Is therapy-free remission a realistic goal with cladribine tablets in multiple sclerosis? New insights into the mechanism of action and clinical implications of immune reconstitution with cladribine tablets in MS therapy

Abstract

Oral cladribine is a highly effective pulsed selective immune reconstitution therapy (SIRT) that received approval for the treatment of relapsing multiple sclerosis (RMS) in 2017. The concept of SIRT is characterized by brief exposure to active substances with long-term effectiveness, repopulation of lymphocytes, and maintenance of immune competence. In consequence, cladribine tablets allow patients to enter a prolonged treatment-free period, which offers time windows for family planning and vaccinations. Long-term control of disease activity has been linked to the sustained reduction of memory B cells. Based on more than 17 years of follow-up, the favorable safety profile is characterized by manageable front loading side effects and a low cumulative risk. Overall, therapy with cladribine tablets is associated with a low monitoring burden and leads to high treatment satisfaction. Meanwhile, 15 years after primary results from the pivotal trial were published, a vast amount of new data has emerged, including central effects of cladribine tablets. This narrative review discusses existing and emerging efficacy and safety data for cladribine tablets in MS and links these learnings to different patient profiles encountered in clinical practice. These include young patients with newly diagnosed RMS, young patients with highly active disease, and older patients switching from anti-CD20 antibodies or spingosine-1-phosphate modulators.

Introduction

Oral cladribine is a highly effective pulsed selective immune reconstitution therapy that received approval for the treatment of relapsing multiple sclerosis (RMS) in 2017. Since then, long-term clinical experience has been gained in a large number of people with MS, and real-world data confirmed the positive benefit-risk profile established in clinical trials. By June 2025, a total of 131,017 patients, amounting to 367,021 patient-years, have been treated with cladribine tablets since market authorization [Merck, Data on file]. Unlike maintenance treatments, immune reconstitution therapies (IRTs) use short dosing periods to induce long-term immunological changes. As such, a full treatment course of cladribine tablets comprises two treatment cycles of eight to ten treatment days given one year apart, followed by two treatment-free years. At its core, immune reconstitution describes the restoration of a fully competent immune system following one or more cycles of lymphocyte depletion. During the subsequent reconstitution phase, the immune system recovers; immune competence—defined as the ability to fight infections (including opportunistic ones), generate a strong vaccine response, and perform tumor surveillance—is regained. Cladribine is considered a selective IRT (SIRT) because its depleting effect is limited mainly to B and T cells, with a significantly stronger impact on B cells. The therapeutic effect is hypothesized to be driven by the combined benefit of reducing pathogenic lymphocytes and the emergence of a naive lymphocyte population during regeneration. These long-term qualitative changes in immune function are considered the prerequisite for sustained efficacy [1].

Originally developed as continuous treatment, approval was based on the results of the randomized controlled trial CLARITY (NCT00213135) in patients with active relapsing–remitting MS [2, 3]. Compared to placebo, the later approved dose of cladribine tablets (3.5 mg/kg) demonstrated benefits in terms of significant reductions in annualized relapse rate (ARR) at 96 weeks, risk of 3-month sustained disability progression, and lesion counts on brain magnetic resonance imaging (MRI). The most commonly reported adverse event (AE) was mild (800–1000 × 10⁹ cells/L) to moderate lymphopenia (500–800 × 10⁹ cells/L), an anticipated consequence due to the pharmacological properties of cladribine and the selective depletion of lymphocytes [3]. The results of the CLARITY Extension trial (NCT0064153) provided evidence of long-term disease control without further treatment cycles in year 3 and 4 and a consistent safety profile [4], leading to approval and an increased use in clinical practice. The SIRT concept was further verified by real-world data showing an extended period free of disease activity after the initial treatment courses [5–9]. Meanwhile, 15 years after primary results from CLARITY were published [3], a vast amount of new data has emerged. This narrative review discusses new data of cladribine tablets and how to apply them to patient care in practical cases.

Long-term treatment-free disease control due to unique mode of action

Migration of lymphocytes into the CNS is a critical event in the pathogenesis of MS, which leads to immune-mediated inflammation and damage of myelin and neurons [10]. Cladribine’s mode of action involves selective depletion of dividing and non-dividing T and B cells, thus limiting the number of lymphocytes transitioning into the CNS. Deoxycytidine kinase (DCK) is required for the phosphorylation of cladribine to its active metabolite 2-chlorodeoxyadenosine triphosphate (Cd-ATP), while 5’-nucleotidase degrades Cd-ATP. In dividing cells, Cd-ATP impairs DNA synthesis. In resting cells, cladribine causes DNA single-strand breaks, rapid nicotinamide adenine dinucleotide consumption, ATP depletion and cell death [11]. Lymphocytes are particularly susceptible to apoptosis due to their relatively high DCK/5′-nucleotidase ratio, favoring the accumulation of Cd-ATP. In consequence of variations in the expression levels of DCK and 5’-nucleotidase between immune cell subtypes, cells of the innate immune system are less affected by cladribine treatment than those of the adaptive immune system [12].

Intake of cladribine tablets triggers a rapid and prominent reduction of CD20 + and CD19 + B cells. Additionally, CD3 + T cells with the respective CD3 + CD4 + and CD3 + CD8 + T cell subsets as well as NK cells are significantly reduced 2 weeks after treatment initiation [13]. The less severe reduction of regulatory T cells compared to other T cell subtypes is important to prevent excessive immune reactions of T cells, which could trigger the development of secondary autoimmune diseases [12]. Analyses of pooled data from the CLARITY trial, CLARITY Extension trial and the PREMIERE registry (long-term CLARITY cohort; NCT01013350) to characterize long-term changes in lymphocyte counts in peripheral blood, indicated that recovery of absolute lymphocyte counts (ALC) to the normal range begins soon after treatment in each of years 1 and 2. Interestingly, repopulation dynamics differed for various lymphocyte subsets. After a moderate and temporary reduction in T cell numbers, median CD4 + T cell counts recovered to threshold values (0.35 × 10⁹ cells/L) approximately 43 weeks after the last dose of cladribine tablets in year 2, while median CD8 + cell counts never dropped below the threshold value of 0.20 × 10⁹ cells/L [14]. Regulatory T cells increased by 24 weeks after each cladribine tablets course, which may contribute to long-term immune control [15]. In addition, a rapid decrease in B cell numbers was followed by repopulation reaching threshold values (0.10 × 10⁹ cells/L) within 30 weeks after the last cladribine tablets dose in year 2 [14]. Immunophenotyping revealed the reduction of memory B cells to be most profound and persistent up to 7 years [16–19]. At 24 months, memory B cells remained reduced by 89% from baseline. This effect was maintained over 48 months (Fig. 1) [15, 20]. It is not yet clear how long this reduction will last. The observed change in the B cell subset composition correlated with clinical and cranial MRI disease activity [21]. Long-term data confirmed control of disease activity even beyond year 4 [22, 23]. The actual proportion of patients maintaining freedom of disease activity without additional treatment varies between studies, due to different follow-up periods and endpoints (relapse activity, progression independent of relapses, confirmed disability accumulation, no evidence of disease activity) used for assessment (range 48% relapse-free after a median time of 10.9 years since the last dose to 90% relapse-free in year 5) [22–24]. Further research and a consensus definition of remission are required in this context. Control of disease activity has been linked to the sustained reduction of memory B cells [25]. This longevity of the memory B cell depletion far beyond the administration period is therefore considered a key mechanism of SIRT [16]. These observations were supported by data on the transcriptome and proteome level, indicating a reduction of possibly disease-relevant clones in the memory B cell subset without disrupting the overall clonal composition of B cells [21, 26]. The concept of SIRT was further supported by sustained reductions of the fluid biomarker serum neurofilament light chain (sNfL), which is indicative of intrathecal neuroinflammation and neuroaxonal damage [27].

Fig. 1.

Long-term effect of cladribine tablets on memory B cells. BL, baseline; TC, treatment course. Each treatment course consists of 2 treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year. Each treatment week consists of 4 or 5 days on which a patient receives 10 mg or 20 mg (one or two tablets) as a single daily dose, depending on body weight

Increasing evidence for effects in the CNS

Underlying pathologies for progressive MS are located in the CNS. These include focal MS lesions, B cell rich lymphoid aggregates in the meninges, widespread diffuse microglial inflammation and astrogliosis throughout the CNS white matter, as well as age-related neurodegeneration [28]. Targeting these sites of inflammation, demyelination and neuroaxonal damage require penetration of the blood–brain barrier (BBB) [29]. Presence of 25% of serum cladribine in the cerebrospinal fluid (CSF) indicated that cladribine is actually able to pass the BBB into the CNS [30–32], where it affects pathological parameters of central inflammation (Fig. 2) [33, 34]. The observed neutralization of lymphocytes in the CSF corresponds to a decrease in inflammatory markers as evidenced by reductions of oligoclonal bands (OCBs) [27, 35], kappa-free light chains (K-FLC) [33], as well as memory B cells [33, 36, 37]. In fact, the first study to demonstrate that cladribine tablets have sustained effects on reducing intrathecal antibody production was a prospective, longitudinal study with cladribine tablets over 96 weeks, showing a sustained reduction of K-FLC in serum and the CNS. This mirrors a decrease in total intrathecal IgG and B cell chemoattractant CXCL-13 production in the CSF. As the study was limited by the small sample size (N = 10) and study duration of 96 weeks, further studies are warranted to confirm the effect on intrathecal antibody production and its correlation to effectiveness [33]. Concurrently, the MAGNIFY-MS study confirmed reductions of K-FLC and IgG indices from baseline at Month 24 [27]. Preclinical studies also indicated an effect on microglia [38, 39]. Taken together, these results suggest potential effects of cladribine within the CNS itself.

Fig. 2.

Cladribine tablets trigger effects in both the peripheral and the central nervous system. ARR, annualized relapse rate; Gd +, gadolinium-enhancing lesion; OCB, oligoclonal band; PIRA, progression independent of relapse activity; RAW, relapse-associated worsening; SEL, slowly expanding lesion

The reduction and disappearance of OCBs in cladribine tablets-treated patients was observed in parallel with improvements in the clinical parameters no evidence of disease activity (NEDA)−3, Timed 25-Foot Walk Test (T25FW), Nine-Hole-Peg-Test (9HPT) [27], and Symbol Digit Modalities Test (SDMT) [40]. Whether these clinical benefits are a result of reduced intrathecal inflammation or achieved through peripheral effects needs to be further elucidated. Improved parameters of cognition were observed in the studies MAGNIFY-MS (NCT03364036), CLARIFY-MS (NCT03369665) and CLARIFY-MS Extension (NCT04776213). In MAGNIFY-MS, 43% of patients achieved a clinically relevant improvement in cognitive processing speed by 4 SDMT score points and 45% of patients showed stable cognitive processing speed at Month 24 [41]. This improvement was durable as demonstrated in year 4 of the MAGNIFY-MS Extension. A proportion of 51.6% of patients achieved a 4-score improvement, which is clinically relevant on the group level, and 29.7% achieved an 8-score improvement, reflecting clinical relevance on the individual level [42]. Results from the CLARIFY-MS parent study demonstrated significant improvement in the cognitive function domain of the MSQoL-54 at 24 months [43]. Additionally, preserved mental processing speed as well as verbal and visuospatial memory in years 3 and 4 was observed in the CLARIFY-MS Extension study [44].

Furthermore, depletion of CSF-resident lymphocytes corresponds to a decrease in brain damage as evidenced by less brain atrophy: two years after cladribine tablets initiation, significant treatment effects were observed in the thalamus, corpus callosum, as well as grey and white matter [45, 46]. A subgroup analysis of MAGNIFY-MS by SDMT score at baseline (< 53.5 vs. > 53.5) revealed a positive correlation between preserved brain volume of gray and deep gray matter and SDMT scores [47]. Consistently, a decrease in the incidence rate ratio of paramagnetic rim lesions (PRLs) has been observed after complete treatment with cladribine tablets [48]. PRLs are a subset of MS lesions that remain active in the post-active phase and which are associated with significant degeneration of deep gray matter structures [49, 50]. This outcome is also reflected in low rates of progression independent of relapses (PIRA) observed at month 24 (> 93%) [27, 51]. Furthermore, and in line with post hoc data from CLARITY Extension [52], real-world data confirm sustained effects on EDSS in years 3 and 4 following cladribine tablets initiation. Most patients were stable (54% in year 3, 57% in year 4), some got worse (16% in year 3, 14% in year 4), and about 30% improved [53]. In year 4 after the last dose of cladribine tablets, a total of 79.2% of patients from the MAGNIFY-MS Extension reached NEDA-3 (absence of relapses, confirmed 6-month disability progression, and new T1 Gd + and/or active T2 MRI lesions) [42].

Impact of the SIRT concept on safety

Overall, cladribine tablets are well tolerated and display a favorable benefit/risk ratio. In line with the SIRT concept and in differentiation from continuous therapies, most AEs occur within the first 6 weeks after initiation of cladribine tablets [9]. Cumulative to July 2024, the safety profile of cladribine tablets remained consistent with findings from the clinical development program [2, 54] and previous safety updates [55]. Table 1 provides a summary of reported adverse events of special interest. As a consequence of CD8 + cell dynamics, which decrease more slowly than B lymphocytes, and often remain within normal range, no confirmed cases of PML related to oral cladribine have been observed [54]. Following selective, transient lymphocyte reduction after administration of cladribine tablets, lymphopenia is an expected adverse event. The risk of severe lymphopenia (< 500 × 10⁹ cells/L) is low (0.10 per 100 patient-years; 95% CI 0.09–0.12) and varies among patients, depending on individual factors such as prior treatment with DMTs, age, comorbidities, and baseline immune status. For instance, pre-treatment with dimethyl fumarate is associated with a profound risk of developing severe lymphopenia and subsequent herpes virus infections [8].The risk of lymphopenia and its subsequent potential for infections, most often herpes zoster, can be mitigated by pre-emptive measures that include treatment initiation at adequately recovered lymphocyte counts, implementation of personalized monitoring strategies during the acute treatment period, and optimization of vaccination strategies [56].

Table 1.

Cumulative adverse events of special interest (as of 07 July 2024) [65]

	Adjusted reporting ratea per 100 patient-years, (95% CI)
Hypersensitivity (2858 reports)	1.13 (1.09; 1.18)
Serious infections (1270 reports)	0.50 (0.48; 0.53)
Herpes zoster (830 reports)	0.33 (0.31; 0.35)
Liver injury (623 reports)	0.25 (0.23; 0.27)
Malignanciesb (397 reports)	0.16 (0.14; 0.17)
Severe lymphopeniac (259 reports)	0.10 (0.09; 0.12)
Seizures (160 reports)	0.06 (0.05; 0.07)
Opportunistic infections (excluding PMLd and tuberculosis) (39 reports)	0.02 (0.01; 0.02)
Tuberculosis (35 reports)	0.01 (0.01; 0.02)

AE, adverse event, CI, confidence interval, PML, progressive multifocal leukoencephalopathy

^aThe reporting rate is adjusted for the cumulative duration of patient exposure to cladribine tablets

^bThe spectrum of malignancies resembled the distribution of cancer types seen in the general population, without any clustering of specific tumor types

^c < 500 × 10⁹ cells/L

^dAs of 07 July 2024, there were no confirmed cases of PML related to oral cladribine

The SIRT concept allows pregnancy planning during the treatment-free period, whereby females should observe a 6-month safety period between the last dose of cladribine tablets and conception. Due to possible effects on gametogenesis, male patients must take precautions to prevent pregnancy of their partner during cladribine treatment and for at least 6 months after the last dose. The effect of cladribine tablets on exposed pregnancies is being investigated in MAPLE-MS, a 10-year enhanced pharmacovigilance program initiated as a post-marketing requirement for the US Food and Drug Administration (FDA). Based on 157 maternal and 16 paternal exposure pregnancies with known outcomes evaluated in an interim analysis at year 7, the frequency of stillbirths was low, and the majority of pregnancies resulted in live births. Within 7 years, a single major congenital anomaly (atrial septal defect) has been reported to the global patients’ safety database. The outcomes are in line with published estimates from the general population and MS patient cohorts [57].

Due to the recovery of B and T cells, patients treated with cladribine tablets are able to mount an adequate immune response to seasonal influenza vaccination regardless of the duration of cladribine tablets therapy and the time interval since the last dose, as demonstrated in a controlled prospective vaccination study [58]. Similarly, treatment with cladribine tablets did not impair humoral response to COVID-19 vaccination, whereby the time since last cladribine tablets dose, age, prior therapy, lymphocyte count as well as B and T cell counts had no effect on seropositivity of anti-SARS-CoV-2 IgG antibodies [59, 60].

Cladribine tablets’ position within the MS treatment landscape

Currently, a total of 21 DMTs are approved for the treatment of MS. There are no prospective controlled head-to-head trials comparing cladribine tablets with other high-efficacy therapies. In some highly active cases, disease control may prove challenging to achieve and treatment with anti-CD20 antibodies may be more efficacious. However, in light of continuous immunosuppression with anti-CD20 antibodies and natalizumab, cladribine tablets provide an additional high-efficacy disease-modifying treatment option. The advantages of cladribine tablets include absence of cumulative safety risks inherent to continuous immunosuppression and absence of immunoglobulin deficiency. In particular, cladribine tablets represent a viable therapeutic choice when a high efficacy therapy is required at an early stage in the course of the disease, as well as for subsequent therapy following anti-CD20 treatment at a later stage in the disease course. The concept of SIRT allows patients to enter a prolonged period of treatment-free remission if they achieve complete freedom from disease activity. The length of this status is currently investigated in several real-world cohorts, yet likely depends on individual factors, such as prior disease activity, age, disease duration, and baseline disability. Predictive factors for treatment failure or need for re-treatment are still a subject of investigations. In case of recurring disease activity, additional courses of cladribine can be administered in years 5 and 6. According to the SmPC, lymphocyte counts must be normal (≥ 1000 × 10⁹ cells/L) before initiating treatment in year 1 and at least 800 × 10⁹ cells/L before initiating treatment in year 2 [61]. The same criteria should be applied to redosing with additional courses of cladribine tablets. Real-world data have shown that lymphocytes are usually sufficiently recovered by the time redosing is considered [22]. The treatment-free period and its inherent opportunities for the patient regarding family planning and a life without restrictions due to continuous therapy and possible side effects are a compelling argument in favor of cladribine tablets.

Implications for clinical practice

The learnings derived from cladribine’s unique mode of action as an immune reconstitution therapy offer a variety of implications for clinical practice when linking them to different patient profiles. Overall, the choice for cladribine tablets over other high-efficacy therapies is not only based on specific clinical or paraclinical parameters, but also on patient-relevant factors, which have gained importance in the treatment decision. These include family planning, the need for a convenient therapy, non-response under anti-CD20 antibodies, and high infection rate under continuous immunosuppression. The following patient profiles depict these scenarios and may serve as guidance in the decision process for cladribine tablets.

Patient profile 1: Early use in female DMT-naïve patients

A 25-year-old woman with newly diagnosed RMS and factors indicating highly active disease would like to have children before turning 30. She prefers not to expose her child to medication during pregnancy.

MS is most commonly diagnosed in women in primary child-bearing years. Accordingly, treatment choice should consider family planning. According to the SmPCs, treatment with anti-CD20 antibodies should be avoided during pregnancy unless the potential benefit to the mother outweighs the potential risk to the fetus. Some women prefer taking no medication at all during pregnancy; however, discontinuing fingolimod or natalizumab has been associated with a relevant risk of disabling relapses [62, 63]. Therefore, cladribine tablets are a good alternative if a pregnancy is planned. While cladribine tablets are contra-indicated during pregnancy, the treatment-free period after the full dose has been administered in year 2 offers a time window for women to become pregnant without pressure of time under highly effective therapeutic protection during pregnancy and postpartum [64]. In line with the current SmPC, a safety window of 6 months after the last cladribine tablets dose should be observed before conception [61]. In this context, the favorable response to vaccinations during therapy with cladribine tablets is relevant for vaccinations recommended during pregnancy, such as influenza and pertussis [58]. So far, post-approval surveillance data did not indicate any new safety signals in pregnant women. Out of 157 pregnancies with known outcomes, 20.4% resulted in spontaneous abortions and one major (atrial septal defect) and three minor congenital anomalies occurred, which is within the scope observed in the general population (10.0–24.0% and 2.0–4.4%, respectively) [57, 65]. Limited data from case reports have shown that cladribine is excreted in human milk. The quantity is not yet well established; however, plasma concentrations of cladribine decline rapidly, with an effective half-life of approximately 1 day. Because of the potential for serious adverse reactions in breast-fed infants, breast-feeding is contraindicated during treatment with cladribine tablets and for 1 week after the last dose [61]. During the treatment-free period, breast-feeding is possible. If women become pregnant after the first course, breast-feeding should be paused twice when the second course is due to allow administration for 4–5 days and observation of the 1-week safety margin in each of the two administration months, respectively. If women become pregnant in the time window after two courses of cladribine tablets have been completed, the breast-feeding period falls within the treatment-free period and can be executed without risk of exposure. Generally, data indicate beneficial effects of cladribine tablets in terms of delayed disability worsening when initiated at an early stage. In particular, in patients with clinically isolated syndrome (CIS), cladribine tablets effectively reduced the rate of conversion to MS [66, 67].

Patient profile 2: Early use in DMT-naïve patients

A 29-year-old male has been newly diagnosed with highly active RMS. His job requires frequent traveling, which leaves little time for regular visits to the physician and monitoring appointments. The patient displays adherence issues and needle phobia. He would like to “forget” his disease.

The oral administration route, the convenient dosing regimen and the durable effect after the full dose has been administered make cladribine tablets a good option for patients with adherence problems [68]. Real-world studies have shown that the short administration time totaling 20 days, and oral route of administration of cladribine tablets result in a high degree of adherence and patient satisfaction [9, 69]. The monitoring burden following each treatment phase is low and the treatment-free periods offer time windows for traveling between monitoring appointments. The absence of an active therapy is reflected in improved quality of life scores over 2 years compared to baseline [43].

Patient profile 3: Switch from anti-CD20 antibodies due to non-response

A 32-year-old woman fails to respond to a therapy with anti-CD20 antibodies.

Anti-CD20 antibodies are usually highly effective in people with MS. Yet, effectiveness and tolerability are limited in a small proportion of patients for various reasons. Recent data indicate that patients showing signs of chronic or acute inflammatory disease activity under anti-CD20 therapies may benefit from a switch to cladribine tablets [70–74]. Out of 30 patients from a retrospective analysis, who switched from anti-CD20 therapies to cladribine tablets, 60% achieved NEDA-3 under the second therapy [74]. Similarly, presence of MRI activity declined from 44% to ≤ 17% and ARR decreased from 0.35 to ≤ 0.18 after switching from another high-efficacy therapy to cladribine tablets [72]. Consistently, retrospective data from the US showed that all patients switching from natalizumab or ocrelizumab to cladribine tablets were relapse-free and free of MRI activity in years 2 (natalizumab, n = 25; ocrelizumab, n = 14) and 3 (natalizumab, n = 10; ocrelizumab, n = 8). The annualized relapse rate (ARR) at baseline (initiation of cladribine tablets) was 0.16 (n = 37) and 0.28 (n = 32) after prior natalizumab and ocrelizumab therapy, respectively. A total of 86.4% and 84.4% had been free of MRI activity at baseline, respectively [70]. The obtained benefit after switching from anti-CD20 antibodies may be ascribed to the capability of cladribine tablets to penetrate the blood–brain barrier and affect pathological parameters of central inflammation [33, 34]. Switching to natalizumab would also be an option. However, in case of John Cunningham virus (JCV) positivity or high JCV antibody index, this is usually avoided in clinical practice.

Patient profile 4: Switch from anti-CD20 antibodies due to increased infection risk

A 55-year-old woman received anti-CD20 therapies over 7 years with good results in terms of disease control. During the last year she repeatedly suffered from infections and hypogammaglobulinemia.

Meanwhile, patients aged 45–65 years form a large group among MS patients [75]. The risks in elderly patients must be taken into account during any therapy. As a consequence of continuous B cell depletion during prolonged treatment with anti-CD20 antibodies and coupled with immunosenescence, there is an increased risk of serious infections in the elder population [76]. Current studies examine the feasibility of discontinuing therapy after 5 years of maintained stable disease control. Whereas the randomized clinical trials DISCOMS and DOT-MS indicated the potential risk of disease reactivation following treatment discontinuation, both investigated mainly patients on platform therapies [77, 78]. A French observational study examining discontinuation of high efficacy DMTs found that discontinuation was associated with a significantly higher relapse risk (Hazard ratio of 4.1), especially for natalizumab and fingolimod. Patients stopping anti-CD20 antibodies did not experience increased relapse rates within a mean follow-up time of 3.0 years after discontinuation [79]. Consistently, a multicenter retrospective study indicated a rate of disease recurrence < 10% within a short observation period of 1.5 years after discontinuing ocrelizumab [80]. However, resuming treatment is indicated when disease activity returns. Cladribine tablets are the only MS therapy that included people with MS up to the age of 65 years in its pivotal study CLARITY (NCT00213135). A subgroup analysis of CLARITY confirmed that cladribine tablets were highly efficacious (defined as relapse reduction greater than 50% from baseline) in patients > 40 years [81]. Superior relapse control was shown in a propensity score matched analysis from the international longitudinal MS registry MSBase in patients > 50 years starting cladribine tablets compared to DMT continuation [82]. This circumstance together with the favorable efficacy and safety profile makes cladribine tablets a viable option after anti-CD20 therapies or as exit strategy for MS patients of age. Hypogammaglobulinemia is a side effect observed under anti-CD20 therapy, whereas IgG titers as a marker of immune competence have been shown to remain stable up to 4 years in patients receiving cladribine tablets [1, 14, 83–88]. Concordantly, data from an Australian single center cohort demonstrated increased IgG levels after switching older patients (mean age 53 years) after a mean duration of 17 months from ocrelizumab to cladribine tablets [71]. These observations are backed by a recent study investigating the switch from anti-CD20 therapies to cladribine tablets. Prevalent IgG deficiency resolved in most cases within 6 to 12 months after switching to cladribine tablets [74].

Neutropenia is another side effect during CD20-depleting therapies that may trigger a decision to switch therapies [89]. A reduction in neutrophils has also been observed during therapy with cladribine tablets, but not below the normal range [90].

Patient profile 5: Switch from S1P receptor modulators due to increased infection risk

A 52-year-old woman taking fingolimod over 10 years achieved adequate disease control. The frequency of infections increased over the last 2 years.

Similarly, an increased risk of infections is observed in aging patients receiving S1P receptor modulators. Data from the US showed reduced ARR in years 1–3 following a switch from S1P receptor modulators to cladribine tablets, whereby no lymphopenia issues were observed [91]. The transition from fingolimod to another DMT requires careful management because its discontinuation can trigger rapid lymphocyte redistribution, leading to increased inflammation and rebounds [92]. Key risk factors include younger age, prolonged use of fingolimod, and extended washout periods, with the highest relapse risk typically occurring within the first 3–6 months following discontinuation [93–95]. Zhou et al. have reported a higher frequency of relapses when switching from fingolimod to cladribine tablets compared to ocrelizumab and natalizumab, with a median washout period of 40 days [96]. Nygaard et al. have mentioned that 7 of 33 patients experienced disease activity, which they classified as rebound. The washout time between fingolimod and cladribine tablets was 44 ± 31 days [97]. Because the effect of cladribine tablets starts with a certain delay, the question arises as to the optimum wash-out time. A French expert opinion recommended initiating cladribine tablets within two weeks of fingolimod cessation to mitigate inflammatory rebound [98]. The employment of a 2-week washout period is supported by results from the FinClad study that evaluated the safety and short-term efficacy of cladribine tablets in people with MS who were discontinuing fingolimod due to elevated liver enzyme levels. A longer washout period was significantly associated with the presence of disease activity [99]. The risks of omitting a washout period or even overlapping the therapy for two weeks remain unclear.

Key benefits of cladribine tablets

The expanded treatment landscape includes many options for highly active MS, allowing a personalized approach according to the needs of each individual patient. The choice of treatment should be based on a shared decision-making process including factors such as disease activity, benefit–risk profile, and patient preference [100]. In addition, potential treatment sequences in case of response failure or tolerability issues should be considered. The key benefits of pulsed immune reconstitution therapy with cladribine tablets comprise brief exposure to active substances with long-term effectiveness, repopulation of lymphocytes, and maintenance of immune competence. Cladribine tablets deliver high flexibility with a potential for extended treatment-free periods and unrestricted long-term management options. The extended treatment-free period offers a window of opportunity for vaccinations and pregnancies. Based on more than 17 years of follow-up, the favorable safety profile is characterized by manageable front loading side effects and a low cumulative risk. Therapy with cladribine tablets is associated with a low monitoring burden and leads to high treatment satisfaction [9]. Regarding treatment costs over 4 years, the brief administration period of a pulsed therapy offers obvious economic benefits compared to continuously administered therapies and anti-CD20 antibodies in general. According to an analysis of prescription data, no further treatment costs were due for 63% of patients who did not require treatment between years 3 and 6 following cladribine tablet initiation [24]. The cost-effectiveness has been confirmed in several country-specific models [101–105].

Conclusion and outlook

Overall, the data confirmed the predicted benefit of cladribine tablets: very short exposure time, maintained competency of immune system, high efficacy of cladribine tablets even beyond year five, good safety profile with well characterized and manageable side effects linked to the intake phases and low cumulative risk, and low burden of treatment and monitoring. Key characteristics that distinguish cladribine tablets from other high-efficacy DMTs are summarized in Table 2. Of note, some of the data presented here are limited by small patient numbers and non-peer-reviewed publications. Confirmation in peer-reviewed journals is eagerly awaited within the next few years. Options for cladribine tablets in DMT-naïve patients with radiological signs plus paraclinical markers according to the new McDonald criteria 2024 [106], as an exit strategy, and in SPMS are currently being explored. The duration of the treatment-free period varies between individuals, depending on factors such as disease activity before cladribine tablets initiation and prior DMTs. How far the treatment-free period can be stretched remains to be established as more data become available with each additional year following cladribine tablets initiation. However, a subset of patients may not achieve sufficient disease control and show signs of ongoing inflammatory activity, requiring either additional cladribine tablets treatment or a timely switch to an alternative high-efficacy therapy. Additional open research questions include predictive biomarkers for treatment response. In this context, preliminary 24-month data from MAGNIFY-MS showed that cladribine tablets effectively reduced peripheral biomarkers GFAP and NfL. A trend toward association of CNS intrathecal activity markers CXCL-13 and K-FLC indices with clinical outcomes 6-month confirmed disability progression (6mCDP), PIRA, and relapses was observed. However, since very few patients experienced 6mCDP, PIRA, or relapses, the statistical power to detect significant associations was reduced, warranting confirmation in larger populations [107]. Long-term safety data up to 8 years have been captured in the prospective PREMIERE registry, which ran from 2009 to 2018 and included patients who had completed the RCTs CLARITY and CLARITY Extension. Long-term efficacy data are captured in CLASSIC-MS, of which follow-up data of 10.9 years (median) are available so far. As approval was in 2017, no long-term real-world data beyond 10 years are yet available. However, several patient cohorts are continuously monitored to capture data on effectiveness and safety over time. Safety data are continuously reported to the pharmacovigilance department. So far, the positive benefit–risk profile established in clinical trials has been confirmed with the additional patient-years gained in clinical practice.

Table 2.

Key characteristics that distinguish cladribine tablets from other high-efficacy DMTs

Characteristics	Cladribine Tablets	Other HE-DMTsa
Administration schedule	Short exposure time, followed by extended treatment-free period	Continuous therapy
Safety profile	Front-loading, side effects mainly linked to intake phase	Cumulative risk
Immune competency	Maintained	Continuous immunosuppression
Pregnancy	Possible during treatment-free period	Depending on type of DMT possible after benefit-risk considerations (anti-CD20 antibodies, natalizumab) or contraindicated for S1P-RM
Treatment burden	Low	Higher (depending on type of DMT)

DMT, disease-modifying therapy; HE-DMT, high-efficacy disease-modifying therapy; S1P-RM, sphingosine-1-phosphate receptor modulator

^aOther high-efficacy DMTs include anti-CD20-antibodies, natalizumab, and S1P-RM

Key clinical take-aways

• Short-course cladribine tablets provide long-term control of disability progression with low rates of PIRA, RAW, and CDA

• Maintained competency of immune system

• Manageable side effects mainly linked to the intake phases and low cumulative risk

• Low burden of treatment and monitoring

• The extended treatment-free period offers time windows for family planning and vaccinations

Author contributions

Christoph Kleinschnitz, Judith Knaup and Torsten Wagner made substantial contributions to the conception of the work and analysis of data. All authors made substantial contributions to interpretation of data. Christoph Kleinschnitz, Judith Knaup and Torsten Wagner drafted the work. T Skripuletz, S Pfeuffer, M Pawlitzki, P Rieckmann, I.K. Penner, M. Hübschen, K. Hellwig, and R Pul revised the work critically for important intellectual content. All authors approved the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Funding

Open Access funding enabled and organized by Projekt DEAL. Merck Healthcare Germany GmbH, Weiterstadt, an affiliate of Merck KGaA.

Data availability

No new data were generated or analyzed in the course of this review. All data referenced are available in the cited sources.

Declarations

Conflicts of interest

Christoph Kleinschnitz received honoraria for lecturing and travel expenses for attending meetings from Alexion, Almirall, Astra Zenica, Bayer, Biogen, Biontech, Boehringer Ingelheim Bristol Myers-Squibb, C.T.I., Daiichi Sankyo, Docspert, Merck Healthcare Germany GmbH, Weiterstadt, an affiliate of Merck KGaA, Mylan/Viatris, Novartis, Pfizer, Roche, Sanofi-Aventis, Stada, Teva, Janssen-Cilag, Horizon Therapeutics, Medscape LLC, Baumgart Consultants, StreamedUp!, Hexal/Sandoz, Agentur Süss, Viatris. Thomas Skripuletz reports research support from Alnylam, CSL Behring, Merck Healthcare Germany GmbH, Weiterstadt, an affiliate of Merck KGaA, Novartis, Siemens; honoraria for lectures, travel support for meeting attendance, and/or consultancy fees from Alexion, Alnylam, argenx, Bayer, Biogen, Bristol Myers Squibb, Centogene, CSL Behring, Grifols, Hexal AG, Horizon, Janssen, Merck Healthcare Germany GmbH, Weiterstadt, an affiliate of Merck KGaA, Novartis, Pfizer, Roche, Sanofi, Siemens, SOBI, Teva, Viatris. Steffen Pfeuffer received honoraria for lecturing and for serving on advisory boards from argenx, Alexion, Biogen, Hexal, Merck Healthcare Germany GmbH, Weiterstadt, an affiliate of Merck KGaA, Novartis, Roche, and Sanofi Aventis; travel reimbursements from Alexion, Biogen, Merck Healthcare Germany GmbH, Weiterstadt, an affiliate of Merck KGaA, neuraxpharm, and Roche; research support from Biogen, Merck Healthcare Germany GmbH, Weiterstadt, an affiliate of Merck KGaA, and Novartis. Marc Pawlitzki received honoraria for lecturing and travel expenses for attending meetings from Alexion, ArgenX, Bayer Health Care, Biogen, Hexal, Merck Healthcare Germany GmbH, Weiterstadt, an affiliate of Merck KGaA, Novartis, Roche, Sanofi-Aventis, Takeda and Teva. His research is funded by ArgenX, Biogen, Demecan, Hexal, Horizon, Merck Healthcare Germany GmbH, Weiterstadt, an affiliate of Merck KGaA, Novartis, Roche, Viatris, Takeda and Teva, all outside the scope of this work. His research is funded by the by the German Multiple Sclerosis Foundation (DMSG), the B.Braun Foundation and the German Alzheimer Society. Peter Rieckmann received honoraria for lectures from Almirall, Apple Healthcare, Baxter, Bayer, Biogen Idec, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Genpharm, Genzyme, Medtronic, Merck Healthcare Germany GmbH, Weiterstadt, an affiliate of Merck KGaA, Novartis, Pfizer, Roche, Sanofi, Siemens AG, and Teva. He received research grants from Brainlight, German Neurology Foundation, h/p/Cosmos, Max Aicher Foundation, Oberfranken-Stiftung, Red Bull, and Teva. He served on advisory boards or steering committees for Aycan, Bayer, Biogen Idec, Canada Drug Review, the German Multiple Sclerosis Society, Novartis, Merck Healthcare Germany GmbH, Weiterstadt, an affiliate of Merck KGaA, and Teva. Iris-Katharina Penner received honoraria for speaking at scientific meetings, serving at scientific advisory boards and consulting activities from Almirall, Celgene, Sanofi-Genzyme, Janssen, Merck Healthcare Germany GmbH, Weiterstadt, an affiliate of Merck KGaA, Novartis, Roche, and Teva. She received research support from the German MS Society, Celgene, Novartis, Roche, and Teva. Judith Knaup, Torsten Wagner and Michael Hübschen are employees of Merck Healthcare Germany GmbH, Weiterstadt, an affiliate of Merck KGaA. Kerstin Hellwig received research support, honoraria for lecturing and travel expenses for attending meetings from Alexion, Almirall, Bayer, Biogen, Merck Healthcare Germany GmbH, Weiterstadt, an affiliate of Merck KGaA, Mylan/Viatris, Novartis, Pfizer, Roche, Sanofi-Aventis, Teva, Horizon Therapeutics, Medscape LLC, StreamedUp!, Hexal/Sandoz. Refik Pul received honoraria for lecturing and consulting from Alexion, Amgen, Bayer Healthcare, Biogen, Bristol Myers Squibb/Celgene, Chiesi, Janssen, Juvisé, Merck Healthcare Germany GmbH, Weiterstadt, an affiliate of Merck KGaA, Neuraxpharm, Novartis, Roche, Sanofi Genzyme and Viatris. He received research funds from Merck Healthcare Germany GmbH, Weiterstadt, an affiliate of Merck KGaA, Neuraxpharm, and Novartis.