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

Open AccessPublished:December 08, 2022DOI:https://doi.org/10.1016/j.msard.2022.104459

      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 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.

      Keywords

      Non-standard abbreviations

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

      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 (). 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 ().
      Cladribine selectively targets B and T lymphocytes (). There is a preferential reduction in certain lymphocyte sub-populations, while leaving the innate immune system relatively spared (
      • Rammohan K.
      • Coyle P.K.
      • Sylvester E.
      • et al.
      The development of cladribine tablets for the treatment of multiple sclerosis: a comprehensive review.
      ). 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 G.
      • Cook S.
      • Giovannoni G.
      • et al.
      Effect of cladribine tablets on lymphocyte reduction and repopulation dynamics in patients with relapsing multiple sclerosis.
      ).
      In the CLARITY study, treatment with CladT was associated with significant improvements in clinical and imaging parameters (
      • Giovannoni G.
      • Comi G.
      • Cook S.
      • et al.
      A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis.
      ). 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 G.
      • Sorensen P.S.
      • Cook S.
      • et al.
      Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study.
      ;
      • De Stefano N.
      • Sormani M.P.
      • Giovannoni G.
      • et al.
      Analysis of frequency and severity of relapses in multiple sclerosis patients treated with cladribine tablets or placebo: the CLARITY and CLARITY extension studies.
      ). 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 G.
      • Comi G.
      • Rammohan K.
      • et al.
      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.
      ). Results of the CLARITY and CLARITY-EXT studies have been comprehensively reported (
      • Comi G.
      • Cook S.
      • Giovannoni G.
      • et al.
      Effect of cladribine tablets on lymphocyte reduction and repopulation dynamics in patients with relapsing multiple sclerosis.
      ;
      • Giovannoni G.
      • Comi G.
      • Cook S.
      • et al.
      A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis.
      ,
      • Giovannoni G.
      • Sorensen P.S.
      • Cook S.
      • et al.
      Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study.
      ,
      • Giovannoni G.
      • Comi G.
      • Rammohan K.
      • et al.
      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.
      ,
      • Giovannoni G.
      • Singer B.A.
      • Issard D.
      • et al.
      Durability of no evidence of disease activity-3 (NEDA-3) in patients receiving cladribine tablets: the CLARITY extension study.
      ,
      • Giovannoni G.
      • Sorensen P.S.
      • Cook S.
      • et al.
      Efficacy of cladribine tablets in high disease activity subgroups of patients with relapsing multiple sclerosis: A post hoc analysis of the CLARITY study.
      ;
      • De Stefano N.
      • Sormani M.P.
      • Giovannoni G.
      • et al.
      Analysis of frequency and severity of relapses in multiple sclerosis patients treated with cladribine tablets or placebo: the CLARITY and CLARITY extension studies.
      ;
      • Comi G.
      • Cook S.
      • Rammohan K.
      • et al.
      Long-term effects of cladribine tablets on MRI activity outcomes in patients with relapsing-remitting multiple sclerosis: the CLARITY extension study.
      ;
      • Cook S.
      • Leist T.
      • Comi G.
      • et al.
      Safety of cladribine tablets in the treatment of patients with multiple sclerosis: an integrated analysis.
      ;
      • Vermersch P.
      • Galazka A.
      • Dangond F.
      • et al.
      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.
      )
      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 G.
      • Leist T.
      • Jack D.
      • et al.
      Updated post-approval safety of cladribine tablets in the treatment of multiple sclerosis, with particular reference to liver safety.
      ). 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.
      Table 1Inclusion criteria for the research questions (PICOS).
      DomainInclusion criteriaExclusion criteria
      PopulationRMS patients

      Previously treated patients/Naive patients
      SPMS, PPMS, other diseases
      InterventionCladribine (oral or tablet)Parenteral cladribine

      Any other intervention
      ComparatorsAny comparator/no comparator-
      OutcomesQ1: Evidence of disease Year 1

      • Reactivation/breakthrough of DA within 1 year

      • Severe/catastrophic relapse

      • Lymphopenia + prior treatment - inc. level of lymphocyte depletion post 1st course
      Time > Year 1

      Studies reporting only safety data

      Q2/3: Evidence of disease end of Year 2, 3, 4 and beyond 4 years

      • Disease activities in this time frame

      • Disease relapse

      • Disease progression

      • Clinical activity

      • MRI activity

      • Annualised qualifying relapse rate

      • MRI assessed lesions

      • Number of active MRI lesions

      • Lymphocyte count

      • Age of patient at time of relapse
      Time < Year 2

      Studies reporting only safety data
      Q4: Stable disease or NEDA

      • Patients remained relapse free or with stable disease

      • Percentage of relapse-free participants
      Patients with relapsed disease

      Studies reporting only the safety data
      Q5: Safety (retreatment or redosing)

      • Risk of malignancy

      • Incidence of malignancies

      • Incidence of infection (herpes zoster)

      • Long-term infection rate

      • Incidence of lymphopenia events
      DA, clinical efficacy

      Q6: Event (retreatment or redosing)

      • Patients receiving additional courses of CladT

      • Recommended number of courses/cycles

      • Retreatment with CladT

      • Redosing CladT
      Study design• Phase II, III and IV clinical trials

      • Observational studies

      • RWE/data

      • Case reports/case series

      • Congress abstracts

      • Systematic review and meta-analysis
      Animal, in-vitro studies

      Pharmacokinetic studies

      Review articles

      Letters, notes, editorial, correspondence, opinions

      Recommendations, consensus, guidelines
      LanguageEnglishNon-English
      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.

      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.
      Fig 1
      Fig. 1Modified PRISMA flow.
      PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; SLR, systematic literature review.
      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 Table 2, Table 3, Table 4. Studies that are relevant for multiple questions have been duplicated within the tables and relevant information for the question provided.
      Table 2Summary of results for Q1
      Refs.Study descriptionNDisease activity (clinical or MRI)Discontinuation/switchesComments
      Studies reporting frequency and management of relapses in the first year
      • Annovazzi P.
      • Prosperini L.
      • Capuano R.
      • et al.
      Relapse-free and neda status with cladribine in a real life population: a multicentre study.
      (Abs)
      Italian multicenter retrospective cohort study (mean follow up 12.2 + 5 months)23684.7% release free

      15.3% relapsed
      N/S-
      • Bain J.
      • Oh J.
      • Jones A.
      • et al.
      Early real-world safety, tolerability, and efficacy of cladribine tablets: a single center experience.
      (Abs)
      Retrospective chart review of Canadian patients11111/111 (10%) had ≥1 relapse (at mean 2.3 months post CladT initiation)0 patients discontinued treatment-
      • Barbuti E.
      • Ianniello A.
      • Nistri R.
      • et al.
      Real world experience with cladribine at S. Andrea hospital of Rome.
      (Abs)
      Italian single center (median follow up 16 months)604/60 (6.7%) had relapses

      10/60 (16.7%) developed ≥1 new lesions
      1 switch (1.7%) due to lack of efficacy-
      • Barros A.
      • Santos M.
      • Sequeira J.
      • et al.
      Effectiveness of cladribine in multiple sclerosis – clinical experience of two tertiary centers.
      (Abs)
      Observational, multicentric, prospective study from two tertiary hospitals in Lisbon (mean follow up 13 ± 6 months)8515 relapses registered in 12 patients (14.1%)5/85 (5.9%) discontinued treatment in first year due to DA-
      • Brownlee W.
      • Haghikia A.
      • Hayward B.
      • et al.
      Comparative effectiveness of cladribine versus fingolimod in the treatment of highly active relapsing multiple sclerosis: The MERLYN (MavEnclad Real worLd comparative efficacY non-iNterventional) study.
      (Abs)
      Multicenter, retrospective chart review study (MERLYN)610N/S1 (0.2%) switched within 12 months-
      • Butzkueven H.
      • Spelman T.
      • Hodgkinson S.
      • et al.
      Real-world experience with cladribine in the MSBase registry.
      (Abs)
      Analysis of MSBase registry data782N/S4% discontinuation at 12 months-
      • Celius E.G.
      • Berg-Hansen P.
      Cladribine as a treatment of multiple sclerosis, real world experience.
      (Abs)
      Post-market cohort from Oslo University Hospital903/90 (3.3%) relapsed within the first 3 monthsN/S2 switchers from fingolimod; 1 treatment naive
      • Ciampi E.
      • Soler B.
      • Uribe-San-Martin R.
      • et al.
      Real-world evidence of immune reconstitution therapies: use of Cladribine and Alemtuzumab in Chile.
      (Abs)
      Chilean prospective longitudinal multicenter study (median follow up 14 months)344/34 (11.8%) experienced breakthrough disease (multifocal relapse)2/34 (5.9%) switched to ocrelizumab due to treatment failureAll patients with breakthrough DA were switching from fingolimod
      • Eichau S.
      • Dotor J.
      • Lopez-Ruiz R.
      Cladribine in a real world setting. The real patients.
      (Abs)
      Retrospective observational study from a single center in Spain887 (8.0%) with new T2 lesions in the first year2 (2.3%) switched due to DA-
      • Ellenberger D.
      • Frahm N.
      • Flachenecker P.
      • et al.
      Treatment patterns prior to and post cladribine in patients with multiple sclerosis.
      (Abs)
      Analysis of CladT-treated patients from the German MS Registry (2017–2021)390Within the first 12 months, 58 relapses were recorded in cumulative follow-up time of 320.1 yearsN/S-
      • Forsberg L.
      • Kågström S.
      • Leandersson Å.
      • et al.
      A swedish post-market surveillance study: long-term effectiveness and safety of cladribine tablets (IMSE 10) for patients treated at least 12 months.
      (Abs)
      Swedish post-market surveillance study (IMSE)852/42 (4.8%) relapsed in 12 monthsN/S42 patients treated for ≥12 months
      • Horáková D.
      • Vachová M.
      • Tvaroh A.
      • et al.
      Oral cladribine in the treatment of multiple sclerosis – data from the national registry ReMuS® registry.
      Analysis of Czech ReMuS registry43678.1% 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 6–1212/436 (2.8%) switched due to DA or EDSS progressionIn Year 1, 17.2% of patients had 1 relapse; 3.7% 2 relapses and 0.9% ≥3 relapses; most mild or moderate
      • Kalincik T.
      • Jokubaitis V.
      • Spelman T.
      • et al.
      Cladribine versus fingolimod, natalizumab and interferon β for multiple sclerosis.
      Propensity score–matched analysis from MSBase37Patients free from relapses at end of year 1 ranged from 79–86% (with relapses in 14–21%)N/SPatients received only one course of CladT (the drug was withdrawn in Australia in 2011)
      • Nicholas J.
      • Mackie D.S.
      • Costantino H.
      • et al.
      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.
      (Abs)
      Internet-based survey of patients enrolled in the US MS LifeLines patients support programme616N/S1.0% switched in Year 1-
      • Pfeuffer S.
      • Rolfes L.
      • Hackert J.
      • et al.
      Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres.
      Prospective cohort from two tertiary centers in Germany27040 (14.8%) relapsed within Year 13 (1.1%) switched to ocrelizumab due to ongoing DA in Month 12
      • Rojas J.I.
      • Alonso R.
      • Luetic G.
      • et al.
      Real world data from the argentine MS national registry of patients under cladribine.
      (Abs)
      Sub-study of RelevarEM, a nationwide MS and neuromyelitis optica registry in Argentina (NCT03375177)10295.1% free from relapses (relapses in 4.9%)

      90.2% free from Gd+ lesions
      N/S-
      • Rosengren V.
      • Ekström E.
      • Forsberg L.
      • et al.
      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).
      Swedish post-market surveillance study (IMSE)1405/47 (10.6%) relapsed during first 12 months3.5% discontinued within Year 1 – no reasons provided (one-year drug survival rate = 96.5%)Relapse data only available for 47 patients
      • Santos M.
      • Sequeira J.
      • Santos M.
      • et al.
      Safety and effectiveness of cladribine in multiple sclerosis – clinical experience of five tertiary centers.
      (Abs)
      Observational, multicentric, prospective study of five tertiary hospitals18289% relapse free at 12 months; 11% relapsed

      13 (11%) discontinued

      9 (7.4%) due to DA
      Follow-up data available for 121 patients at 12 months
      • Thakre M.
      • Inshasi J.
      Real world experience of oral immune reconstitution therapy (cladribine) in the treatment of multiple sclerosis in the united arab emirates.
      (Abs)
      UAE real-world cohort881/88 (1.1%) relapsed after 2 months

      1/88 (1.1%) persistent MRI activity at end of year 1
      0 discontinued due to DA

      1 discontinuation due to pregnancy
      -
      • Viitala M.
      • Rauma I.
      • Kuusisto H.
      • et al.
      Characterization of cladribine tablets treated MS patients in Finland.
      (Abs)
      Non-interventional cohort analysis of data from the Finnish MS registry (mean follow up 11 months)1268/55 (14.5%) relapsed – mean time to first relapse 6 months (Q1–Q3 1.2–9.8)3 discontinued (reasons were inefficiency, change of diagnosis and unknown) and 2/55 (3.6%) switchedSubset of patients (n=55) were followed for over a year
      • Ziemssen T.
      • Cepek L.
      • Reifschneider G.
      • et al.
      Evaluation of therapy satisfaction with cladribine tablets in RMS patients – final results of the non-interventional study CLEVER.
      (Abs)
      Non-interventional prospective, multicenter study, CLEVER, conducted in Germany49110% relapsed within 24 weeksN/S-
      Studies reporting prognostic factors for relapses in the first year
      • Annovazzi P.
      • Frau J.
      • Margoni M.
      • et al.
      Two year relapse-free and NEDA status with Cladribine in a real-life population: a multicentre study.
      (Abs)
      Italian multicenter retrospective cohort study (described above)236Relapses 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)N/SHigher baseline ARR predicted clinical activity on treatment (HR 1.9, 95% CI: 1.2–2.9; p=0.04)
      • Möhn N.
      • Skripuletz T.
      • Sühs K.W.
      • et al.
      Therapy with cladribine is efficient and safe in patients previously treated with natalizumab.
      Retrospective chart review in a single center in Germany (median follow up 9.7 months)170/17 (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
      0 discontinued-
      • Nygaard G.O.
      • Torgauten H.
      • Skattebøl L.
      • et al.
      Risk of fingolimod rebound after switching to cladribine or rituximab in multiple sclerosis.
      Retrospective cohort study from two university hospitals in Oslo of patients switching from fingolimod337 (21.1%) had rebound disease following switch from fingolimod to CladT

      N/SYounger age and

      previous high relapse rate were associated with increased risk of rebound in the CladT group
      • Petracca M.
      • Ruggieri S.
      • Barbuti E.
      • et al.
      Predictors of cladribine effectiveness in multiple sclerosis: a real-world, multicenter, two-year follow-up study.
      Retrospective observational analysis of eight tertiary MS centers in Italy (2-year follow-up study)243Patients 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%)

      N/S

      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.
      • Pfeuffer S.
      • Rolfes L.
      • Hackert J.
      • et al.
      Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres.
      Prospective cohort from two tertiary centers in Germany (described above)27012/23 (52.3%) patients switching from natalizumab had rebound DA within first 6 months-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.
      • Zanetta C.
      • Sangalli F.
      • Guerrieri S.
      • et al.
      Efficacy/safety profile of cladribine in an italian real-life cohort of relapsing remitting multiple sclerosis patients.
      Italian real-life cohort60Treatment naive patients were more likely to achieve NEDA-3 with CladT that those switching from other DMTsN/S-
      • Zhong M.
      • Van der Walt A.
      • Hodgkinson S.
      • et al.
      Relapse during the washout period predicts time to relapse after switching to cladribine.
      MSBase registry analysis33317 patients (5.1%) relapsed during the washout period and 24 (7.2%) relapsed within one year of starting CladTOf 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 relapseRelapse 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.
      Other studies of interest/relevance
      • Garbo R.
      • Cutuli D.
      • Lorenzut S.
      • et al.
      Opportunities and obstacles associated with sequential immune reconstitution therapy for multiple sclerosis: a case report.
      Case report of a patient experiencing considerable DA during first year of treatment with CladT1Patient switched from fingolimod after a 9-week washout period

      Relapse and MRI activity (new Gd+ enhancing lesions)
      Patient switched to alemtuzumab
      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 3Summary of results for Q2.
      Refs.Study descriptionNDisease activity (clinical or MRI)Switches/additional courseComments
      Studies reporting frequency and management of relapses in Years 3 and 4
      • Annovazzi P.
      • Prosperini L.
      • Capuano R.
      • et al.
      Relapse-free and neda status with cladribine in a real life population: a multicentre study.
      Italian multicenter retrospective cohort study (mean follow up 21.1 +7.6 months)23681.3% relapse free at follow up (18.7% relapsed)

      56.6% reached NEDA at follow up
      N/S-
      • Ellenberger D.
      • Frahm N.
      • Flachenecker P.
      • et al.
      Treatment patterns prior to and post cladribine in patients with multiple sclerosis.
      (Abs)
      Analysis of CladT-treated patients from the German MS Registry (2017–2021)390Within 12–36 months after CladT initiation, 50 relapses were recorded in cumulative follow-up time of 289.5 yearsAtypical cessation of CladT was reported in 23 patients during the 4-year observation period; insufficient efficacy was the reason in 17 (73.9%) patientsIn 30 patients who started another DMT after cessation of CladT, 18 (60%) switched to ocrelizumab
      • Oreja-Guevara C.
      • Gómez-Estévez I.
      • Alba-Suárez E.
      • et al.
      4-year follow-up of multiple sclerosis patients treated with cladribine: clinical outcomes and third-year course.
      (Abs/poster)
      Observational prospective study in Spain10088% relapse free in Years 3/4

      (12% relapsed)
      N/SOf 7 patients who relapsed, 6 received an additional (third) course of CladT
      • Patti F.
      • Visconti A.
      • Capacchione A.
      • et al.
      Long-term effectiveness in patients previously treated with cladribine tablets: a real-world analysis of the Italian multiple sclerosis registry (CLARINET-MS).
      CLARINET-MS – a non-interventional, retrospective, exploratory analysis of patients from the Italian MS Registry8084.8% relapse free 12 months after last dose (Year 3)

      (15.2% relapsed)
      Probability of not initiating another DMT 12 months after the last dose was 79.4%Includes 34 patients from CLARITY study
      • Pfeuffer S.
      • Rolfes L.
      • Hackert J.
      • et al.
      Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres.
      Prospective cohort from two tertiary centers in Germany2705/142 patients received additional courses of CladT (months 24, 25, 28, 34 and 36, respectively) due to ongoing DA142 patients in the cohort passed month 24
      Other studies of interest/relevance
      • Lizak N.
      • Hodgkinson S.
      • Butler E.
      • et al.
      Real-world effectiveness of cladribine for Australian patients with multiple sclerosis: An MSBase registry substudy.
      Australian Product Familiarisation Program with a median follow up of 3.5 years90Over 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 relapseThe median (95% CI) time to next DMT in the RRMS cohort was 1.16 years (1.06–1.79)

      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
      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 4Summary of results for Q3.
      ReferenceStudy descriptionNDisease activity (clinical or MRI)Switches/additional courseComments
      Studies reporting frequency and management of relapses beyond Year 4
      • Dive D.
      • Ernon C.
      • Brouwers A.
      Cladribine: 14 years atrophy and clinical follow-up.
      (Abs)
      Long-term outcomes in patients from single center in Belgium included in the CLARITY and CLARITY-EXT studies10No additional therapy required in 70% patients – remained NEDA-3

      30% relapsed within 5 years
      30% switched due to DA (within 5 years)14.4 years mean time of follow up
      • Giovannoni G.
      • Aydemir A.
      • Verdun Di Cantogno E.
      • et al.
      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.


      CLASSIC-MS – an exploratory, low-interventional, ambispective phase IV study of patients previously enrolled into phase III parent trials394No evidence of disease reactivation was observed in 50.3% (198/394) of patients exposed to CladT in 4 years since last dose (Year 5)55.8% (220/394) of the exposed cohort received no subsequent DMT during follow upMedian follow up of 10.9 years since last dose
      • Patti F.
      • Visconti A.
      • Capacchione A.
      • et al.
      Long-term effectiveness in patients previously treated with cladribine tablets: a real-world analysis of the Italian multiple sclerosis registry (CLARINET-MS).
      CLARINET-MS (described above)8066.2% relapse free 36 months after last dose

      58.9% relapse free 60 months after last dose

      Probability of not initiating another disease-modifying treatment 36 and 60 months after the last dose was 55.6% and 32.4%, respectivelyMedian time to

      treatment change from last dose in CLARITY

      patients – 37.1 months
      • Yamout B.
      • Sormani M.P.
      • Hajj T.
      • et al.
      Long term effectiveness of Cladribine in patients enrolled in the CLARITY trial: real world experience from the lebanese cohort.
      (Abs)
      Long-term outcomes in patients from single center in Lebanon included in the CLARITY and CLARITY-EXT studies243/22 patients had an EDSS increase over the whole follow-up period, 13 had a decrease and 6 were stable13/22 patients started a new DMT during follow up; reasons for these treatment switches are not providedFollow-up time was 9.8 years
      Other studies of interest/relevance
      • Moccia M.
      • Lanzillo R.
      • Petruzzo M.
      • et al.
      Single-center 8-years clinical follow-up of Cladribine-treated patients from phase 2 and 3 trials.
      Retrospective analysis on prospectively collected data from a single center. Follow up of patients from the phase II/III trials for CladT13Time to post-trial relapse 5.4 ± 3.4 years for CladTApproximately 70% of patients were treated with an additional DMT after trial termination, of whom ∼20% received a second-line post-trial DMTFrom 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)
      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.

      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 P.
      • Prosperini L.
      • Capuano R.
      • et al.
      Relapse-free and neda status with cladribine in a real life population: a multicentre study.
      ;
      • Bain J.
      • Oh J.
      • Jones A.
      • et al.
      Early real-world safety, tolerability, and efficacy of cladribine tablets: a single center experience.
      ;
      • Barbuti E.
      • Ianniello A.
      • Nistri R.
      • et al.
      Real world experience with cladribine at S. Andrea hospital of Rome.
      ;
      • Barros A.
      • Santos M.
      • Sequeira J.
      • et al.
      Effectiveness of cladribine in multiple sclerosis – clinical experience of two tertiary centers.
      ;
      • Celius E.G.
      • Berg-Hansen P.
      Cladribine as a treatment of multiple sclerosis, real world experience.
      ;
      • Ciampi E.
      • Soler B.
      • Uribe-San-Martin R.
      • et al.
      Real-world evidence of immune reconstitution therapies: use of Cladribine and Alemtuzumab in Chile.
      ;
      • Forsberg L.
      • Kågström S.
      • Leandersson Å.
      • et al.
      A swedish post-market surveillance study: long-term effectiveness and safety of cladribine tablets (IMSE 10) for patients treated at least 12 months.
      ;
      • Horáková D.
      • Vachová M.
      • Tvaroh A.
      • et al.
      Oral cladribine in the treatment of multiple sclerosis – data from the national registry ReMuS® registry.
      ;
      • Kalincik T.
      • Jokubaitis V.
      • Spelman T.
      • et al.
      Cladribine versus fingolimod, natalizumab and interferon β for multiple sclerosis.
      ;
      • Pfeuffer S.
      • Rolfes L.
      • Hackert J.
      • et al.
      Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres.
      ,
      • Rojas J.I.
      • Alonso R.
      • Luetic G.
      • et al.
      Real world data from the argentine MS national registry of patients under cladribine.
      ;
      • Rosengren V.
      • Ekström E.
      • Forsberg L.
      • et al.
      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).
      ;
      • Santos M.
      • Sequeira J.
      • Santos M.
      • et al.
      Safety and effectiveness of cladribine in multiple sclerosis – clinical experience of five tertiary centers.
      ,
      • Thakre M.
      • Inshasi J.
      Real world experience of oral immune reconstitution therapy (cladribine) in the treatment of multiple sclerosis in the united arab emirates.
      ;
      • Viitala M.
      • Rauma I.
      • Kuusisto H.
      • et al.
      Characterization of cladribine tablets treated MS patients in Finland.
      ;
      • Ziemssen T.
      • Cepek L.
      • Reifschneider G.
      • et al.
      Evaluation of therapy satisfaction with cladribine tablets in RMS patients – final results of the non-interventional study CLEVER.
      ) and five reported MRI activity in the first year (
      • Barbuti E.
      • Ianniello A.
      • Nistri R.
      • et al.
      Real world experience with cladribine at S. Andrea hospital of Rome.
      ;
      • Horáková D.
      • Vachová M.
      • Tvaroh A.
      • et al.
      Oral cladribine in the treatment of multiple sclerosis – data from the national registry ReMuS® registry.
      ;
      • Rojas J.I.
      • Alonso R.
      • Luetic G.
      • et al.
      Real world data from the argentine MS national registry of patients under cladribine.
      ;
      • Thakre M.
      • Inshasi J.
      Real world experience of oral immune reconstitution therapy (cladribine) in the treatment of multiple sclerosis in the united arab emirates.
      ;
      • Eichau S.
      • Dotor J.
      • Lopez-Ruiz R.
      Cladribine in a real world setting. The real patients.
      ). The proportion of patients relapsing within the first 6 and 12 months ranged from 1.1 to 10% (
      • Bain J.
      • Oh J.
      • Jones A.
      • et al.
      Early real-world safety, tolerability, and efficacy of cladribine tablets: a single center experience.
      ;
      • Celius E.G.
      • Berg-Hansen P.
      Cladribine as a treatment of multiple sclerosis, real world experience.
      ;
      • Thakre M.
      • Inshasi J.
      Real world experience of oral immune reconstitution therapy (cladribine) in the treatment of multiple sclerosis in the united arab emirates.
      ;
      • Ziemssen T.
      • Cepek L.
      • Reifschneider G.
      • et al.
      Evaluation of therapy satisfaction with cladribine tablets in RMS patients – final results of the non-interventional study CLEVER.
      ) and 4.8 to 21.9% (
      • Annovazzi P.
      • Prosperini L.
      • Capuano R.
      • et al.
      Relapse-free and neda status with cladribine in a real life population: a multicentre study.
      ;
      • Barbuti E.
      • Ianniello A.
      • Nistri R.
      • et al.
      Real world experience with cladribine at S. Andrea hospital of Rome.
      ;
      • Barros A.
      • Santos M.
      • Sequeira J.
      • et al.
      Effectiveness of cladribine in multiple sclerosis – clinical experience of two tertiary centers.
      ;
      • Ciampi E.
      • Soler B.
      • Uribe-San-Martin R.
      • et al.
      Real-world evidence of immune reconstitution therapies: use of Cladribine and Alemtuzumab in Chile.
      ,
      • Forsberg L.
      • Kågström S.
      • Leandersson Å.
      • et al.
      A swedish post-market surveillance study: long-term effectiveness and safety of cladribine tablets (IMSE 10) for patients treated at least 12 months.
      ;
      • Horáková D.
      • Vachová M.
      • Tvaroh A.
      • et al.
      Oral cladribine in the treatment of multiple sclerosis – data from the national registry ReMuS® registry.
      ;
      • Kalincik T.
      • Jokubaitis V.
      • Spelman T.
      • et al.
      Cladribine versus fingolimod, natalizumab and interferon β for multiple sclerosis.
      ;
      • Pfeuffer S.
      • Rolfes L.
      • Hackert J.
      • et al.
      Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres.
      ,
      • Rojas J.I.
      • Alonso R.
      • Luetic G.
      • et al.
      Real world data from the argentine MS national registry of patients under cladribine.
      ;
      • Rosengren V.
      • Ekström E.
      • Forsberg L.
      • et al.
      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).
      ;
      • Santos M.
      • Sequeira J.
      • Santos M.
      • et al.
      Safety and effectiveness of cladribine in multiple sclerosis – clinical experience of five tertiary centers.
      ;
      • Thakre M.
      • Inshasi J.
      Real world experience of oral immune reconstitution therapy (cladribine) in the treatment of multiple sclerosis in the united arab emirates.
      ;
      • Viitala M.
      • Rauma I.
      • Kuusisto H.
      • et al.
      Characterization of cladribine tablets treated MS patients in Finland.
      ), respectively.
      Details of MRI outcomes (T2 and gadolinium enhancing [Gd+] T1) varied among studies.
      • Barbuti E.
      • Ianniello A.
      • Nistri R.
      • et al.
      Real world experience with cladribine at S. Andrea hospital of Rome.
      reported ≥ 1 new lesion in 16.7% of patients (n=60).
      • Eichau S.
      • Dotor J.
      • Lopez-Ruiz R.
      Cladribine in a real world setting. The real patients.
      reported 8.0% of patients with new T2 lesions in the first year and
      • Rojas J.I.
      • Alonso R.
      • Luetic G.
      • et al.
      Real world data from the argentine MS national registry of patients under cladribine.
      observed new Gd+ lesions in 9.8% of patients. Non-specified MRI activity was reported in 10.1% of patients by
      • Horáková D.
      • Vachová M.
      • Tvaroh A.
      • et al.
      Oral cladribine in the treatment of multiple sclerosis – data from the national registry ReMuS® registry.
      and 1.1% of patients in a real-world UAE cohort (
      • Thakre M.
      • Inshasi J.
      Real world experience of oral immune reconstitution therapy (cladribine) in the treatment of multiple sclerosis in the united arab emirates.
      ). 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 E.
      • Ianniello A.
      • Nistri R.
      • et al.
      Real world experience with cladribine at S. Andrea hospital of Rome.
      ;
      • Barros A.
      • Santos M.
      • Sequeira J.
      • et al.
      Effectiveness of cladribine in multiple sclerosis – clinical experience of two tertiary centers.
      ;
      • Ciampi E.
      • Soler B.
      • Uribe-San-Martin R.
      • et al.
      Real-world evidence of immune reconstitution therapies: use of Cladribine and Alemtuzumab in Chile.
      ;
      • Horáková D.
      • Vachová M.
      • Tvaroh A.
      • et al.
      Oral cladribine in the treatment of multiple sclerosis – data from the national registry ReMuS® registry.
      ;
      • Pfeuffer S.
      • Rolfes L.
      • Hackert J.
      • et al.
      Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres.
      ;
      • Santos M.
      • Sequeira J.
      • Santos M.
      • et al.
      Safety and effectiveness of cladribine in multiple sclerosis – clinical experience of five tertiary centers.
      ;
      • Thakre M.
      • Inshasi J.
      Real world experience of oral immune reconstitution therapy (cladribine) in the treatment of multiple sclerosis in the united arab emirates.
      ;
      • Eichau S.
      • Dotor J.
      • Lopez-Ruiz R.
      Cladribine in a real world setting. The real patients.
      ). Two studies reported subsequent disease-modifying therapies (DMTs);
      • Ciampi E.
      • Soler B.
      • Uribe-San-Martin R.
      • et al.
      Real-world evidence of immune reconstitution therapies: use of Cladribine and Alemtuzumab in Chile.
      reported that 2/34 (5.9%) of patients switched to ocrelizumab due to CladT treatment failure and similarly,
      • Pfeuffer S.
      • Rolfes L.
      • Hackert J.
      • et al.
      Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres.
      detailed a switch to ocrelizumab 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 P.
      • Frau J.
      • Margoni M.
      • et al.
      Two year relapse-free and NEDA status with Cladribine in a real-life population: a multicentre study.
      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 S.
      • Rolfes L.
      • Hackert J.
      • et al.
      Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres.
      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 N.
      • Skripuletz T.
      • Sühs K.W.
      • et al.
      Therapy with cladribine is efficient and safe in patients previously treated with natalizumab.
      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 C.
      • Sangalli F.
      • Guerrieri S.
      • et al.
      Efficacy/safety profile of cladribine in an italian real-life cohort of relapsing remitting multiple sclerosis patients.
      ) and retention of NEDA-3 status correlated with a lower number of prior therapies (
      • Petracca M.
      • Ruggieri S.
      • Barbuti E.
      • et al.
      Predictors of cladribine effectiveness in multiple sclerosis: a real-world, multicenter, two-year follow-up study.
      ) in real-world analyses of Italian patients.
      • Zhong M.
      • Van der Walt A.
      • Hodgkinson S.
      • et al.
      Relapse during the washout period predicts time to relapse after switching to cladribine.
      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 M.
      • Van der Walt A.
      • Hodgkinson S.
      • et al.
      Relapse during the washout period predicts time to relapse after switching to cladribine.
      ).
      • Nygaard G.O.
      • Torgauten H.
      • Skattebøl L.
      • et al.
      Risk of fingolimod rebound after switching to cladribine or rituximab in multiple sclerosis.
      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 S.
      • Rolfes L.
      • Hackert J.
      • et al.
      Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres.
      ;
      • Annovazzi P.
      • Frau J.
      • Margoni M.
      • et al.
      Two year relapse-free and NEDA status with Cladribine in a real-life population: a multicentre study.
      ;
      • Ellenberger D.
      • Frahm N.
      • Flachenecker P.
      • et al.
      Treatment patterns prior to and post cladribine in patients with multiple sclerosis.
      ;
      • Oreja-Guevara C.
      • Gómez-Estévez I.
      • Alba-Suárez E.
      • et al.
      4-year follow-up of multiple sclerosis patients treated with cladribine: clinical outcomes and third-year course.
      ;
      • Patti F.
      • Visconti A.
      • Capacchione A.
      • et al.
      Long-term effectiveness in patients previously treated with cladribine tablets: a real-world analysis of the Italian multiple sclerosis registry (CLARINET-MS).
      ). 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 C.
      • Gómez-Estévez I.
      • Alba-Suárez E.
      • et al.
      4-year follow-up of multiple sclerosis patients treated with cladribine: clinical outcomes and third-year course.
      reported that 6/7 patients who relapsed in Year 3/4 received an additional (third) course of CladT.
      • Pfeuffer S.
      • Rolfes L.
      • Hackert J.
      • et al.
      Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres.
      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; ocrelizumab was the most common subsequent DMT (18/30) in those initiating another treatment (
      • Ellenberger D.
      • Frahm N.
      • Flachenecker P.
      • et al.
      Treatment patterns prior to and post cladribine in patients with multiple sclerosis.
      ). In the Italian MS registry, the probability of switching to another DMT at the beginning of Year 3 was around 20% (
      • Patti F.
      • Visconti A.
      • Capacchione A.
      • et al.
      Long-term effectiveness in patients previously treated with cladribine tablets: a real-world analysis of the Italian multiple sclerosis registry (CLARINET-MS).
      ). 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 considerations 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 F.
      • Visconti A.
      • Capacchione A.
      • et al.
      Long-term effectiveness in patients previously treated with cladribine tablets: a real-world analysis of the Italian multiple sclerosis registry (CLARINET-MS).
      ;
      • Dive D.
      • Ernon C.
      • Brouwers A.
      Cladribine: 14 years atrophy and clinical follow-up.
      ;
      • Giovannoni G.
      • Aydemir A.
      • Verdun Di Cantogno E.
      • et al.
      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.
      ;
      • Yamout B.
      • Sormani M.P.
      • Hajj T.
      • et al.
      Long term effectiveness of Cladribine in patients enrolled in the CLARITY trial: real world experience from the lebanese cohort.
      ) 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 F.
      • Visconti A.
      • Capacchione A.
      • et al.
      Long-term effectiveness in patients previously treated with cladribine tablets: a real-world analysis of the Italian multiple sclerosis registry (CLARINET-MS).
      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 D.
      • Ernon C.
      • Brouwers A.
      Cladribine: 14 years atrophy and clinical follow-up.
      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 B.
      • Sormani M.P.
      • Hajj T.
      • et al.
      Long term effectiveness of Cladribine in patients enrolled in the CLARITY trial: real world experience from the lebanese cohort.
      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 G.
      • Aydemir A.
      • Verdun Di Cantogno E.
      • et al.
      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.
      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 M.
      • Lanzillo R.
      • Petruzzo M.
      • et al.
      Single-center 8-years clinical follow-up of Cladribine-treated patients from phase 2 and 3 trials.
      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 N.
      • Hodgkinson S.
      • Butler E.
      • et al.
      Real-world effectiveness of cladribine for Australian patients with multiple sclerosis: An MSBase registry substudy.
      . 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 C.
      • Gómez-Estévez I.
      • Alba-Suárez E.
      • et al.
      4-year follow-up of multiple sclerosis patients treated with cladribine: clinical outcomes and third-year course.
      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 S.
      • Rolfes L.
      • Hackert J.
      • et al.
      Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres.
      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 H.
      • Spelman T.
      • Hodgkinson S.
      • et al.
      Outcomes after late Cladribine re-dosing in the Australian MSBase cohort.
      , 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 T.
      • Cook S.
      • Comi G.
      • et al.
      Long-term safety data from the cladribine tablets clinical development program in multiple sclerosis.
      ). 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 T.
      • Cook S.
      • Comi G.
      • et al.
      Long-term safety data from the cladribine tablets clinical development program in multiple sclerosis.
      ). 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 (;
      • Cook S.
      • Leist T.
      • Comi G.
      • et al.
      Safety of cladribine tablets in the treatment of patients with multiple sclerosis: an integrated analysis.
      ). Rates of malignancies were similar to those of a GLOBOCAN matched reference population, and to those observed with other DMTs (
      • Cook S.
      • Leist T.
      • Comi G.
      • et al.
      Safety of cladribine tablets in the treatment of patients with multiple sclerosis: an integrated analysis.
      ).
      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 G.
      • Sorensen P.S.
      • Cook S.
      • et al.
      Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study.
      ). 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 (). 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 S.
      • Comi G.
      • Giovannoni G.
      • et al.
      Rates of lymphopenia year-by-year in patients with relapsing multiple sclerosis treated and retreated with cladribine tablets 3.5 mg/kg.
      ).

      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 S.
      • Rolfes L.
      • Hackert J.
      • et al.
      Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres.
      ;
      • Oreja-Guevara C.
      • Gómez-Estévez I.
      • Alba-Suárez E.
      • et al.
      4-year follow-up of multiple sclerosis patients treated with cladribine: clinical outcomes and third-year course.
      ). 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 B.
      • Erwin A.A.
      • Stevens J.
      • et al.
      Fingolimod rebound: a review of the clinical experience and management considerations.
      ;
      • Prosperini L.
      • Kinkel R.P.
      • Miravalle A.A.
      • et al.
      Post-natalizumab disease reactivation in multiple sclerosis: systematic review and meta-analysis.
      ) 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 E.
      • Ianniello A.
      • Nistri R.
      • et al.
      Real world experience with cladribine at S. Andrea hospital of Rome.
      ;
      • Barros A.
      • Santos M.
      • Sequeira J.
      • et al.
      Effectiveness of cladribine in multiple sclerosis – clinical experience of two tertiary centers.
      ;
      • Ciampi E.
      • Soler B.
      • Uribe-San-Martin R.
      • et al.
      Real-world evidence of immune reconstitution therapies: use of Cladribine and Alemtuzumab in Chile.
      ;
      • Horáková D.
      • Vachová M.
      • Tvaroh A.
      • et al.
      Oral cladribine in the treatment of multiple sclerosis – data from the national registry ReMuS® registry.
      ;
      • Pfeuffer S.
      • Rolfes L.
      • Hackert J.
      • et al.
      Effectiveness and safety of cladribine in MS: Real-world experience from two tertiary centres.
      ;
      • Santos M.
      • Sequeira J.
      • Santos M.
      • et al.
      Safety and effectiveness of cladribine in multiple sclerosis – clinical experience of five tertiary centers.
      ;
      • Thakre M.
      • Inshasi J.
      Real world experience of oral immune reconstitution therapy (cladribine) in the treatment of multiple sclerosis in the united arab emirates.
      ;
      • Eichau S.
      • Dotor J.
      • Lopez-Ruiz R.
      Cladribine in a real world setting. The real patients.
      ) 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 B.
      • Erwin A.A.
      • Stevens J.
      • et al.
      Fingolimod rebound: a review of the clinical experience and management considerations.
      ) as well as applying shorter washout periods upon switching from anti-lymphocyte trafficking agents (
      • Pardo G.
      • Jones DE.
      The sequence of disease-modifying therapies in relapsing multiple sclerosis: safety and immunologic considerations.
      ;
      • Goncuoglu C.
      • Tuncer A.
      • Bayraktar-Ekincioglu A.
      • et al.
      Factors associated with fingolimod rebound: a single center real-life experience.
      ;
      • Korsen M.
      • Pfeuffer S.
      • Rolfes L.
      • et al.
      Neurological update: treatment escalation in multiple sclerosis patients refractory to fingolimod-potentials and risks of subsequent highly active agents.
      ).
      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 J.
      • Rommer PS.
      Immunological consequences of “immune reconstitution therapy” in multiple sclerosis: a systematic review.
      ;
      • Sorensen P.S.
      • Sellebjerg F.
      Pulsed immune reconstitution therapy in multiple sclerosis.
      ). 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 F.
      • Visconti A.
      • Capacchione A.
      • et al.
      Long-term effectiveness in patients previously treated with cladribine tablets: a real-world analysis of the Italian multiple sclerosis registry (CLARINET-MS).
      ;
      • Dive D.
      • Ernon C.
      • Brouwers A.
      Cladribine: 14 years atrophy and clinical follow-up.
      ;
      • Giovannoni G.
      • Aydemir A.
      • Verdun Di Cantogno E.
      • et al.
      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.
      ;
      • Yamout B.
      • Sormani M.P.
      • Hajj T.
      • et al.
      Long term effectiveness of Cladribine in patients enrolled in the CLARITY trial: real world experience from the lebanese cohort.
      ). 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 F.D.
      • Häring D.A.
      • Ganjgahi H.
      • et al.
      How patients with multiple sclerosis acquire disability.
      ). 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 S.
      • Munafo A.
      • Ben-Amor A.F.
      • et al.
      Predicting disease activity in patients with multiple sclerosis: an explainable machine-learning approach in the Mavenclad trials.
      ). 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 G.
      • Singer B.A.
      • Issard D.
      • et al.
      Durability of no evidence of disease activity-3 (NEDA-3) in patients receiving cladribine tablets: The CLARITY extension study.
      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 L.
      No evidence of disease activity (NEDA) in multiple sclerosis - shifting the goal posts.
      ;
      • Smith A.L.
      • Cohen J.A.
      • Hua LH.
      Therapeutic targets for multiple sclerosis: current treatment goals and future directions.
      ).
      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 S.G.
      • Bayas A.
      • Kallmann B.
      • et al.
      Long-term management of multiple sclerosis patients treated with cladribine tablets beyond year 4.
      ). 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 K.
      • Zasybska A.
      • Pietruczuk A.
      • et al.
      Long-term safety and efficacy of subcutaneous cladribine used in increased dosage in patients with relapsing multiple sclerosis: 20-year observational study.
      ). 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 K.
      • Zasybska A.
      • Pietruczuk A.
      • et al.
      Long-term safety and efficacy of subcutaneous cladribine used in increased dosage in patients with relapsing multiple sclerosis: 20-year observational study.
      ). 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 K.
      • Marta M.
      • Gnanapavan K.
      • et al.
      Disease activity after cladribine immune reconstitution therapy: to repeat or to retreat?.
      ). 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 K.
      • Marta M.
      • Gnanapavan K.
      • et al.
      Disease activity after cladribine immune reconstitution therapy: to repeat or to retreat?.
      ). 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 S.
      • Leist T.
      • Comi G.
      • et al.
      Safety of cladribine tablets in the treatment of patients with multiple sclerosis: an integrated analysis.
      ;
      • Leist T.
      • Cook S.
      • Comi G.
      • et al.
      Long-term safety data from the cladribine tablets clinical development program in multiple sclerosis.
      ). 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 A.N.
      • Boyko OV.
      Cladribine tablets’ potential role as a key example of selective immune reconstitution therapy in multiple sclerosis.
      ). 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 A.N.
      • Boyko OV.
      Cladribine tablets’ potential role as a key example of selective immune reconstitution therapy in multiple sclerosis.
      ;
      • Giovannoni G.
      • Mathews J.
      Cladribine tablets for relapsing-remitting multiple sclerosis: a clinician’s review.
      ). 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 G.
      • Comi G.
      • Cook S.
      • et al.
      A placebo-controlled trial of oral cladribine for relapsing multiple sclerosis.
      ,
      • Giovannoni G.
      • Sorensen P.S.
      • Cook S.
      • et al.
      Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study.
      ). 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.

      Appendix. Supplementary materials

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