If you don't remember your password, you can reset it by entering your email address and clicking the Reset Password button. You will then receive an email that contains a secure link for resetting your password
If the address matches a valid account an email will be sent to __email__ with instructions for resetting your password
Department of Neurology and Center of Clinical Neuroscience, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
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.
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 (
). The lowest absolute lymphocyte counts occur approximately 2–3 months after the start of each treatment course, followed by a gradual recovery (immune reconstitution) (
). 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 (
Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study.
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% (
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.
Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study.
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.
Efficacy of cladribine tablets in high disease activity subgroups of patients with relapsing multiple sclerosis: A post hoc analysis of the CLARITY study.
Analysis of frequency and severity of relapses in multiple sclerosis patients treated with cladribine tablets or placebo: the CLARITY and CLARITY extension studies.
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 (
). 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 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).
Q1: 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
Following review of the results and data from the SLR, the SC drafted, refined and agreed on expert opinion statements for each question. For questions 2 and 4, opinions differed within the group; therefore, voting on different versions of draft statements was performed via an online survey. The options with most votes were carried forward. Voting options and results are provided in Tables S1 and S2.
3. Results
The process of study identification and selection is summarised in Fig. 1. Electronic searches yielded a total of 3163 hits after removal of duplicates (n=470), which were screened in the first pass, based on the predefined criteria. A total of 447 references (including congress search results) were included for the full text review, which resulted in identification of 226 relevant publications then reviewed by an expert. Of 49 publications selected for inclusion, eight were common between the questions and six were further excluded due to insufficient data/relevance. Finally, 35 publications reporting the RWE data were selected for inclusion.
Most studies (n=25) were summarised only as abstracts. Studies included those from: Italy (n=9); Germany (n=4); international (n=3); Canada, Norway, Portugal, Spain and Sweden (all n=2); Australia, Argentina, Belgium, Lebanon, Chile, the Czech Republic, Finland, the United Arab Emirates (UAE), and the United Kingdom (UK) (all n=1). The number of patients ranged between 1 and 782, and the median/mean follow up (when reported) ranged from 9 months to 14.4 years. A summary of the relevant real-world studies for each question is provided below and in 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 description
N
Disease activity (clinical or MRI)
Discontinuation/switches
Comments
Studies reporting frequency and management of relapses in the first year
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.
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.
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).
Retrospective observational analysis of eight tertiary MS centers in Italy (2-year follow-up study)
243
Patients with a higher number of prior therapies were less likely to retain NEDA-3 status on CladT Mean number (range) of previous DMTs was 1.5 (0–7) Majority of patients were treatment naive (29.3%) or switched from DMF (29.7%)
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.
Prospective cohort from two tertiary centers in Germany (described above)
270
12/23 (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.
17 patients (5.1%) relapsed during the washout period and 24 (7.2%) relapsed within one year of starting CladT
Of those who relapsed during their washout period, seven (41.2%) also relapsed on CladT, compared to 5.4% of those who did not experience a washout relapse
Relapse on CladT was predicted by washout relapse (HR=7.18, 95% CI = 1.48-34.88, p=0.015) and younger age (HR=0.96, 95% CI 0.93-0.99, p=0.038). Washout durations longer than two months increased relapse risk during the washout but did not alter relapse risk on CladT. Cox proportional hazard regression models were used to analyze time to first relapse in the first year of CladT.
Analysis of CladT-treated patients from the German MS Registry (2017–2021)
390
Within 12–36 months after CladT initiation, 50 relapses were recorded in cumulative follow-up time of 289.5 years
Atypical cessation of CladT was reported in 23 patients during the 4-year observation period; insufficient efficacy was the reason in 17 (73.9%) patients
In 30 patients who started another DMT after cessation of CladT, 18 (60%) switched to ocrelizumab
Long-term effectiveness in patients previously treated with cladribine tablets: a real-world analysis of the Italian multiple sclerosis registry (CLARINET-MS).
Australian Product Familiarisation Program with a median follow up of 3.5 years
90
Over two-thirds of patients with RRMS (67%; n=47/70) received an alternative DMT after CladT during the follow-up period, 26% of whom (n=12/47) experienced relapses prior to switching, but 74% (35/47) switched before a relapse
The 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.
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.
Long-term effectiveness in patients previously treated with cladribine tablets: a real-world analysis of the Italian multiple sclerosis registry (CLARINET-MS).
Retrospective analysis on prospectively collected data from a single center. Follow up of patients from the phase II/III trials for CladT
13
Time to post-trial relapse 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
From baseline to Year 4, patients treated with CladT showed reduced relapse risk, vs placebo (HR=0.062, 95% CI 0.004–0.937; p=0.045), while no differences were found from Year 4 to Year 8 (HR=4.006, 95% CI 0.415–38.636; p=0.230)
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 (
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).
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).
). 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% (
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.
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.
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,
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 (
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) (
Long-term effectiveness in patients previously treated with cladribine tablets: a real-world analysis of the Italian multiple sclerosis registry (CLARINET-MS).
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.
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 (
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 (
Long-term effectiveness in patients previously treated with cladribine tablets: a real-world analysis of the Italian multiple sclerosis registry (CLARINET-MS).
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.
) 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.
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.
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.
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
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.
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
. 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.
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.
, 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) (
). 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 (
). 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 (
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) (
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 (
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 (
). 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 (
) 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 (
) 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 (
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 (
). 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 (
Long-term effectiveness in patients previously treated with cladribine tablets: a real-world analysis of the Italian multiple sclerosis registry (CLARINET-MS).
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.
). 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 (
). 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 (
). 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,
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 (
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 (
). 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 (
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 (
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 (
). 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 (
). 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 (
). 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 (
). 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 (
). 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 (
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.
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.
Analysis of frequency and severity of relapses in multiple sclerosis patients treated with cladribine tablets or placebo: the CLARITY and CLARITY extension studies.
Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study.
Efficacy of cladribine tablets in high disease activity subgroups of patients with relapsing multiple sclerosis: A post hoc analysis of the CLARITY study.
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: long-term efficacy and real-world treatment patterns for patients with relapsing multiple sclerosis who received cladribine tablets in phase III parent trials.
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.
Neurological update: treatment escalation in multiple sclerosis patients refractory to fingolimod-potentials and risks of subsequent highly active agents.
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.
Long-term effectiveness in patients previously treated with cladribine tablets: a real-world analysis of the Italian multiple sclerosis registry (CLARINET-MS).
Long-term safety and efficacy of subcutaneous cladribine used in increased dosage in patients with relapsing multiple sclerosis: 20-year observational study.
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).
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.
00963-4&id=gr1.jpg){kind=link}