (Merck, 2022). There is a preferential reduction in certain lymphocyte sub-populations, while leaving the innate immune system relatively spared (Rammohan et al., 2020). The lowest absolute lymphocyte counts occur

approximately 2–3 months after the start of each treatment course, followed by a gradual recovery (immune reconstitution) (Comi et al., 2019).

In the CLARITY study, treatment with CladT was associated with significant improvements in clinical and imaging parameters (Giovannoni et al., 2010). In the CLARITY-Extension (CLARITY-EXT) study, 98 patients who received CladT 3.5 mg/kg in CLARITY received placebo for 2 years, and demonstrated durable efficacy at Year 4, with over 73% remaining free of relapses (Giovannoni et al., 2018; De Stefano et al., 2022). During Year 5, Expanded Disability Status Scale (EDSS) score stability was observed in 53.9% of patients, improvement in 21.3% and worsening in 24.7% (Giovannoni et al., 2021). Results of the CLARITY and CLARITY-EXT studies have been comprehensively reported (Comi et al., 2019; Giovannoni et al., 2010, 2018, 2021a, 2021b, 2019; De Stefano et al., 2022; Comi et al., 2018; Cook et al., 2019; Vermersch et al., 2021)

It is clear from clinical studies that most patients achieve sustained efficacy with CladT. However, a small proportion experience relapses, magnetic resonance imaging (MRI) activity and/or disease progression on treatment. Consequently, treating healthcare professionals (HCPs) have unanswered questions relating to the management of patients on CladT, particularly regarding breakthrough disease activity (DA) in Year 1, new DA after the initial 2 years or more of treatment, and whether additional courses of CladT are required or feasible. Clinical evidence and guidance on these issues are lacking.

Following the EU and US approval (in 2017 and 2019, respectively), CladT has gained marketing authorisation in more than 80 countries. As of July 2022, an estimated 56,300 patients have received CladT, with 95,664 patients-years of exposure since approval (Giovannoni et al., 2022). Therefore, publication of real-world-use case studies, cohorts and registry data has become increasingly prevalent, possibly providing answers and guidance to some of these questions. Real-world evidence (RWE) can usually offer more realistic insights into the use, safety and efficacy of a treatment outside of the stringent inclusion criteria (e.g., age, prior treatments, level of DA) of clinical trials.

We performed a systematic literature review (SLR), with a focus on RWE, with the aim of identifying data to help answer six questions relating to the use of CladT:

1. How would you manage a case of reactivation of disease/breakthrough DA within Year 1?

2. How would you manage a patient who has taken the indicated two courses of CladT but has evidence of DA after achieving the full therapeutic effect (end of Year 2, 3 or 4)?

3. How would you manage a patient who has taken the indicated two courses of CladT but has evidence of DA in Year 5 or later?

4. How would you manage a patient who has taken the indicated two courses of CladT and remains stable/no evidence of DA in Year 5 or later?

5. What are the safety considerations for continued treatment with CladT?

6. In the event of continued treatment with CladT, in the context of DA, what are the recommended number of additional courses?
A plain language summary video of this review can be found in the supplementary materials.

## 2. Methodology

A steering committee (SC) of 14 international multiple sclerosis (MS) experts, co-chaired by Celia Oreja-Guevara and Bassem Yamout, led the programme and agreed on the six clinical questions to be addressed.

An SLR was performed in EMBASE and PubMed on 3 March 2022 using the population, intervention, comparators, outcomes, study design (PICOS) framework to identify relevant studies within the last 15 years. Key word strings were developed for each question. Manual searches of key congress proceedings for the last 2–3 years were also performed (ECTRIMS, EAN, ACTRIMS, AAN, MENACTRIMS, CONy, WCN, European Charcot Foundation).

### 2.1. Study selection and data extraction

The hits identified through electronic searches were subjected to screening. A systematic approach was applied to identify publications of real-world data relating to each question. A single independent analyst screened the titles/abstracts using the inclusion and exclusion PICOS criteria listed in Table 1. A second independent reviewer screened ~10% of records selected at random to check criteria were being applied consistently. Discrepancies in the screening were resolved by a senior reviewer. Positive exclusion methods were employed to selected records for full text review. Where it was unclear whether the inclusion criteria were met, the article remained in the review until sufficient information was available to determine eligibility. Full texts of all the citations included in the first-pass screening were obtained. All the full text articles were then critically reviewed by an expert to see if they carried information/data relevant to the respective study question. A final list of references was compiled for each study question for inclusion.

### 2.2. Development of expert opinion statements

Following review of the results and data from the SLR, the SC drafted, refined and agreed on expert opinion statements for each question. For questions 2 and 4, opinions differed within the group; therefore, voting on different versions of draft statements was performed via an online survey. The options with most votes were carried forward. Voting options and results are provided in Tables S1 and S2.

## 3. Results

The process of study identification and selection is summarised in Fig. 1. Electronic searches yielded a total of 3163 hits after removal of duplicates (n=470), which were screened in the first pass, based on the predefined criteria. A total of 447 references (including congress search results) were included for the full text review, which resulted in identification of 226 relevant publications then reviewed by an expert. Of 49 publications selected for inclusion, eight were common between the questions and six were further excluded due to insufficient data/relevance. Finally, 35 publications reporting the RWE data were selected for inclusion.

Most studies (n=25) were summarised only as abstracts. Studies included those from: Italy (n=9); Germany (n=4); international (n=3); Canada, Norway, Portugal, Spain and Sweden (all n=2); Australia, Argentina, Belgium, Lebanon, Chile, the Czech Republic, Finland, the United Arab Emirates (UAE), and the United Kingdom (UK) (all n=1). The number of patients ranged between 1 and 782, and the median/mean follow up (when reported) ranged from 9 months to 14.4 years. A summary of the relevant real-world studies for each question is provided below and in Tables 2–4. Studies that are relevant for multiple questions have been duplicated within the tables and relevant information for the question provided.

<table><caption>**Table 1**

Inclusion criteria for the research questions (PICOS).</caption><thead><tr><th>Domain</th><th>Inclusion criteria</th><th>Exclusion criteria</th></tr></thead><tbody><tr><td>Population</td><td>RMS patients<br>Previously treated patients/Naïve patients</td><td>SPMS, PPMS, other diseases</td></tr><tr><td>Intervention</td><td>Cladribine (oral or tablet)</td><td>Parenteral cladribine<br>Any other intervention</td></tr><tr><td>Comparators<br>Outcomes</td><td>Any comparator/no comparator<br>Q1: Evidence of disease Year 1<br>• Reactivation/breakthrough of DA within 1 year<br>• Severe/catastrophic relapse<br>• Lymphopenia + prior treatment - inc. level of lymphocyte depletion post 1st course<br>Q2/3: Evidence of disease end of Year 2, 3, 4 and beyond 4 years<br>• Disease activities in this time frame<br>• Disease relapse<br>• Disease progression<br>• Clinical activity<br>• MRI activity<br>• Annualised qualifying relapse rate<br>• MRI assessed lesions<br>• Number of active MRI lesions<br>• Lymphocyte count<br>• Age of patient at time of relapse<br>Q4: Stable disease or NEDA<br>• Patients remained relapse free or with stable disease<br>• Percentage of relapse-free participants<br>Q5: Safety (retreatment or redosing)<br>• Risk of malignancy<br>• Incidence of malignancies<br>• Incidence of infection (herpes zoster)<br>• Long-term infection rate<br>• Incidence of lymphopenia events<br>Q6: Event (retreatment or redosing)<br>• Patients receiving additional courses of CladT<br>• Recommended number of courses/cycles<br>• Retreatment with CladT<br>• Redosing CladT</td><td>Time > Year 1<br>Studies reporting only safety data<br><br>Time < Year 2<br>Studies reporting only safety data<br><br>Patients with relapsed disease<br>Studies reporting only the safety data<br><br>DA, clinical efficacy</td></tr><tr><td>Study design</td><td>Phase II, III and IV clinical trials<br>• Observational studies<br>• RWE/data<br>• Case reports/case series<br>• Congress abstracts<br>• Systematic review and meta-analysis</td><td>Animal, in-vitro studies<br>Pharmacokinetic studies<br>Review articles<br>Letters, notes, editorial, correspondence, opinions<br>Recommendations, consensus, guidelines</td></tr><tr><td>Language</td><td>English</td><td>Non-English</td></tr></tbody></table>

CladT, cladribine tablets; DA, disease activity; MRI, magnetic resonance imaging; NEDA, no evidence of DA; PICOS, Population, Intervention, Comparators, Outcomes, Study design; PPMS, primary progressive MS; RMS, Relapsing MS; RWE, real-world evidence; Q, question; SPMS, secondary progressive MS.

### 3.1. Q1. How would you manage a case of reactivation of disease/breakthrough DA within Year 1?

#### 3.1.1. Summary of available data: frequency and management of relapses in Year 1

Twenty-one real-world studies reported on the frequency and management of relapses in the first year of treatment with CladT (summarised in Table 2). Sixteen of these reported incidence of relapses within the first year (Annovazzi et al., 2020; Bain et al., 2020; Barbuti et al., 2021; Barros et al., 2020; Celius and Berg-Hansen, 2019; Ciampi et al., 2021; Forsberg et al., 2020; Horáková et al., 2021; Kalincik et al., 2018;
<figure><img src="image_3.png" /><figcaption>**Fig. 1.** Modified PRISMA flow.
PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; SLR, systematic literature review.</figcaption></figure>

Pfeuffer et al., 2022; Rojas et al., 2021; Rosengren et al., 2021; Santos et al., 2021; Thakre and Inshasi, 2020; Viitala et al., 2020; Ziemssen et al., 2021) and five reported MRI activity in the first year (Barbuti et al., 2021; Horáková et al., 2021; Rojas et al., 2021; Thakre and Inshasi, 2020; Eichau et al., 2021). The proportion of patients relapsing

within the first 6 and 12 months ranged from 1.1 to 10% (Bain et al., 2020; Celius and Berg-Hansen, 2019; Thakre and Inshasi, 2020; Ziemssen et al., 2021) and 4.8 to 21.9% (Annovazzi et al., 2020; Barbuti et al., 2021; Barros et al., 2020; Ciampi et al., 2021, Forsberg et al., 2020; Horáková et al., 2021; Kalincik et al., 2018; Pfeuffer et al., 2022,
<table><caption>**Table 2**
Summary of results for Q1</caption><thead><tr><th>Refs.</th><th>Study description</th><th>N</th><th>Disease activity (clinical or MRI)</th><th>Discontinuation/switches</th><th>Comments</th></tr></thead><tbody><tr><td colspan="6">Studies reporting frequency and management of relapses in the first year</td></tr><tr><td>Annovazzi et al. (2020) (Abs)</td><td>Italian multicenter retrospective cohort study (mean follow up 12.2 + 5 months)</td><td>236</td><td>84.7% release free<br>15.3% relapsed</td><td>N/S</td><td>-</td></tr><tr><td>Bain et al. (2020) (Abs)</td><td>Retrospective chart review of Canadian patients</td><td>111</td><td>11/111 (10%) had ≥1 relapse (at mean 2.3 months post CladT initiation)</td><td>0 patients discontinued treatment</td><td>-</td></tr><tr><td>Barbuti et al. (2021) (Abs)</td><td>Italian single center (median follow up 16 months)</td><td>60</td><td>4/60 (6.7%) had relapses<br>10/60 (16.7%) developed ≥1 new lesions</td><td>1 switch (1.7%) due to lack of efficacy</td><td>-</td></tr><tr><td>Barros et al. (2020) (Abs)</td><td>Observational, multicentric, prospective study from two tertiary hospitals in Lisbon (mean follow up 13 ± 6 months)</td><td>85</td><td>15 relapses registered in 12 patients (14.1%)</td><td>5/85 (5.9%) discontinued treatment in first year due to DA</td><td>-</td></tr><tr><td>Brownlee et al. (2022) (Abs)</td><td>Multicenter, retrospective chart review study (MERLYN)</td><td>610</td><td>N/S</td><td>1 (0.2%) switched within 12 months</td><td>-</td></tr><tr><td>Butzkueven et al. (2021) (Abs)</td><td>Analysis of MSBase registry data</td><td>782</td><td>N/S</td><td>4% discontinuation at 12 months</td><td>-</td></tr><tr><td>Celius and Berg-Hansen (2019) (Abs)</td><td>Post-market cohort from Oslo University Hospital</td><td>90</td><td>3/90 (3.3%) relapsed within the first 3 months</td><td>N/S</td><td>2 switchers from fingolimod; 1 treatment naive</td></tr><tr><td>Ciampi et al. (2021) (Abs)</td><td>Chilean prospective longitudinal multicenter study (median follow up 14 months)</td><td>34</td><td>4/34 (11.8%) experienced breakthrough disease (multifocal relapse)</td><td>2/34 (5.9%) switched to ocrelizumab due to treatment failure</td><td>All patients with breakthrough DA were switching from fingolimod</td></tr><tr><td>Eichau et al. (2021) (Abs)</td><td>Retrospective observational study from a single center in Spain</td><td>88</td><td>7 (8.0%) with new T2 lesions in the first year</td><td>2 (2.3%) switched due to DA</td><td>-</td></tr><tr><td>Ellenberger et al. (2022) (Abs)</td><td>Analysis of CladT-treated patients from the German MS Registry (2017–2021)</td><td>390</td><td>Within the first 12 months, 58 relapses were recorded in cumulative follow-up time of 320.1 years</td><td>N/S</td><td>-</td></tr><tr><td>Forsberg et al. (2020) (Abs)</td><td>Swedish post-market surveillance study (IMSE)</td><td>85</td><td>2/42 (4.8%) relapsed in 12 months</td><td>N/S</td><td>42 patients treated for ≥12 months</td></tr><tr><td>Horáková et al. (2021)</td><td>Analysis of Czech ReMuS registry</td><td>436</td><td>78.1% free from relapses in first year; 21.9% relapsed; MRI activity was seen in 10.2% in months 0–6 and 10.1% in months 6–12</td><td>12/436 (2.8%) switched due to DA or EDSS progression</td><td>In Year 1, 17.2% of patients had 1 relapse; 3.7% 2 relapses and 0.9% ≥3 relapses; most mild or moderate</td></tr><tr><td>Kalincik et al. (2018)</td><td>Propensity score–matched analysis from MSBase</td><td>37</td><td>Patients free from relapses at end of year 1 ranged from 79–86% (with relapses in 14–21%)</td><td>N/S</td><td>Patients received only one course of CladT (the drug was withdrawn in Australia in 2011)</td></tr><tr><td>Nicholas et al. (2022) (Abs)</td><td>Internet-based survey of patients enrolled in the US MS LifeLines patients support programme</td><td>616</td><td>N/S</td><td>1.0% switched in Year 1</td><td>-</td></tr><tr><td>Pfeuffer et al. (2022)</td><td>Prospective cohort from two tertiary centers in Germany</td><td>270</td><td>40 (14.8%) relapsed within Year 1</td><td>3 (1.1%) switched to ocrelizumab due to ongoing DA in Month 12</td><td>-</td></tr><tr><td>Rojas et al. (2021) (Abs)</td><td>Sub-study of RelevarEM, a nationwide MS and neuromyelitis optica registry in Argentina (NCT03375177)</td><td>102</td><td>95.1% free from relapses (relapses in 4.9%)<br>90.2% free from Gd+ lesions</td><td>N/S</td><td>-</td></tr><tr><td>Rosengren et al. (2021)</td><td>Swedish post-market surveillance study (IMSE)</td><td>140</td><td>5/47 (10.6%) relapsed during first 12 months</td><td>3.5% discontinued within Year 1 – no reasons provided (one-year drug survival rate = 96.5%)</td><td>Relapse data only available for 47 patients</td></tr><tr><td>Santos et al. (2021) (Abs)</td><td>Observational, multicentric, prospective study of five tertiary hospitals</td><td>182</td><td>89% relapse free at 12 months; 11% relapsed</td><td>13 (11%) discontinued<br>9 (7.4%) due to DA</td><td>Follow-up data available for 121 patients at 12 months</td></tr><tr><td>Thakre and Inshasi (2020) (Abs)</td><td>UAE real-world cohort</td><td>88</td><td>1/88 (1.1%) relapsed after 2 months<br>1/88 (1.1%) persistent MRI activity at end of year 1</td><td>0 discontinued due to DA<br>1 discontinuation due to pregnancy</td><td>-</td></tr><tr><td>Viitala et al. (2020) (Abs)</td><td>Non-interventional cohort analysis of data from the Finnish MS registry (mean follow up 11 months)</td><td>126</td><td>8/55 (14.5%) relapsed – mean time to first relapse 6 months (Q1–Q3 1.2–9.8)</td><td>3 discontinued (reasons were inefficiency, change of diagnosis and unknown) and 2/55 (3.6%) switched</td><td>Subset of patients (n=55) were followed for over a year</td></tr><tr><td>Ziemssen et al. (2021) (Abs)</td><td>Non-interventional prospective, multicenter study, CLEVER, conducted in Germany</td><td>491</td><td>10% relapsed within 24 weeks</td><td>N/S</td><td>-</td></tr></tbody></table>

(continued on next page)
<table><caption>Table 2 (continued)</caption><thead><tr><th>Refs.</th><th>Study description</th><th>N</th><th>Disease activity (clinical or MRI)</th><th>Discontinuation/switches</th><th>Comments</th></tr></thead><tbody><tr><td colspan="6">Studies reporting prognostic factors for relapses in the first year</td></tr><tr><td>Annovazzi et al. (2021) (Abs)</td><td>Italian multicenter retrospective cohort study (described above)</td><td>236</td><td>Relapses on CladT more likely in patients switching from other DMTs than those receiving first line CladT (HR 0.2; 95% CI: 0.05–0.7; p=0.01)</td><td>N/S</td><td>Higher baseline ARR predicted clinical activity on treatment (HR 1.9, 95% CI: 1.2–2.9; p=0.04)</td></tr><tr><td>Möhn et al. (2019)</td><td>Retrospective chart review in a single center in Germany (median follow up 9.7 months)</td><td>17</td><td>0/17 (0%) patients switching from natalizumab to CladT experienced a clinical relapse 2/17 (11.8%) showed a new T2 lesion on MRI within 3 months</td><td>0 discontinued</td><td>-</td></tr><tr><td>Nygaard et al. (2022)</td><td>Retrospective cohort study from two university hospitals in Oslo of patients switching from fingolimod</td><td>33</td><td>7 (21.1%) had rebound disease following switch from fingolimod to CladT</td><td>N/S</td><td>Younger age and previous high relapse rate were associated with increased risk of rebound in the CladT group</td></tr><tr><td>Petracca et al. (2022)</td><td>Retrospective observational analysis of eight tertiary MS centers in Italy (2-year follow-up study)</td><td>243</td><td>Patients with a higher number of prior therapies were less likely to retain NEDA-3 status on CladT Mean number (range) of previous DMTs was 1.5 (0–7) Majority of patients were treatment naive (29.3%) or switched from DMF (29.7%)</td><td>N/S</td><td>Association between baseline characteristics and NEDA-3 was tested via logistic regression models. Each model included several covariates: sex, age at CladT start, disease duration, number of prior treatments, relapses in the year prior to CladT, presence of basal active lesions, basal EDSS, basal lymphocytes, switch or naive status.</td></tr><tr><td>Pfeuffer et al. (2022)</td><td>Prospective cohort from two tertiary centers in Germany (described above)</td><td>270</td><td>12/23 (52.3%) patients switching from natalizumab had rebound DA within first 6 months</td><td>-</td><td>Multivariate analysis was conducted using the Cox proportional hazards model. Sex, age at baseline, last previous DMT, baseline EDSS, baseline relapse rate and disease duration were used as covariates in an enter method.</td></tr><tr><td>Zanetta et al. (2021)</td><td>Italian real-life cohort</td><td>60</td><td>Treatment naive patients were more likely to achieve NEDA-3 with CladT that those switching from other DMTs</td><td>N/S</td><td>-</td></tr><tr><td>Zhong et al. (2021)</td><td>MSBase registry analysis</td><td>333</td><td>17 patients (5.1%) relapsed during the washout period and 24 (7.2%) relapsed within one year of starting CladT</td><td>Of those who relapsed during their washout period, seven (41.2%) also relapsed on CladT, compared to 5.4% of those who did not experience a washout relapse</td><td>Relapse on CladT was predicted by washout relapse (HR=7.18, 95% CI = 1.48-34.88, p=0.015) and younger age (HR=0.96, 95% CI 0.93-0.99, p=0.038). Washout durations longer than two months increased relapse risk during the washout but did not alter relapse risk on CladT. Cox proportional hazard regression models were used to analyze time to first relapse in the first year of CladT.</td></tr><tr><td colspan="6">Other studies of interest/relevance</td></tr><tr><td>Garbo et al. (2021)</td><td>Case report of a patient experiencing considerable DA during first year of treatment with CladT</td><td>1</td><td>Patient switched from fingolimod after a 9-week washout period Relapse and MRI activity (new Gd+ enhancing lesions)</td><td>Patient switched to alemtuzumab</td><td></td></tr></tbody></table>

Abs, abstract; ARR, annualised relapse rate; CladT, cladribine tablets; CLEVER, CLadribine Tablets – EValuation of thERapy satisfaction; CI, confidence interval; DA, disease activity; DMF, dimethyl fumarate; DMT, disease-modifying therapy; EDSS, Expanded Disability Status Scale; Gd+, gadolinium enhancing; HR, hazard ratio; IMSE, immunomodulation and multiple sclerosis epidemiology; MERLYN, MavEnclad Real-worLd comparative efficacY non-iNterventional; MRI, magnetic resonance imaging; MS, multiple sclerosis; NEDA, no evidence of disease activity; N/S, not specified; UAE, United Arab Emirates.
<table><caption>**Table 3**
Summary of results for Q2.</caption><thead><tr><th>Refs.</th><th>Study description</th><th>N</th><th>Disease activity (clinical or MRI)</th><th>Switches/additional course</th><th>Comments</th></tr></thead><tbody><tr><td colspan="6">Studies reporting frequency and management of relapses in Years 3 and 4</td></tr><tr><td>Annovazzi et al. (2020)</td><td>Italian multicenter retrospective cohort study (mean follow up 21.1 +7.6 months)</td><td>236</td><td>81.3% relapse free at follow up (18.7% relapsed)<br>56.6% reached NEDA at follow up</td><td>N/S</td><td>-</td></tr><tr><td>Ellenberger et al. (2022) (Abs)</td><td>Analysis of CladT-treated patients from the German MS Registry (2017–2021)</td><td>390</td><td>Within 12–36 months after CladT initiation, 50 relapses were recorded in cumulative follow-up time of 289.5 years</td><td>Atypical cessation of CladT was reported in 23 patients during the 4-year observation period; insufficient efficacy was the reason in 17 (73.9%) patients</td><td>In 30 patients who started another DMT after cessation of CladT, 18 (60%) switched to ocrelizumab</td></tr><tr><td>Oreja-Guevara et al. (2022) (Abs/poster)</td><td>Observational prospective study in Spain</td><td>100</td><td>88% relapse free in Years 3/4 (12% relapsed)</td><td>N/S</td><td>Of 7 patients who relapsed, 6 received an additional (third) course of CladT</td></tr><tr><td>Patti et al. (2020)</td><td>CLARINET-MS – a non-interventional, retrospective, exploratory analysis of patients from the Italian MS Registry</td><td>80</td><td>84.8% relapse free 12 months after last dose (Year 3) (15.2% relapsed)</td><td>Probability of not initiating another DMT 12 months after the last dose was 79.4%</td><td>Includes 34 patients from CLARITY study</td></tr><tr><td>Pfeuffer et al. (2022)</td><td>Prospective cohort from two tertiary centers in Germany</td><td>270</td><td></td><td>5/142 patients received additional courses of CladT (months 24, 25, 28, 34 and 36, respectively) due to ongoing DA</td><td>142 patients in the cohort passed month 24</td></tr><tr><td colspan="6">Other studies of interest/relevance</td></tr><tr><td>Lizak et al. (2021)</td><td>Australian Product Familiarisation Program with a median follow up of 3.5 years</td><td>90</td><td>Over two-thirds of patients with RRMS (67%; n=47/70) received an alternative DMT after CladT during the follow-up period, 26% of whom (n=12/47) experienced relapses prior to switching, but 74% (35/47) switched before a relapse</td><td>The median (95% CI) time to next DMT in the RRMS cohort was 1.16 years (1.06–1.79)</td><td>Due to the withdrawal of the commercially available product before the second year of treatment was due, the 87 patients only received the first year of CladT treatment</td></tr></tbody></table>

Abs, abstract; CI, confidence interval; CladT, cladribine tablets; DA, disease activity; DMT, disease-modifying therapy; MS, multiple sclerosis; NEDA, no evidence of disease activity; N/S, not specified; RRMS, relapsing-remitting multiple sclerosis.

<table><caption>**Table 4**
Summary of results for Q3.</caption><thead><tr><th>Reference</th><th>Study description</th><th>N</th><th>Disease activity (clinical or MRI)</th><th>Switches/additional course</th><th>Comments</th></tr></thead><tbody><tr><td colspan="6">Studies reporting frequency and management of relapses beyond Year 4</td></tr><tr><td>Dive et al. (2020) (Abs)</td><td>Long-term outcomes in patients from single center in Belgium included in the CLARITY and CLARITY-EXT studies</td><td>10</td><td>No additional therapy required in 70% patients – remained NEDA-3<br>30% relapsed within 5 years</td><td>30% switched due to DA (within 5 years)</td><td>14.4 years mean time of follow up</td></tr><tr><td>Giovannoni et al. (2021)</td><td>CLASSIC-MS – an exploratory, low-interventional, ambispective phase IV study of patients previously enrolled into phase III parent trials</td><td>394</td><td>No evidence of disease reactivation was observed in 50.3% (198/394) of patients exposed to CladT in 4 years since last dose (Year 5)</td><td>55.8% (220/394) of the exposed cohort received no subsequent DMT during follow up</td><td>Median follow up of 10.9 years since last dose</td></tr><tr><td>Patti et al. (2020)</td><td>CLARINET-MS (described above)</td><td>80</td><td>66.2% relapse free 36 months after last dose<br>58.9% relapse free 60 months after last dose</td><td>Probability of not initiating another disease-modifying treatment 36 and 60 months after the last dose was 55.6% and 32.4%, respectively</td><td>Median time to treatment change from last dose in CLARITY patients – 37.1 months</td></tr><tr><td>Yamout et al. (2020) (Abs)</td><td>Long-term outcomes in patients from single center in Lebanon included in the CLARITY and CLARITY-EXT studies</td><td>24</td><td>3/22 patients had an EDSS increase over the whole follow-up period, 13 had a decrease and 6 were stable</td><td>13/22 patients started a new DMT during follow up; reasons for these treatment switches are not provided</td><td>Follow-up time was 9.8 years</td></tr><tr><td colspan="6">Other studies of interest/relevance</td></tr><tr><td>Moccia, et al. (2020)</td><td>Retrospective analysis on prospectively collected data from a single center. Follow up of patients from the phase II/III trials for CladT</td><td>13</td><td>Time to post-trial relapse 5.4 ± 3.4 years for CladT</td><td>Approximately 70% of patients were treated with an additional DMT after trial termination, of whom ~20% received a second-line post-trial DMT</td><td>From baseline to Year 4, patients treated with CladT showed reduced relapse risk, vs placebo (HR=0.062, 95% CI 0.004–0.937; p=0.045), while no differences were found from Year 4 to Year 8 (HR=4.006, 95% CI 0.415–38.636; p=0.230)</td></tr></tbody></table>

Abs, abstract; CI, confidence interval; CladT, cladribine tablets; DA, disease activity; DMT, disease-modifying therapy; EDSS, expanded disability Status Scale; HR, hazard ratio; NEDA, no evidence of disease activity.

Rojas et al., 2021; Rosengren et al., 2021; Santos et al., 2021; Thakre and Inshasi, 2020; Viitala et al., 2020), respectively.

Details of MRI outcomes (T2 and gadolinium enhancing [Gd+] T1)

varied among studies. Barbuti et al. (2021) reported ≥ 1 new lesion in 16.7% of patients (n=60). Eichau et al. (2021) reported 8.0% of patients with new T2 lesions in the first year and Rojas et al. (2021) observed
new Gd⁺ lesions in 9.8% of patients. Non-specified MRI activity was reported in 10.1% of patients by Horáková et al. (2021) and 1.1% of patients in a real-world UAE cohort (Thakre and Inshasi, 2020). Details and timing of rebaselining scans were not provided in these studies, which may account for differences in rates of MRI activity within the first year.

Fourteen studies reported on discontinuation/switch rates within the first year; rates ranging from 0–11%. Discontinuations/switches due to ongoing DA were reported in 0–7.4% (Barbuti et al., 2021; Barros et al., 2020; Ciampi et al., 2021; Horáková et al., 2021; Pfeuffer et al., 2022; Santos et al., 2021; Thakre and Inshasi, 2020; Eichau et al., 2021). Two studies reported subsequent disease-modifying therapies (DMTs); Ciampi et al. (2021) reported that 2/34 (5.9%) of patients switched to ocelizumab due to CladT treatment failure and similarly, Pfeuffer et al. (2022) detailed a switch to ocelizumab in 3/270 (1.1%) of patients, due to ongoing DA. In general, treatment discontinuations and switches were lower than relapse rates, suggesting that relapses on treatment during Year 1 did not necessarily lead to discontinuation, with most patients remaining on treatment since the full therapeutic potential of CladT is not achieved until after the second course.

### 3.1.2. Summary of available data: prognostic factors for relapses in Year 1

Seven studies reported on possible prognostic factors for relapse in the first year of treatment with CladT (summarised in Table 2); the majority were naive indirect comparisons. Annovazzi et al. (2021) reported on 236 patients from 56 MS centers and found that relapses were more likely in patients switching from other DMTs than in those receiving CladT as first DMT (*p*=0.01). Furthermore, a higher baseline annualised relapse rate (ARR) predicted clinical activity on treatment (*p*=0.04).

There were conflicting reports of breakthrough DA when switching from natalizumab. Pfeuffer et al. (2022) found that patients switching to CladT from natalizumab were prone to rebound DA, observed in 18/23 patients (median washout time before starting CladT was 66 days). Of those, 12 experienced this within the first 6 months. In contrast, Möhn et al. (2019) observed no clinical relapses in 17 patients switching from natalizumab to CladT (mean washout of 16 weeks).

Treatment-naive patients were more likely to achieve no evidence of DA (NEDA)-3 with CladT than those switching from other DMTs (Zanetta et al., 2021) and retention of NEDA-3 status correlated with a lower number of prior therapies (Petracca et al., 2022) in real-world analyses of Italian patients. Zhong et al. (2021) described 333 patients from the MSBase registry who switched to CladT from a prior DMT (DMF, teriflunomide, fingolimod or natalizumab), with a mean washout of 43.1 days. Relapse on CladT was predicted by washout time (*p*=0.015) and younger age (*p*=0.038). Washout durations longer than two months increased relapse risk during the washout, but did not alter relapse risk on CladT (Zhong et al., 2021). Nygaard et al. (2022) found that younger patients with previous high relapse rate were at increased risk of rebounding when switching from fingolimod to CladT.

### 3.1.3. Expert opinion on management of reactivation of disease/ breakthrough DA within year 1

* In the real world, reactivation of disease, or breakthrough DA, is of low incidence (1.1–21.9%) but can occur within the first few months of treatment with CladT, particularly in patients switching from anti-lymphocyte trafficking agents (e.g., fingolimod, natalizumab)

* Real-world data suggest that patients with a higher baseline ARR, prior DMT treatment, younger age and who relapsed during the washout period had an increased risk of relapsing on CladT

* For patients who are switching from anti-lymphocyte trafficking agents we recommend frequent monitoring of lymphocyte counts and a washout of no more than 4 weeks

* RWE suggests that in most patients, DA within the first year does not lead to treatment discontinuation (rates of discontinuation due to DA

range from 0 to 7.4%), indicating that most patients receive the second course of CladT as planned

* It is recommended that patients receive the full indicated cumulative dose (2 courses) of CladT

* The exception to this would be in rare situations where DA is unabated or paradoxically increased, in which case we recommend switching to another high-efficacy DMT

* A patient's prior DMT and level of DA pre-CladT should be taken into consideration when making any treatment decisions

## 3.2. Q2. How would you manage a patient who has taken the indicated two courses of CladT but has evidence of DA after achieving the full therapeutic effect* (end of Year 2, 3 or 4)?

*The full therapeutic effect: proposed to be 3–6 months after the second course of treatment with CladT (to coincide with the lymphocyte nadir post-second course)

### 3.2.1. Summary of available data

Five studies reported DA in patients during the time after which the full efficacy of CladT had been achieved (end of Year 2, 3 and 4) (Pfeuffer et al., 2022; Annovazzi et al., 2021; Ellenberger et al., 2022; Oreja-Guevara et al., 2022; Patti et al., 2020). These studies are summarised in Table 3.

Relapses during this time occurred in 12.0–18.7% of patients. Information regarding the management of relapses during this time and the outcomes for patients who relapsed was limited. Oreja-Guevara et al. (2022) reported that 6/7 patients who relapsed in Year 3/4 received an additional (third) course of CladT. Pfeuffer et al. (2022) also reported that 5/142 patients received additional courses of CladT (in months 24, 25, 28, 34 and 36, respectively) due to ongoing DA. Within 4 years of CladT initiation, 23/390 (5.9%) patients from the German MS Registry discontinued CladT treatment; ocelizumab was the most common subsequent DMT (18/30) in those initiating another treatment (Ellenberger et al., 2022). In the Italian MS registry, the probability of switching to another DMT at the beginning of Year 3 was around 20% (Patti et al., 2020). Reasons and outcomes for any switches during this time were not provided.

### 3.2.2. Expert opinion on management of DA at the end of Year 2, or in Year 3 or 4

* RWE is scarce and follow-up time inconsistent, but reported rates of DA after the full therapeutic effect of CladT has been achieved (end of Year 2, 3 or 4) range from 12–18.7%

* In the event of new DA during this time consider:

* Additional courses of CladT*

* To avoid risks associated with lymphopenia, patient lymphocyte counts should be at least 800 cells/mm³ before initiating another treatment course

OR

* Switching to another DMT. There are no contraindications for subsequent DMTs following CladT

* Follow-up therapy should be based on patient-related and immunological considerations, but usually includes either a B-cell depleter or transmigration blocker. Potential additive effects on the immune system should be considered when choosing subsequent DMTs

* Factors such as level or severity of DA, the timing of DA in relation to last course of CladT, and prior response of patient to CladT should be taken into consideration when making treatment decisions

*There are no label contraindications for additional courses of CladT
in Years 3 and 4; however, this may depend on country-specific con-
siderations on reimbursement or on-label status

### 3.3. Q3. How would you manage a patient who has taken the indicated two courses of CladT but has evidence of DA in Year 5 or later?

#### 3.3.1. Summary of available data

Four studies reported on longer-term efficacy beyond Year 4 of treatment with CladT (Patti et al., 2020; Dive et al., 2020; Giovannoni et al., 2021; Yamout et al., 2020) summarised in Table 4. They all reported long-term, real-world follow up of patients who took part in the clinical trials for CladT; DA was reported in 30–50% of patients.

Patti et al. (2020) reported outcomes from 80 patients in the Italian MS registry (CLARINET-MS) who had completed ≥1 full course of CladT. Median follow up was 80.3 (1–137) months. The probability of being relapse free was 66.2 and 57.2% at 36 and 60 months after the last dose of CladT, respectively (end of Year 4/Year 6). The probability of being free from disability progression was 73.3 and 63.7% at 36 and 60 months, after the last dose of CladT, respectively, and the probability of not initiating another treatment was 55.6 and 32.4%. Median time from last CladT dose to new DMT was 32.1 (95% confidence interval [CI 15.5–39.5]) months, although no reasons for DMT switches were provided.

Dive et al. (2020) described long-term outcomes from 10 patients included in the CLARITY/CLARITY-EXT studies. Over 14 years, 7/10 patients didn't require additional therapy after CladT. Three patients relapsed within 5 years and moved to other treatments.

Yamout et al. (2020) assessed long-term outcomes for 24 Lebanese patients who received CladT in CLARITY. The follow-up time was 9.8 years (standard deviation [SD]=2). Of 22 patients, 13 started a new DMT during follow up; reasons for these switches were not provided. The ARR was 0.20 (95% CI 0.12–0.33) during the study and 0.20 (95% CI 0.14–0.29) during the post-study follow up

Giovannoni et al. (2021) described the CLASSIC-MS study, assessing 435 patients with a median follow up of 10.9 years (range 9.3–14.9), including 394 who were exposed to CladT in CLARITY and 41 patients who received placebo. For patients who received CladT 3.5 mg/kg over 2 years (n=160) findings suggested numerical improvements in mobility and disability outcomes. Additionally, 58.1% of these patients used no subsequent DMTs, compared to 26.8% of patients in the placebo group.

Moccia et al. (2020) detailed an 8-year follow up of 27 Italian patients from the phase II or III trials (n=13 for CladT; n=14 for placebo). Time to post-trial relapse was 4.5 ± 2.9 years for placebo and 5.4 ± 3.4 years for CladT. Approximately 70% of patients were treated with an additional DMT after trial termination, of whom ~20% received a second-line post-trial DMT. Between baseline and Year 4, patients treated with CladT presented with reduced relapse risk vs placebo (p=0.045). However, no differences were found between Year 4 and Year 8 (p=0.230). This is possibly due to the use of other DMTs in the absence of long-term efficacy data for CladT at the time of study conduction, and possibly due to reduced efficacy of CladT after 4 years. While this study is of interest, few conclusions can be drawn since the population included patients from the ORACLE-MS and ONWARD studies, who had either clinically isolated syndrome, or received CladT in combination with interferon.

#### 3.3.2. Expert opinion on management of DA in Year 5 or later

* RWE is scarce and variable, but reported rates of DA range from 30–50% within 5 years of last dose or end of study

* Long-term responders to CladT (more than 4 years) can be administered additional courses of CladT in Year 5 or later in case of new DA

* There are no label contraindications for additional courses of CladT in Year 5 or later

### 3.4. Q4. How would you manage a patient who has taken the indicated two courses of CladT and remains stable/no evidence of DA* in Year 5 or later?

*NEDA refers to no clinical relapses, no disability progression (EDSS) and no MRI activity

#### 3.4.1. Summary of available data

There were no real-world studies identified that described management of stable patients beyond Year 4. However, a study of interest is by Lizak et al. (2021). This report included 70 patients with relapsing-remitting MS (RRMS) from the Australian Product Familiarisation Program (median follow up 3.5 years), who received only the first year of CladT due to withdrawal of the commercially available product before the second year of treatment was due. Over two-thirds of patients (67%; n=47/70) received an alternative DMT after CladT during the follow-up period, 26% of whom (n=12/47) experienced relapse prior to switching. It is difficult to draw conclusions from this study since patients did not receive the full cumulative dose. However, of interest is that 74% of patients (35/47) switched from CladT to another DMT before a relapse.

#### 3.4.2. Expert opinion on management of stable disease in Year 5 or later

* Recommend no further treatment, with regular, close monitoring (MRI every 6–12 months, assessment of patient-reported outcomes [PROs], such as fatigue, bladder function and cognition, and biomarkers, such as neurofilament light chain [NfL])*

*This scenario was the most debated, with a few experts considering CladT treatment continuation treatment under certain circumstances (see discussion and Table S2 for further information)

### 3.5. Q5. What are the safety considerations for continued treatment with CladT?

#### 3.5.1. Summary of available data

Two studies reported additional courses with CladT. Oreja-Guevara et al. (2022) reported that an additional course of CladT in six patients was well tolerated, with only very mild adverse events (AEs), no cases of serious or opportunistic infections, and no Grade 4 lymphopenia. Pfeuffer et al. (2022) also detailed 5/142 patients who received additional courses of CladT due to ongoing DA, but no safety information was provided.

An additional study of interest is from Butzkueven et al. (2021), reporting outcomes from 16 MS patients in Australia treated with CladT 1.75 mg/kg in 2010–2011, and again in 2018. These patients have now received three courses, but with a long treatment gap (approx. 9 years) between courses 1 and 2. Of 11 patients with recorded lymphocyte counts post CladT, none recorded Grade 4 lymphopenia, and five patients recorded Grade 3 lymphopenia. One patient experienced an episode of herpes zoster (shingles).

In the absence of real-world data, it may be useful to consider integrated long-term safety data from the clinical development programme for CladT and the PREMIERE registry. The most recent analysis included 923 patients who received CladT monotherapy (3.5 mg/kg) (Leist et al., 2020). This confirmed a low level of serious treatment-emergent AEs. No new major safety findings were identified, and no new/significant AEs emerged during long-term follow up (Leist et al., 2020). No increased malignancy risk over time and no clustering of malignancies of a particular type were identified in the monotherapy cohort or in the all exposed cohort (n=1976) (which included patients receiving higher doses than those recommended in the EU SmPC) over >8 years (Merck, 2022; Cook et al., 2019). Rates of malignancies were similar to those of a GLOBOCAN matched reference population, and to those observed with other DMTs (Cook et al., 2019).
In CLARITY-EXT, 186 patients received two additional courses of CladT (7 mg/kg cumulative dose), 12 months apart, with a mean gap between courses 2 and 3 of 42.08 weeks (SD 25.37) (Giovannoni et al., 2018). Over 40% of these patients had Grade 3 or 4 lymphopenia, which was persistent. It is important to mention that in CLARITY-EXT there was no stipulation for a minimum lymphocyte count of 800 cells/mm³ before reinitiation of CladT, which is now specified in the label (Merck, 2022). In patients with ≥800 cells/mm³ prior to administration of additional courses, the incidence of lymphopenia dropped to 11% and 12% in Years 3 and 4, respectively (Cook et al., 2017).

### 3.5.2. Expert opinion on the safety of treatment continuation with CladT

* Real-world data on additional courses are rare, but in general additional courses of CladT have been well tolerated

* There are no longer-term malignancy or infection concerns to date following two courses of CladT, and no increased rates of malignancies or infections in patients receiving higher and additional courses of CladT during the clinical studies, however, risks after additional courses in the real-world remain largely unknown

* Screening for infections and malignancies should be followed as per the indicated label or according to local screening recommendations. Patients must meet the criteria for initiating/continuing treatment, including a lymphocyte count of at least 800 cells/mm³ before initiating another treatment course to avoid risks associated with lymphopenia

## 3.6. Q6. In the event of continued treatment with CladT, in the context of DA, what are the recommended number of additional courses?

### 3.6.1. Summary of available data

There were no real-world studies comparing one versus two additional courses of CladT. As discussed in the results for Q2, additional courses in a small number of patients have been reported in two studies (Pfeuffer et al., 2022; Oreja-Guevara et al., 2022). One and two additional courses have been used effectively with an acceptable safety profile in the real-world and clinical trial settings.

### 3.6.2. Expert opinion on additional courses of CladT

* The recommended cumulative dose* of CladT is 3.5 mg/kg body weight over two years, administered as one treatment course of 1.75 mg/kg per year

* One and two additional courses of CladT have been used safely,† however, long-term follow up for safety and efficacy is still lacking in the real-world

* We recommend administering a minimum of one additional course of CladT with the possibility of a second course depending on clinical response

* Two additional courses are generally not recommended unless DA is not controlled with one additional course

*Each treatment course consists of two treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year. A treatment cycle consists of two treatment courses

†The safety of two additional courses has been tested in a phase III clinical study (CLARITY-EXT), with an average interval of approximately 1 year between the second and third course.

## 4. Discussion

This is, to our knowledge, the first SLR of RWE for CladT. The studies identified provided some guidance for three of the six questions (Q1–3). For the remaining questions (Q4–6), evidence is still lacking, and expert statements are based more on opinion than data. The studies identified

support the low relapse and discontinuation rates observed in the clinical studies of CladT.

The largest number of real-world studies identified were for Q1, regarding the management of reactivation of disease/breakthrough DA in the first year. Breakthrough DA is a known phenomenon, particularly when switching from fingolimod or natalizumab (Barry et al., 2019; Prosperini et al., 2019) and appears to occur in some patients irrespective of subsequent DMT. Relapses in the first 12 months of real-world treatment with CladT occur in a minority of patients, and do not normally lead to treatment discontinuation (Barbuti et al., 2021; Barros et al., 2020; Ciampi et al., 2021; Horáková et al., 2021; Pfeuffer et al., 2022; Santos et al., 2021; Thakre and Inshasi, 2020; Eichau et al., 2021) suggesting low-level DA in most cases. Rarely, a severe rebound may be observed where DA is unabated or paradoxically increased, versus pre-treatment levels. Several treatment strategies have been employed to manage such severe relapses/rebound including corticosteroids, plasma exchange and anti-CD20 B-cell depletion (Barry et al., 2019) as well as applying shorter washout periods upon switching from anti-lymphocyte trafficking agents (Pardo and Jones, 2017; Goncuoglu et al., 2021; Korsen et al., 2022).

Expert agreement on statements was achieved on 4/6 questions without the need for voting. While the group agreed on most of the expert opinion for Q2, voting was needed for a statement on subsequent DMTs (Table S1). Voting was also required for Q4, regarding the management of patients who have taken two courses of CladT and who remain stable in Year 5 or later. Most experts (9/14) would prefer close monitoring of stable patients, with regular assessment of multiple indicators of DA (MRI activity, EDSS, PROs, NfL levels) and consideration of additional CladT courses in the event of DA. This approach, in their opinion, aligns with the concept of IRT, which is to induce long-term disease stability/remission (Sellner and Rommer, 2020; Sorensen and Sellebjerg, 2019). Indeed, long-term follow up of patients enrolled in the CLARITY and ORACLE trials showed that a proportion of patients can remain stable without DA and no further treatment for 5–14 years (Patti et al., 2020; Dive et al., 2020; Giovannoni et al., 2021; Yamout et al., 2020). The remaining five experts (36%) would consider an additional course of CladT in a stable patient as part of an individual treatment decision or as part of a clinical study (Table S2). Such decisions are not simple and may be influenced by a patient's own preferences and clinical parameters, such as the presence of high-risk prognostic factors, in addition to aspects of individual management, for example the feasibility of frequent clinical and MRI assessments. MS is a chronic disease with no known cure and waiting for DA to recur may increase the accrual of further irreversible disability, especially for those patients who presented with highly active disease, who were subsequently stabilised by a DMT. This is complicated further in that around half of disability worsening in RMS occurs independently of relapses, arguing for a more vigilant and proactive approach (Lublin et al., 2022). A recent analysis of clinical trial data from 1935 patients enrolled in CLARITY, CLARITY-EXT and ORACLE-MS applied a machine-learning approach to predict future DA (Basu et al., 2022). Five criteria were used to assess DA, of which 3-month sustained EDSS progression was the most informative. In this model, the probability of future DA decreases with the increasing number of treatment weeks, up to 4 weeks, confirming the optimal CladT dose of 3.5 mg/kg given over 2 years. Similarly, increasing counts of new combined unique active lesions and new T1 hypointense lesions raise the predicted probability of future DA. Indeed, Giovannoni et al. (2022) observed that the percentage of patients with NEDA-3 numerically decreases as the bridging interval between CLARTY and CLARITY-EXT exceeded 48 weeks. Therefore, there is a delicate balance between 'wait and see' and proactive intervention to limit future progression (Pandit, 2019; Smith et al., 2017).

In the event of continued treatment with CladT, a minimum of one additional course of CladT was recommended with the possibility of a second course depending on clinical response (Q6). This contrasts with a recent consensus publication, in which the approved two courses were
recommended, unless there were safety considerations (Meuth et al., 2022). The longer-term safety of CladT and any potential cumulative effects of additional courses is of interest, however, there were few real-world data reporting such outcomes (Q5). While articles reporting alternative formulations of cladribine were excluded from the SLR, longer follow ups with subcutaneous (s.c.) cladribine are available and may provide some reassurance on the long-term safety. In a retrospective, observational study of 52 patients with RMS who received off-label s.c. cladribine over a 5-20-year follow-up period, 80% of patients received additional courses (Rejdak et al., 2021). Increased cumulative doses of s.c. cladribine over a prolonged time period suggest that repeated courses of the drug can keep MS stable and are generally well tolerated by patients (Rejdak et al., 2021). In a real-world cohort of 242 MS patients who received two courses of s.c. cladribine, 18 received a third course of treatment; 7/18 patients received CladT as their additional course, and 11/18 received an additional course of s.c. cladribine (Allen-Philbey et al., 2022). The decision to administer a third course was based on: MRI activity (8 patients), clinical relapse (2 patients), both MRI activity and clinical relapse (5 patients), elevated CSF neurofilament levels (2 patients) and lack of compliance with first treatment (1 patient). The time between completing the first cladribine treatment (~Month 12) to the beginning of the additional treatment course was 37.2 months (Allen-Philbey et al., 2022). A longer-term safety follow-up of these patients would be of great interest and relevance.

Integrated safety analyses from the CladT clinical programme showed no increased rates of malignancies or infections in patients receiving higher and additional courses of CladT during the clinical studies (Cook et al., 2019; Leist et al., 2020). Chronic immunosuppression may increase the risk of infections and certain malignancies, and, with maintenance therapies, the risk of AEs increases with cumulative exposure to the drug (Boyko and Boyko, 2018). However, with selective IRTs, such as CladT, the majority of risk is front loaded due to the dosing schedule. The risk of the most frequent AEs (e.g. lymphopenia) is greatest following treatment administration (Boyko and Boyko, 2018; Giovannoni and Mathews, 2022). From the clinical programme of CladT, it has been observed that lymphopenia does not lead to an increased risk of common or severe infections, with the exception of herpes zoster (Giovannoni et al., 2010, 2018). These data together offer some insights regarding long-term safety of additional courses; however, more real-world cohort and registry data are needed.

Studies including MAGNIFY-MS (NCT03364036), CLASSIC-MS (NCT03961204), CAMELOT-MS (NCT04997148), CLARION (EUPAS24484), CLOBAS (ACTRN12619000257167), CLIP-5 (BfARM ID 7623), and country-specific cohorts will provide further data and evidence regarding the use of CladT. Of particular interest is the phase IV MAGNIFY-MS study, which evaluates whether early changes in immune cell phenotypes correlate with MRI-detectable disease control, possibly providing further evidence to support management decisions in the first 2 years of CladT treatment. CLIP-5 will investigate the efficacy and safety of CladT continuation at Year 5. Additionally, CLOBAS will evaluate CladT safety and efficacy over 6 years, offering continuation of therapy in the third year, based on DA after the initial two courses. The results are keenly anticipated.

Limitations of this review include the scarcity of real-world data for some questions, particularly those relating to long-term follow up with CladT, and those where additional courses have been administered. It is 5 years since EU approval of CladT, and more real-world studies with longer follow-up periods are expected to be published in the coming months. Another limitation is that since most eligible studies were in abstract form, detailed information on methodology, patient management and outcomes were lacking in many cases.

## 5. Conclusion

RWE for the long-term use of CladT in the treatment of RMS is increasing, but gaps in knowledge remain. In the absence of evidence,

expert opinion and experiences are useful to provide guidance on topics and questions that occur in daily clinical practice. Further clinical and real-world studies are required to investigate whether additional courses of CladT are effective and well tolerated, in addition to providing information on which patients are likely to need and/or benefit from further treatment.

## Funding

This work was supported by Merck KGaA, Darmstadt, Germany who provided funding for the project (CrossRef Funder ID: 10.13039/100009945). The SC members received financial compensation for attendance at two advisory board meetings as part of this programme. No payments were made to the authors for the writing of this manuscript.

## Disclosures

CO-G has received speaker and consulting fees from Biogen, BMS, Janssen, Merck KGaA (Darmstadt, Germany), Novartis, Roche, Sanofi-Genzyme, Teva and Viatris.

WB has received speaker honoraria and/or acted as a consultant for Biogen, Janssen, Merck, Novartis, Roche, Sanofi and Viatris.

EGC has received speaker honoraria and/or participated in advisory boards for Biogen, BMS, Janssen, Merck, Roche, Novartis, Sanofi and Teva.

DC is an advisory board member of Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva; and has received honoraria for speaking or consultation fees from Almirall, Bayer Schering, Biogen, GW Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. He is also the principal investigator in clinical trials for Bayer Schering, Biogen, Merck KGaA (Darmstadt, Germany), Mitsubishi, Novartis, Roche, Sanofi-Genzyme, and Teva. His preclinical and clinical research was supported by grants from Bayer Schering, Biogen Idec, Celgene, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva.

GG has received speaker honoraria and consulting fees from AbbVie, Actelion, Atara Bio, Almirall, Bayer Schering Pharma, Biogen Idec, FivePrime, GlaxoSmithKline, GW Pharmaceuticals, Merck & Co., Merck KGaA (Darmstadt, Germany), Pfizer Inc, Protein Discovery Laboratories, Teva Pharmaceutical Industries Ltd, Sanofi-Genzyme, UCB, Vertex Pharmaceuticals, Ironwood, and Novartis; and has received research support unrelated to this study from Biogen Idec, Merck & Co., Novartis, and Ironwood.

SH received honoraria and consulting fees from Merck, Novartis, Bayer Schering and Sanofi, and travel grants from Novartis, Biogen Idec and Bayer Schering.

CK has received grants or contracts from Deutsche Forschungsgemeinschaft (DFG), European Commission, Bundesministerium für Bildung und Forschung (BMBF), Merck Serono GmbH, Biogen GmbH, and Roche Pharma GmbH; consulting fees from Alexion, Biogen, Bristol Myers Squibb, Daiichi Sankyo, Merck Serono, Mylan/Viatris, Novartis, Pfizer, Roche, Sanofi-Aventis, Stada, and Teva; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Alexion, Almirall, Amgen, Amicus, Bayer, Biogen, Biotronik, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, CSL Behring, Daiichi Sankyo, Desitin, Eisai, Ever Pharma, GE Healthcare, MedDay Pharmaceuticals, Merck Serono, Mylan/Viatris, Novartis, Pfizer, Roche, Sanofi-Genzyme, Siemens, STADA, Stago, and Teva; support for attending meetings and/or travel from Biogen, Merck Serono, Teva, Roche, Sanofi-Aventis, Alexion. Participation on a data safety monitoring board or advisory board for Alexion, Biogen, Bristol Myers Squibb, Daiichi Sankyo, Merck Serono, Mylan/Viatris, Novartis, Pfizer, Roche, Sanofi-Aventis, Stada, and Teva. He has stock or stock options with Biontec, Sanofi.

EKH has received honoraria/research support from Biogen, Merck
Serono, Novartis, Roche and Teva; has served as a member of advisory boards for Actelion, Biogen, Celgene, Merck Serono, Novartis and Sanofi-Genzyme, and has been supported by the Czech Ministry of Education - project Cooperatio LF1, research area Neuroscience, and the project National Institute for Neurological Research (Programme EXCELES, ID project No LX22NPO5107) - funded by the European Union-Next Generation EU.

MM has served in scientific advisory boards for Sanofi, Novartis, and Merck; and has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, Genzyme, and Bristol Myers Squibb.

DS has received grants and/or personal fees from Teva, Merck KGaA (Darmstadt, Germany), Novartis, Roche, Genzyme, Sanofi-Genzyme, Biogen Inc., and Bayer HealthCare.

PV has received honoraria or consulting fees from AB Science, Biogen, Imcyse, Sanofi-Genzyme, Novartis, Merck KGaA (Darmstadt, Germany), BMS, Roche; and research support from Biogen, Sanofi-Genzyme, and Merck KGaA (Darmstadt, Germany).

HW is a member of scientific advisory boards/steering committees for Bayer HealthCare, Biogen Idec, Sanofi-Genzyme, Merck KGaA (Darmstadt, Germany), Novartis, Roche, and Teva. He received speaker honoraria and travel support from Bayer Vital GmbH, Bayer Schering AG, Biogen, CSL Behring, EMD Serono, Fresenius Medical Care, Genzyme, Merck KGaA (Darmstadt, Germany), Omniamed, Novartis, Sanofi-Aventis, and Teva. He received compensation as a consultant from Biogen Idec, Merck KGaA (Darmstadt, Germany), Novartis, Omniamed, Roche, and Sanofi-Genzyme. He has received research supports from Bayer HealthCare, Bayer Vital, Biogen Idec, Merck KGaA (Darmstadt, Germany), Novartis, Sanofi-Genzyme, Sanofi US, and Teva, as well as German Ministry for Education and Research (BMBF), German Research Foundation (DFG), Else Kröner Fresenius Foundation, Fresenius Foundation, Hertie Foundation, Merck KGaA (Darmstadt, Germany), Novartis, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (ISKF) Muenster, and RE Children's Foundation.

BVW has received research and travel grants, honoraria for MS-Expert Advice, and speaker's fees from Almirall, Biogen Idec, BMS, Imcyse, Janssen, Sanofi/Genzyme, Merck Serono, Novartis, Roche and TEVA.

HS is an employee of Ares Trading SA, Eysins, Switzerland (an affiliate of Merck KGaA Darmstadt, Germany).

BY has received honoraria for lectures and advisory boards from Bayer, Biogen, Genpharm, Genzyme, Merck KGaA (Darmstadt, Germany), Novartis, Sanofi and Roche; and has received research grants from Bayer, Biogen, Merck KGaA (Darmstadt, Germany), Novartis, and Pfizer.

## Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

## Acknowledgments

Medical writing assistance was provided by Emma East, Bedrock Healthcare, UK, and supported by Merck Healthcare KGaA, Darmstadt, Germany.

Assistance with the systematic literature review was provided by AccuScript and supported by Merck Healthcare KGaA, Darmstadt, Germany.

## Supplementary materials

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.msard.2022.104459.

## References

Allen-Philbey, K., Marta, M., Gnanapavan, K., et al., 2022. Disease activity after cladribine immune reconstitution therapy: to repeat or to retreat? Neurology 98. AAN 2022 abstract (P9-4.002).

Annovazzi, P., Prosperini, L., Capuano, R., et al., 2020. Relapse-free and neda status with cladribine in a real life population: a multicentre study. Mult. Scler. 26, 551. ECTRIMS 2020 abstract (P0910).

Annovazzi, P., Frau, J., Margoni, M., et al., 2021. Two year relapse-free and NEDA status with Cladribine in a real-life population: a multicentre study. Mult. Scler. 27, 693. ECTRIMS 2021 abstract (P842).

Bain, J., Oh, J., Jones, A., et al., 2020. Early real-world safety, tolerability, and efficacy of cladribine tablets: a single center experience. Mult. Scler. 26, 274. ECTRIMS 2020 abstract (P0319).

Barbuti, E., Ianniello, A., Nistri, R., et al., 2021. Real world experience with cladribine at S. Andrea hospital of Rome. J. Neurol. Sci. 429, 118113 https://doi.org/10.1016/j.jns.2021.118113.

Barros, A., Santos, M., Sequeira, J., et al., 2020. Effectiveness of cladribine in multiple sclerosis - clinical experience of two tertiary centers. Mult. Scler. 26, 278. ECTRIMS 2020 abstract (P0328).

Barry, B., Erwin, A.A., Stevens, J., et al., 2019. Fingolimod rebound: a review of the clinical experience and management considerations. Neurol. Ther. 8, 241-250. https://doi.org/10.1007/s40120-019-00160-9.

Basu, S., Munafo, A., Ben-Amor, A.F., et al., 2022. Predicting disease activity in patients with multiple sclerosis: an explainable machine-learning approach in the Mavenclad trials. CPT Pharmacome. Syst. Pharmacol. 11, 843-853. https://doi.org/10.1002/psp4.12796.

Boyko, A.N., Boyko, O.V., 2018. Cladribine tablets' potential role as a key example of selective immune reconstitution therapy in multiple sclerosis. Degener. Neurol. Neuromuscul. Dis. 8, 35-44. https://doi.org/10.2147/dndn.S161450.

Brownlee, W., Haghikia, A., Hayward, B., et al., 2022. Comparative effectiveness of cladribine versus fingolimod in the treatment of highly active relapsing multiple sclerosis: The MERLYN (MavEnclad Real worLd comparative efficacY non-iInterventional) study. Neurology 98, 1370. AAN 2022 abstract (P7-4.005).

Butzkueven, H., Spelman, T., Hodgkinson, S., et al., 2021. Real-world experience with cladribine in the MSBase registry. Mult. Scler. 27, 681. ECTRIMS 2021 abstract (P825).

Butzkueven, H., Spelman, T., Hodgkinson, S., et al., 2021. Outcomes after late Cladribine re-dosing in the Australian MSBase cohort. Mult. Scler. 27. ECTRIMS 2021 abstract (P865).

Celius, E.G., Berg-Hansen, P., 2019. Cladribine as a treatment of multiple sclerosis, real world experience. Mult. Scler. 25, 527. ECTRIMS 2019 abstract (P998).

Ciampi, E., Soler, B., Uribe-San-Martin, R., et al., 2021. Real-world evidence of immune reconstitution therapies: use of Cladribine and Alemtuzumab in Chile. Mult. Scler. 27, 701. ECTRIMS 2021 abstract (P852).

Comi, G., Cook, S., Rammohan, K., et al., 2018. Long-term effects of cladribine tablets on MRI activity outcomes in patients with relapsing-remitting multiple sclerosis: the CLARITY extension study. Ther. Adv. Neurol. Disord. 11, 1756285617753365 https://doi.org/10.1177/1756285617753365.

Comi, G., Cook, S., Giovannoni, G., et al., 2019. Effect of cladribine tablets on lymphocyte reduction and repopulation dynamics in patients with relapsing multiple sclerosis. Mult. Scler. Relat. Disord. 29, 168-174. https://doi.org/10.1016/j.msard.2019.01.038.

Cook, S., Comi, G., Giovannoni, G., et al., 2017. Rates of lymphopenia year-by-year in patients with relapsing multiple sclerosis treated and retreated with cladribine tablets 3.5 mg/kg. ECTRIMS/ACTRIMS 2017 Poster (P666).

Cook, S., Leist, T., Comi, G., et al., 2019. Safety of cladribine tablets in the treatment of patients with multiple sclerosis: an integrated analysis. Mult. Scler. Relat. Disord. 29, 157-167. https://doi.org/10.1016/j.msard.2018.11.021.

De Stefano, N., Sormani, M.P., Giovannoni, G., et al., 2022. Analysis of frequency and severity of relapses in multiple sclerosis patients treated with cladribine tablets or placebo: the CLARITY and CLARITY extension studies. Mult. Scler. 28, 111-120. https://doi.org/10.1177/13524585211010294.

Dive, D., Ernon, C., Brouwers, A., 2020. Cladribine: 14 years atrophy and clinical follow-up. Eur. Charcot Found. Virtual congress.

Eichau, S., Dotor, J., Lopez-Ruiz, R., 2021. Cladribine in a real world setting. The real patients. Mult. Scler. 27, 713. ECTRIMS 2021 Abstract (P869).

Ellenberger, D., Frahm, N., Flachenecker, P., et al., 2022. Treatment patterns prior to and post cladribine in patients with multiple sclerosis. Eur. J. Neurol. 29, 629-630. EAN 2022 abstract (EPO-392).

Forsberg, L., Kågström, S., Leandersson, Å., et al., 2020. A Swedish post-market surveillance study: long-term effectiveness and safety of cladribine tablets (IMSE 10) for patients treated at least 12 months. Mult. Scler. 26, 254. ECTRIMS 2020 abstract (P0276).

Garbo, R., Cutuli, D., Lorenzut, S., et al., 2021. Opportunities and obstacles associated with sequential immune reconstitution therapy for multiple sclerosis: a case report. Front. Neurol. 12, 664596 https://doi.org/10.3389/fneur.2021.664596.

Giovannoni, G., Mathews, J., 2022. Cladribine tablets for relapsing-remitting multiple sclerosis: a clinician's review. Neurol. Ther. 11, 571-595. https://doi.org/10.1007/s40120-022-00339-7.

Giovannoni, G., Sorensen, P.S., Cook, S., et al., 2018. Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study. Mult. Scler. 24, 1594-1604. https://doi.org/10.1177/1352458517727603.

Giovannoni, G., Sorensen, P.S., Cook, S., et al., 2019. Efficacy of cladribine tablets in high disease activity subgroups of patients with relapsing multiple sclerosis: A post hoc
analysis of the CLARITY study. Mult. Scler. 25, 819-827. https://doi.org/10.1177/1352458518771875.

Giovannoni, G., Aydemir, A., Verdun Di Cantogno, E., et al., 2021. CLASSIC-MS: long-term efficacy and real-world treatment patterns for patients with relapsing multiple sclerosis who received cladribine tablets in phase III parent trials. Neurology 96. AAN 2021 abstract (1919).

Giovannoni, G., Comi, G., Cook, S., et al., 2010. A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N. Engl. J. Med. 362, 416-426. https://doi.org/10.1056/NEJMoa0902533.

Giovannoni, G., Aydemir, A., Verdun Di Cantogno, E., et al., 2021. CLASSIC-MS: long-term efficacy and real-world treatment patterns for patients with relapsing multiple sclerosis who received cladribine tablets in phase III parent trials. Neurology, 96. AAN 2021 abstract (1919).

Giovannoni, G., Comi, G., Rammohan, K., et al., 2021a. Long-term disease stability assessed by the expanded disability status scale in patients treated with cladribine tablets 3.5 mg/kg for relapsing multiple sclerosis: an exploratory post hoc analysis of the CLARITY and CLARITY extension studies. Adv. Ther. 38, 4975-4985. https://doi.org/10.1007/s12325-021-01865-w.

Giovannoni, G., Singer, B.A., Issard, D., et al., 2021b. Durability of no evidence of disease activity-3 (NEDA-3) in patients receiving cladribine tablets: the CLARITY extension study. Mult. Scler. https://doi.org/10.1177/13524585211049392, 13524585211049392.

Giovannoni, G., Leist, T., Jack, D., et al., 2022. Updated post-approval safety of cladribine tablets in the treatment of multiple sclerosis, with particular reference to liver safety. ECTRIMS. Amsterdam, The Netherlands.

Giovannoni, G., Singer, B.A., Issard, D., et al., 2022. Durability of no evidence of disease activity-3 (NEDA-3) in patients receiving cladribine tablets: The CLARITY extension study. Mult. Scler. 28, 1219-1228. https://doi.org/10.1177/13524585211049392.

Goncuoglu, C., Tuncer, A., Bayraktar-Ekincioglu, A., et al., 2021. Factors associated with fingolimod rebound: a single center real-life experience. Mult. Scler. Relat. Disord. 56, 103278 https://doi.org/10.1016/j.msard.2021.103278.

Horakova, D., Vachova, M., Tvaroh, A., et al., 2021. Oral cladribine in the treatment of multiple sclerosis - data from the national registry ReMuS® registry. Cesk Slov. Neurol. N. 86, 555-561.

Kalincik, T., Jokubaitis, V., Spelman, T., et al., 2018. Cladribine versus fingolimod, natalizumab and interferon β for multiple sclerosis. Mult. Scler. 24, 1617-1626. https://doi.org/10.1177/1352458517728812.

Korsen, M., Pfeuffer, S., Rolfes, L., et al., 2022. Neurological update: treatment escalation in multiple sclerosis patients refractory to fingolimod-potentials and risks of subsequent highly active agents. J. Neurol. 269, 2806-2818. https://doi.org/10.1007/s00415-021-10956-1.

Leist, T., Cook, S., Comi, G., et al., 2020. Long-term safety data from the cladribine tablets clinical development program in multiple sclerosis. Mult. Scler. Relat. Disord. 46, 102572 https://doi.org/10.1016/j.msard.2020.102572.

Lizak, N., Hodgkinson, S., Butler, E., et al., 2021. Real-world effectiveness of cladribine for Australian patients with multiple sclerosis: An MSBase registry substudy. Mult. Scler 27, 465-474. https://doi.org/10.1177/1352458520921087.

Lublin, F.D., Häring, D.A., Ganjgahi, H., et al., 2022. How patients with multiple sclerosis acquire disability. Brain. 145, 3147-3161. https://doi.org/10.1093/brain/awac016.

Möhn, N., Skripuletz, T., Sühs, K.W., et al., 2019. Therapy with cladribine is efficient and safe in patients previously treated with natalizumab. Ther. Adv. Neurol. Disord. 12. https://doi.org/10.1177/1756286419887596.

Merck (2022). Mavenclad 10 mg Tablets SmPC. Available at: https://www.ema.europa.eu/en/documents/product-information/mavenclad-epar-product-information_en.pdf (Accessed Dec 2022).

Meuth, S.G., Bayas, A., Kallmann, B., et al., 2022. Long-term management of multiple sclerosis patients treated with cladribine tablets beyond year 4. Expert Opin. Pharmacother. 23, 1503-1510. https://doi.org/10.1080/14656566.2022.2106783.

Moccia, M., Lanzillo, R., Petruzzo, M., et al., 2020. Single-center 8-years clinical follow-up of Cladribine-treated patients from phase 2 and 3 trials. Front. Neurol. 11, 489 https://doi.org/10.3389/fneur.2020.00489.

Nicholas, J., Mackie, D.S., Costantino, H., et al., 2022. A cross-sectional survey evaluating cladribine tablets treatment patterns among patients with multiple sclerosis across the US enrolled in the MS lifelines patient support program. Neurology 98. AAN 2022 abstract (P1-1).

Nygaard, G.O., Torgauten, H., Skattebøl, L., et al., 2022. Risk of fingolimod rebound after switching to cladribine or rituximab in multiple sclerosis. Mult. Scler. Relat. Disord. 62, 103812 https://doi.org/10.1016/j.msard.2022.103812.

Oreja-Guevara, C., Gómez-Estévez, I., Alba-Suárez, E., et al., 2022. 4-year follow-up of multiple sclerosis patients treated with cladribine: clinical outcomes and third-year course. Eur. J. Neurol. 29, 795. EAN 2022 poster presentation (EPO-654).

Pandit, L., 2019. No evidence of disease activity (NEDA) in multiple sclerosis - shifting the goal posts. Ann. Indian Acad. Neurol. 22, 261-263. https://doi.org/10.4103/iaian.AIAN_159_19.

Pardo, G., Jones, DE., 2017. The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations. J. Neurol. 264, 2351-2374. https://doi.org/10.1007/s00415-017-8594-9.

Patti, F., Visconti, A., Capacchione, A., et al., 2020. Long-term effectiveness in patients previously treated with cladribine tablets: a real-world analysis of the Italian multiple sclerosis registry (CLARINET-MS). Ther. Adv. Neurol. Disord. 13., 1756286420922685 https://doi.org/10.1177/1756286420922685.

Petracca, M., Ruggieri, S., Barbuti, E., et al., 2022. Predictors of cladribine effectiveness in multiple sclerosis: a real-world, multicenter, two-year follow-up study. Eur. J. Neurol. 29, 787. EAN 2022 abstract (EPO-642).

Pfeuffer, S., Rolfes, L., Hackert, J., et al., 2022. Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres. Mult. Scler. 28, 257-268. https://doi.org/10.1177/13524585211012227.

Prosperini, L., Kinkel, R.P., Miravalle, A.A., et al., 2019. Post-natalizumab disease reactivation in multiple sclerosis: systematic review and meta-analysis. Ther. Adv. Neurol. Disord. 12, https://doi.org/10.1177/1756286419837809, 1756286419837809.

Rammohan, K., Coyle, P.K., Sylvester, E., et al., 2020. The development of cladribine tablets for the treatment of multiple sclerosis: a comprehensive review. Drugs 80, 1901-1928. https://doi.org/10.1007/s40265-020-01422-9.

Rejdak, K., Zasybska, A., Pietruczuk, A., et al., 2021. Long-term safety and efficacy of subcutaneous cladribine used in increased dosage in patients with relapsing multiple sclerosis: 20-year observational study. J. Clin. Med. 10, 5207 https://doi.org/10.3390/jcm10215207.

Rojas, J.I., Alonso, R., Luetic, G., et al., 2021. Real world data from the argentine MS national registry of patients under cladribine. Mult. Scler. 27, 701-702. ECTRIMS 2021 abstract (P853).

Rosengren, V., Ekström, E., Forsberg, L., et al., 2021. Clinical effectiveness and safety of cladribine tablets for patients treated at least 12 months in the Swedish post-market surveillance study "immunomodulation and multiple sclerosis epidemiology 10" (IMSE 10). Mult. Scler. 27, 623. ECTRIMS 2021 abstract (P743).

Santos, M., Sequeira, J., Santos, M., et al., 2021. Safety and effectiveness of cladribine in multiple sclerosis - clinical experience of five tertiary centers. Mult. Scler. 27, 588-589. ECTRIMS 2021 abstract (P694).

Sellner, J., Rommer, PS., 2020. Immunological consequences of "immune reconstitution therapy" in multiple sclerosis: a systematic review. Autoimmun. Rev. 19, 102492 https://doi.org/10.1016/j.autrev.2020.102492.

Smith, A.L., Cohen, J.A., Hua, LH., 2017. Therapeutic targets for multiple sclerosis: current treatment goals and future directions. Neurotherapeutics 14, 952-960. https://doi.org/10.1007/s13311-017-0548-5.

Sorensen, P.S., Sellebjerg, F., 2019. Pulsed immune reconstitution therapy in multiple sclerosis. Ther. Adv. Neurol. Disord. 12., 1756286419836913 https://doi.org/10.1177/1756286419836913.

Thakre, M., Inshasi, J., 2020. Real world experience of oral immune reconstitution therapy (cladribine) in the treatment of multiple sclerosis in the united arab emirates. Mult. Scler. 26, 185. ECTRIMS 2021 abstract (P0140).

Vermersch, P., Galazka, A., Dangond, F., et al., 2021. Efficacy of cladribine tablets in high disease activity patients with relapsing multiple sclerosis: post hoc analysis of subgroups with and without prior disease-modifying drug treatment. Curr. Med. Res. Opin. 37, 459-464, 1080/03007995.2020.1865888.

Viitala, M., Rauma, I., Kuusisto, H., et al., 2020. Characterization of cladribine tablets treated MS patients in Finland. Eur. Charcot Found. Virtual congress.

Yamout, B., Sormani, M.P., Hajj, T., et al., 2020. Long term effectiveness of Cladribine in patients enrolled in the CLARITY trial: real world experience from the lebanese cohort. Mult. Scler. Relat. Disord. 37, 101594 https://doi.org/10.1016/j.msard.2019.11.069.

Zanetta, C., Sangalli, F., Guerrieri, S., et al., 2021. Efficacy/safety profile of cladribine in an italian real-life cohort of relapsing remitting multiple sclerosis patients. Eur. J. Neurol. 28, 325. EAN 2021 abstract (EPR-179).

Zhong, M., Van der Walt, A., Hodgkinson, S., et al., 2021. Relapse during the washout period predicts time to relapse after switching to cladribine. Mult. Scler. 27, 706-707. ECTRIMS 2021 abstract (P860).

Ziemssen, T., Cepek, L., Reifschneider, G., et al., 2021. Evaluation of therapy satisfaction with cladribine tablets in RMS patients - final results of the non-interventional study CLEVER. Mult. Scler. 27, 705-706. ECTRIMS 2021 abstract (P859).