FormalPara Key Summary Points

Cladribine tablets are approved for the treatment of relapsing forms of multiple sclerosis (MS)

This is a short-course treatment given for 8–10 treatment days a year, for 2 years

People with MS (PwMS) may have many questions regarding this type of treatment including how it works, its safety, and how long the effects are likely to last

The questions for discussion during consultations of most interest to PwMS regarding cladribine tablets have been answered in this report

Providing healthcare professionals with easy access to answers tailored for discussions with PwMS aims to support an open dialogue between these two key groups, which can lead to PwMS playing a bigger role in shared decision-making regarding their treatment

Introduction

Health literacy refers to an individual’s ability to find, understand, and use information and services to inform health-related decisions [1]. It has been reported that improved health knowledge and skills lead to confidence and empowerment by removing educational barriers and allowing patients to take part in decision-making about their care [2]. As a result, improved health education can also lead to a better quality of life (QoL), which comprises the individual’s perception of various aspects of their life including physical health and psychological state [3, 4]. However, data from a recent survey showed that nearly half of the European adult population has inadequate or problematic health literacy [5]. This can lead to fewer healthy choices, riskier behavior, poor health, less self-management, and more frequent hospitalizations, which may have a considerable impact on health systems’ financial and human resources in comparison to those with strong health literacy competencies [5]. Providing relevant health information alongside opportunities to develop skills, confidence, and knowledge can empower those with chronic diseases in particular to successfully self-manage their condition [5]. With improved health literacy, patients could play a bigger role in shared decision-making regarding their treatment; this open dialogue could also lead to treatment choices being better tailored to individuals with chronic diseases on the basis of their personal experiences, preferences, and circumstances.

People with multiple sclerosis (MS) (PwMS) could benefit from improved health literacy [6]. MS affects 2.8 million people worldwide and has a range of symptoms. These include impaired mobility and coordination, sensory symptoms, pain, fatigue, altered vision, impaired bladder and bowel function, sexual dysfunction, emotional changes, and cognitive decline [7,8,9,10]. Many of these symptoms can worsen over time, and their worsening can vary between patients (Fig. 1); for the majority of PwMS the disease is characterized by periods of relapse and remission (relapsing–remitting MS [RRMS]) [8, 9]. Some people with RRMS will transition to a progressive form of MS over time (secondary progressive MS), while in others, the disease is progressive from the onset of symptoms (primary progressive MS) [8, 9]. The two faces of MS pathology—inflammation and neurodegeneration—are currently understood as a continuum across the course of the disease, in which relapsing and progression are considering overlapping events [11]. The wide range of symptoms together with the unpredictable nature of the disease can severely impact the QoL of PwMS [12]. Having a greater understanding of health information has been associated with improvements in symptom control, self-care behaviors, and QoL in PwMS, while also decreasing the use of healthcare services [6].

Fig. 1
figure 1

Adapted from MSAA 2022, accessed at https://mymsaa.org/ms-information/overview/types

Different characteristics of multiple sclerosis worsening. Multiple sclerosis can cause a variety of symptoms that can differ between individuals. The progression of these symptoms also differs depending on the extent of symptom recovery, if at all, after periods of symptoms.

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Cladribine tablets were granted marketing authorization in 2017 across Europe [13], and were approved in the USA in 2019 [14] to treat relapsing forms of MS. Cladribine tablets are given as 8–10 treatment days a year for 2 years [13]. However, PwMS may be more familiar, and therefore more confident, with treatments requiring long-term and frequent dosing, and this can lead to questions relating to how short-course treatments, such as cladribine tablets, can work and how well such a treatment is tolerated.

To inform the development of this manuscript, MS experts, including healthcare professionals (HCPs) and PwMS, proposed topics around cladribine tablets that PwMS and their families and caregivers would most like to discuss with HCPs during consultations to help them to better understand this treatment (more details can be found in the supplementary material). Examples of the importance given to statements from the survey are shown in Fig. 2, and results are shown in more detail in the supplementary material.

Fig. 2
figure 2

Importance of statements as ranked by people living with multiple sclerosis. Multiple sclerosis (MS) experts, including healthcare professionals (HCPs) and people living with MS (PwMS), proposed topics around cladribine tablets that may be of most interest for PwMS and their caregivers. Statements related to these topics were then ranked from most to least interesting by PwMS. Two example topics are shown here with statements ordered by the weighted average response. Full results can be found in the supplementary material

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Here, we present the information around statements that were ranked most highly by PwMS in two ways: a standard narrative, using language familiar to HCPs, and a plain language narrative. We believe that this approach will facilitate conversations between HCPs and PwMS, assist HCPs in answering relevant questions about cladribine from PwMS, and help HCPs provide PwMS with the knowledge and confidence to have a key role in shared decision-making.

Methods

The themes to be prioritized and explored in this manuscript were identified using a survey that was completed by 12 patients with MS over a period of 3 weeks. Respondents who completed the survey agreed for their anonymized responses to be used by Merck KGaA.

The survey comprised 14 questions which covered the following topics: taking cladribine tablets, efficacy, safety and long-term considerations, special considerations and “other” which allowed respondents to share any specific information requirements they had that were not covered by previous questions.

For each of the categories (excluding special considerations and “other”), respondents were able to rank questions related to each topic, which had been drafted by the authors, on the basis of how interested they were in each one. They were also able to provide additional questions if they thought that what was included in the options did not align with their personal priorities. For special considerations, respondents were asked if they would like more information on fertility and pregnancy planning, getting vaccinated and cladribine tablets, and COVID-19 by responding “yes” or “no”. For each of these questions they were also able to provide optional rationale for their choices. For the “other” section respondents were invited to share if they had any unanswered questions about cladribine, what the main things they would want to know about treatment are, and what they wished they had known about treatment from the start. For results of the survey, please refer to the supplementary materials.

The results of the survey were reviewed and discussed by the article authors in order to confirm which themes would be included in the article. The themes included here are a reflection of the survey results and the information priorities of patients.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors. Ethics committee approval was not required.

How Cladribine Tablets Work

Cladribine tablets are used for treating relapsing MS in adults and are an immune reconstitution therapy, decreasing the number of pathogenic cells believed to cause the symptoms of MS so that after treatment new cells can emerge that have reduced pathogenic potential [15, 16]. Cladribine tablets are semi-selective as they favor the early and sustained reduction of immune cells that may have a pathologic role in MS [15, 17]. Total B cells are reduced dramatically, and T cells are affected significantly less [17]. Also, while naïve B cells recover toward baseline, naïve CD4 and CD8 T cells do not, and memory B cells, which are believed to play a central role in MS pathology, remain reduced until month 12 [17]. This pattern helps explain the semi-selective depletion and repopulation of the immune system and its relationship with the onset of action and durability of effects of cladribine tablets while largely maintaining immune competence [17]. There is relatively limited long-term impact on other types of cells that regulate the immune system [15].

Cladribine is removed from the body within 1 week of treatment [15], and B and T cells reach their lowest level 2 months after the start of treatment [18]. The reduction of these lymphocytes is sustained for at least 10 months after the last dose [19]. Owing to this mechanism, cladribine tablets can induce long-term outcomes from a short course of treatment [20]. The impact that cladribine tablets have on immune cells appears to be associated with an early onset of action with reductions in active magnetic resonance imaging (MRI) lesion counts from month 2 onward [20]. Figure 3 depicts how cladribine tablets work.

Fig. 3
figure 3

How cladribine tablets impact immune cells. Once cladribine tablets are taken, the number of immune cells that mistakenly attack nerves reduces allowing for new immune cells to replace them. Cladribine tablets are taken orally (by mouth) and stay in the body for 1 week, but the resulting reduction in the number of immune cells remains low for 10 months

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Box 1: Explaining to PwMS How Cladribine Tablets Work

∙ MS occurs when immune cells, which usually help to fight off infection, mistakenly attack our nerves [13].

∙ Cladribine tablets work by reducing some of these damaging immune cells, which in turn reduces damage to the nerves [15, 19].

∙ Cladribine tablets are taken by mouth and are used to treat relapsing MS [16, 21].

    ◦ Cladribine is removed from the body within 1 week [15].

    ◦ The damaging immune cells are at their lowest level 2 months after the start of cladribine tablet treatment [18].

    ◦ These numbers remain low for at least 10 months after the last dose [19].

∙ Decreasing the number of immune cells that damage the nerves allows new immune cells—which do not mistakenly damage the nerves—to replace them [15].

∙ A reduction in the damaging immune cells is linked to a reduction in MS activity. The number of active lesions on MRI scans is reduced 1 month after starting treatment [20].

The full course of cladribine tablets is given as 8–10 days of treatment a year, for 2 years (Fig. 4). During year 1, there are two treatment weeks separated by 1 month, where one or two 10 mg cladribine tablets are given daily for 4 to 5 days [16]. This is followed by a long treatment break for the remainder of the year. This cycle is then repeated in year 2. The cumulative dose across the 2 years is 3.5 mg/kg body weight. The dose is adjusted by the number of tablets and number of treatment days, according to the weight of the patient [13, 16, 21].

Fig. 4
figure 4

The full course of cladribine tablets and recommendations for missed doses. Treatment weeks will consist of taking 1 or 2 tablets over 4 or 5 days. The number of tablets and the number of treatment days vary depending on the dose required, which is weight-based. This figure has been adapted from Olek, 2021 [9]. If a tablet is missed, then it should be added to the end of the treatment period, and not taken on the same day as another cladribine tablet

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It is recommended that the daily dose of cladribine tablets during each treatment week is taken at intervals of 24 h at approximately the same time each day [16]. Where a daily dose consists of two tablets, both tablets should be taken together as a single dose [16]. If a dose is missed, it must be taken as soon as remembered on the same day according to the treatment schedule [16]. A missed dose must not be taken together with the next scheduled dose on the following day. In cases where a dose for a given day is missed, the missed dose should be taken on the following day, and the number of days in that treatment week should be extended. If two consecutive doses are missed, the same rule applies, and the number of days in the treatment week is extended by 2 days [16, 21]. These recommendations for missing doses are highlighted in Fig. 4.

If other oral medications are being taken, it is recommended that these are taken either 3 h before or after cladribine tablets to prevent potential drug–drug interactions [16, 21].

Box 2: Explaining to PwMS How Cladribine Tablets Are Taken

∙ Cladribine treatment is given over a 2-year period: year 1 and year 2.

∙ In both year 1 and year 2, cladribine tablets are taken for 8–10 days within the first 2 months of treatment (4 or 5 days in months 1 and 4 or 5 days in month 2 of each year) (Fig. 4) [16, 21].

∙ Cladribine tablets are taken by mouth [16, 21].

∙ On each day of treatment, 1 or 2 cladribine tablets are taken.

    ◦ A healthcare professional will determine if 1 or 2 tablets are to be taken every day, and whether treatment lasts 4 or 5 days [16, 21].

    ◦ They will use your weight measurement to determine the dose [13, 16, 21].

    ◦ When 2 tablets are required, these should be taken at the same time [16, 21].

∙ It is recommended that the tablets are taken at the same time of day on each treatment day [16, 21].

    ◦ If a dose is not taken on the same day as originally scheduled, an extra day should be added to the 4- or 5-day treatment period [16, 21].

    ◦ Extra tablets should not be added to a dose to make up for a missed one [16, 21].

    ◦ Cladribine tablets should only be taken as prescribed [16, 21].

Considerations Prior to and While Taking Cladribine Tablets

There are a number of considerations before and during treatment with cladribine tablets (Fig. 5).

Fig. 5
figure 5

Schedule of screening and monitoring for cladribine tablet treatment. Timeline depicting the screening that occurs before starting treatment and the monitoring required over year 1. A similar schedule of monitoring occurs during year 2

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Screening for active or latent infections (e.g., human immunodeficiency virus, tuberculosis, and hepatitis B and C) must occur before initiation of therapy in year 1 and year 2, as such infections could be activated with, or contraindications to, cladribine tablets treatment. Initiation of cladribine tablets should be delayed until infection has been adequately treated [16, 21]. Alongside screening for latent infections, liver function should also be tested prior to initiation of cladribine tablets in both years 1 and 2 [16, 21]. A comprehensive patient history regarding previous episodes of liver injury that occurred with other drugs or underlying liver disorders should be taken [16]. Once treatment begins, the level of monitoring for those receiving cladribine tablets is less intensive than for other MS medications [22, 23], reducing the time burden that often accompanies treatment of chronic diseases.

As cladribine tablets reduce the number of lymphocytes, it is important to monitor lymphocyte levels during treatment [16, 21]. Lymphocyte counts must be determined before treatment initiation in years 1 and 2, and at 2 and 6 months after start of treatment [16, 21]. Lymphocyte levels should be within normal range before initiating cladribine tablets treatment in year 1 and at least 800 cells/mm3 before initiating cladribine tablets in year 2 [16, 21]. The treatment course in year 2 can be delayed for up to 6 months to allow for recovery of lymphocytes, if necessary; however, if recovery has not occurred by 6 months the patient should not continue receiving cladribine tablets [16, 21]. After the treatment course, if lymphocyte levels drop below 500 cells/mm3, active monitoring for infections is required until lymphocyte counts increase [16, 21]. If lymphocyte counts drop below 200 cells/mm3, anti-herpes prophylaxis may be required until the value returns to more than 200 cells/mm3 [21]. Cladribine tablets are contraindicated for PwMS with an active malignancy. As a result of the risk of malignancies, cancer screening is also recommended prior to starting and during each treatment course [16, 21].

Consideration should be taken when switching to and from cladribine tablets to prevent negative effects caused by a rebound or an additive effect of treatment. As a result of potential additive effects, initiation of cladribine tablets is contraindicated in those who are immunocompromised, which includes PwMS currently receiving immunosuppressive or myelosuppressive therapy, e.g., methotrexate, cyclophosphamide, cyclosporine, azathioprine, or chronic use of corticosteroids [16, 24]. The duration of the effects of the other medications and the risk of rebound of MS activity after their discontinuation should also be considered prior to the initiation of cladribine tablet treatment, with some drugs, such as fingolimod and natalizumab, requiring a wash out period of (a) at least 4 weeks to ensure that there are no additive effects of the two medications, and (b) less than 12 weeks to diminish rebound relapse risk [24, 25]. If switching from another MS medication, a baseline MRI scan should be performed in order to monitor for side effects such as progressive multifocal leukoencephalopathy [16, 21].

Box 3: Describing to PwMS What They Can Expect Before and During Treatment with Cladribine Tablets

To ensure that monitoring is effective, before starting cladribine tablet treatment in both year 1 and year 2, tests are needed to form a “baseline”. A baseline is health information from before treatment that is used to compare against changes that may occur during treatment. Baseline information gained prior to treatment includes:

∙ Clear understanding of medical history through discussions with your healthcare professional, and review of your medical records regarding [16, 21]:

    ◦ Previous liver problems.

    ◦ Use of other similar MS medications.

    ◦ Current symptoms of infection (such as a fever), shingles (such as painful blisters), or any history of cancer.

∙ Blood tests are used to [16, 21]:

    ◦ Determine the number of immune cells present.

    ◦ Detect any infections, even if symptoms are currently not seen or felt by the person with MS.

    ◦ Determine how well the liver is working, known as a liver function test.

Monitoring the effects of cladribine tablets will be done at regular intervals throughout treatment so changes can be detected and treated quickly:

∙ Monitoring the number of immune cells [16, 21].

    ◦ Current numbers will be compared with the baseline levels to highlight any sudden or unexpected changes.

    ◦ This happens 2 and 6 months after starting treatment in years 1 and 2 [16, 21].

        - If the number of immune cells is too low, the person with MS may be at risk of infection.

        - Monitoring the numbers of immune cells will ensure that any significant drops in levels are detected and treated quickly.

        - Monitoring can also detect if preventative treatment against infections (such as antibiotics) or changes to the cladribine treatment are required.

∙ Additional tests may be used to monitor [16, 21]:

    ◦ Changes in the liver.

    ◦ For the development of infections.

    ◦ Skin-related symptoms.

How Cladribine Tablets Affect Relapse Rate

The CLARITY phase III study demonstrated that cladribine tablets reduced the rate of relapses and slowed the worsening of MS symptoms [26]. From the CLARITY study, PwMS treated with cladribine tablets had a significantly higher relapse-free rate over 96 weeks (79.7%) compared with those on placebo (60.9%), as shown in Fig. 6. PwMS receiving cladribine tablets also had a significantly lower yearly relapse rate of 0.14 compared with 0.33 with placebo [26]. The time before first relapse following cladribine treatment was approximately three times longer than in people who received placebo [26].

Fig. 6
figure 6

Improvements in relapse frequency with cladribine tablet treatment compared with placebo. Improvements in the percentage of relapse-free patients and the yearly relapse rate in those receiving cladribine tablet treatment are compared with those receiving placebo

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An extension of the CLARITY study showed that the benefits of cladribine tablets were maintained through years 3 and 4 after active treatment [16, 27]. Although the CLARITY Extension study was not designed to look at long-term efficacy, data on clinical outcomes were collected from PwMS who had received the full 2-year course of cladribine tablets and were then randomized to either placebo or additional courses of cladribine tablets. These data highlighted that PwMS experienced no incremental benefit between these two groups [28]. The label is based on this observation. The “no evidence of disease” (NEDA) rates for data collected in years 3 and 4 were similar between PwMS randomized to placebo or further courses of cladribine tablets. However, progressive inclusion of data after year 4 showed that progressively fewer PwMS achieved NEDA beyond year 4 if they received placebo, which was mostly related to changes in their MRI parameters. PwMS who received additional courses of cladribine tablets showed no reduction in NEDA [28].

In a phase IV long-term follow-up study (CLASSIC-MS) PwMS treated with cladribine tablets had improved long-term mobility and disability status compared with those who never received the drug in the CLARITY or CLARITY Extension studies [29]. From retrospective information, approximately half the PwMS were treated with additional disease-modifying therapies after cladribine tablets, although the reason for this was not recorded [29].

Real-world data on continuation with cladribine tablets after an individual has received a complete course of treatment is scant. In general, decisions on continuation likely depend on the extent to which the disease responded to treatment with cladribine tablets and duration of this effect. Depending on the disease activity, physicians and PwMS may also consider other treatments [24].

Box 4: Describing to PwMS the Likelihood of Them Becoming Relapse-Free After Starting on Cladribine Tablets

∙ From the CLARITY clinical study:

    ◦ The number of relapses seen per year was lower in those taking cladribine tablets compared with those on placebo (a substance that looks like an active substance, such as a therapy or drug, but contains no ingredients that will affect the body) [26].

    ◦ 8 out of 10 people with MS were relapse-free for about 2 years after taking cladribine tablets [26].

∙ Cladribine had a positive effect on relapse rate:

    ◦ Those who received cladribine tablets remained relapse-free for approximately 3 times longer than those taking the placebo treatment [26].

Box 5: Explaining to PwMS How Long the Desired Effects of Cladribine Tablets Will Last

∙ After 2 years of treatment with cladribine tablets, people with MS may continue to see benefits at years 3 and 4 and potentially beyond year 4 [16, 27].

∙ A long-term study found that more than half of those with MS who received cladribine tablets did not require additional treatment for 10 years, highlighting that the effect of cladribine tablets (given for 4 treatment weeks over 2 years) on interrupting the disease can be detected many years later [24, 29].

Time for Cladribine Tablets to Have an Impact on QoL

Here, cladribine tablets significantly improved the physical and mental health composite scores of the Multiple Sclerosis Quality of Life-54 (MSQoL-54) instrument over 24 months by a least squares mean score of 4.9 and 4.8, respectively [30]. These significant improvements were reported at the end of the first 12 months, with both component scores having a least squares mean value of 4.5 [31]. This improvement after 12 months is depicted in Fig. 7. Analysis of the CLARITY dataset also found improvements in QoL, using both the MSQoL-54 and Euro Quality of Life 5 Dimensions (EQ-5D) instruments compared with placebo [32].

Fig. 7
figure 7

Improvements in physical and mental health are seen 12 months after starting cladribine tablets. After 1 year of cladribine tablet treatment people living with multiple sclerosis demonstrate a mean improvement of 4.5 from baseline in both their Multiple Sclerosis Quality of Life-54 physical and mental health composite scores. This improvement occurs with only half the therapeutic dose of cladribine and has been shown to be maintained at the full dose (2 years)

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Box 6: Describing to PwMS How Long it Takes for Cladribine Tablets to Have an Impact on Their Quality of Life (QoL)

∙ Information about the impact of cladribine treatment on several aspects of QoL including anxiety, mobility, ability to do daily activities, and pain has recently been evaluated on the basis of specific questionnaires completed by people with MS [32].

∙ One year after starting treatment, people with MS reported improvements in their physical and mental health [31].

∙ After 2 years, multiple questionnaires suggested that patients with MS taking cladribine had less worsening of symptoms such as perceived ability to move and anxiety, compared with those who received placebo [32].

∙ One questionnaire highlighted positive improvement in symptoms related to self-care, like the ability to wash and dress themselves, for individuals taking cladribine tablets compared with those who were not [32, 33].

The Most Clinically Relevant Side Effects of Cladribine Tablets

Safety data collected during the CLARITY study indicated that the most clinically relevant adverse reactions in PwMS treated with cladribine tablets (3.5 mg/kg) over 2 years were lymphopenia (low lymphocyte levels) and herpes zoster (shingles) [16]. In phase III and follow-up trials, 25% of PwMS treated with cladribine tablets developed severe (grade 3 or 4; < 500 cells/mm2) reductions in lymphocytes; herpes zoster occurred in up to 1 in 10 PwMS [13, 16], with higher rates of infections occurring during instances of grade 3 and 4 lymphopenia [34]. Higher rates of lymphopenia likely occurred during earlier clinical trials as no lymphocyte-level threshold had been introduced for starting the second year of treatment. Currently, before initiating cladribine tablets in year 2, the number of lymphocytes should be at least 800 cells/mm3 [16, 21]. Only 1% of those taking cladribine tablets discontinued treatment because of decreased/abnormal lymphocyte count [35].

The incidence rate for overall infections, severe infections, and infections leading to discontinuation or opportunistic infections was comparable in those treated with placebo and cladribine tablets [34]. However, herpes zoster and other herpetic infections were increased following treatment with cladribine tablets compared with placebo [34]. Herpes zoster was the most frequently reported infection; all cases were dermatomal and followed a normal course of infection, i.e., resolving with standard treatment [31]. The risk of cancer was similar to that seen in the general population [34,35,36]. No long-term side effects have been suggested from current clinical studies, and with additional large, non-interventional studies being conducted to reflect real-world treatment and management in PwMS, further information will be gained on the safety profile and whether there is any risk of rare side effects [37, 38]. The side effects relating to cladribine tablets are depicted in Fig. 8.

Fig. 8
figure 8

Common side effects experienced by people with MS taking cladribine tablets. The most common side effect is a severe reduction in white blood cell count, which occurs in 1 in 4 people taking cladribine tablets. Other common side effects that occur in 1 in 10 people taking cladribine tablets include shingles, cold sores, hair loss, and allergic reactions

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Box 7: Explaining the Risks and Side Effects of Cladribine Tablets to PwMS

∙ Cladribine tablets work by reducing the number of some types of immune cells, which can damage nerves in people with MS [13].

    ◦ Because immune cells are essential to help fight off infection, people with MS taking cladribine tablets can be at a greater risk of infections than the general public, particularly if numbers of immune cells become very low [13, 16, 21].

    ◦ Regular monitoring of immune cell levels, using blood tests, helps minimize the risk of infection during treatment with cladribine tablets [16, 21].

    ◦ 1 in 4 people in clinical trials who take cladribine tablets reach very low levels of immune cells [16, 21]. This risk is now minimized by checking that the number of immune cells is not too low before starting the year 2 treatment course [16, 21].

∙ Chances of getting shingles increased following treatment with cladribine tablets compared with not taking this treatment. In studies, 2% of patients treated with cladribine got shingles compared with 0.2% of patients on placebo [16, 21, 34].

    ◦ Screening for shingles before and during treatment aims to ensure that it is identified quickly and managed appropriately [16, 21].

∙ Other side effects when taking cladribine tablets include rashes, cold sores, hair loss, and allergic reactions [16].

∙ There is currently no evidence of any long-term side effects from cladribine tablets [39].

∙ In clinical trials, the risk of cancer was the same as that in the general population [34,35,36].

Other Side Effects of Cladribine Tablets

Other side effects of cladribine tablets affecting up to 1 in 10 people include rash, cold sores, hair loss, allergic reactions, and reductions in the number of immune cells other than lymphocytes (neutrophils) [16]. On the basis of findings highlighting that skin and subcutaneous tissue disorders may be more common than previously predicted, it is recommended that PwMS receiving treatment with cladribine tablets should undergo careful clinical surveillance for dermatological symptoms, consisting of a complete clinical examination of the skin at regular intervals [40]. These side effects relating to cladribine tablets are depicted in Fig. 8.

Currently there is limited evidence for an increased risk of malignancies with cladribine tablets, with incidences per 100 patient-years being 0.15 with placebo and 0.29 in those taking cladribine tablets [34]. As these numbers are low, statistical methods may not show difference in the rate of malignancies with cladribine, compared with other disease-modifying therapies [36]. This suggests that the risk is theoretical and warrants further investigation in long-term trials.

When Side Effects Are Likely to Happen and for How Long

During years 1 and 2 of treatment with cladribine tablets, there are rapid reductions in absolute lymphocyte counts [19]. Cladribine is removed from the body within 1 week of treatment [15], with the lowest overall lymphocyte levels in years 1 and 2 of treatment being seen after 2 months and 7 weeks of treatment, respectively [18]. With many side effects being related to this reduction in lymphocytes, it is likely that many of these side effects will occur around 2 months after treatment with cladribine tablets, while lymphocyte levels are low. Recovery to normal or grade 1 lymphopenia is expected to occur within 9 months in most PwMS receiving cladribine tablets, without prolonged side effects over the 9 months [16].

How Cladribine Tablets Affect Family Planning and Fertility

MS is often diagnosed in individuals of childbearing age; therefore, understanding the risks associated with pregnancy when undertaking a new disease-modifying treatment is important [41]. Currently, the risk of congenital malformations in human pregnancies exposed to cladribine tablets is not higher than expected [41,42,43]. However, as cladribine tablets affect DNA synthesis and repair in some cell types, treatment with cladribine tablets potentially raises a risk of serious harm to an unborn fetus, as supported by rodent studies showing lethality or induction of malformations to embryos [16, 21]. As a result of this, the CLEAR study, which is currently ongoing and involves data from various healthcare databases and registries of PwMS, aims to detect rare side effects of cladribine tablets on pregnancy [44]. Cladribine can also be transferred via the semen of people receiving treatment with cladribine tablets, which could potentially be harmful to the fetus [21]. Pregnancy should therefore be prevented during, and for at least 6 months after, the last dose of cladribine tablets through the use of effective methods of contraception (i.e., a method with a failure rate of less than 1% per year when used consistently and correctly) [16, 21]. A second barrier method of contraception, such as condoms, should be taken if currently using hormonal contraceptives such as the contraceptive pill [16, 21].

Recent pregnancy outcomes data, such as birth weight and gestational week at birth, gained from PwMS who had cladribine tablet exposure either within 6 months or beyond 6 months of treatment were seen to be comparable to the general population [45]. This indicates that there is no increased risk of pre-term birth or low birth weight [45].

Counselling is required before initiation of treatment with cladribine tablets, in both years 1 and 2, to fully explain to both those taking cladribine tablets and their partners the potential for serious risk to the fetus and the need for effective contraception to avoid becoming pregnant [16, 21]. A timeline of when contraception and counselling is required during treatment can be found in Fig. 9.

Fig. 9
figure 9

Highly effective contraception is required during treatment and for 6 months after the final cladribine tablet. This timeline highlights the requirement of counselling prior to receiving treatment and when the use of contraception is required

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Box 8: Describing to PwMS How Cladribine Tablets Affect Pregnancy and Fertility

Discussions around family planning will occur before treatment with cladribine tablets is started.

∙ If a person is pregnant, they must not take cladribine tablets [16, 21].

∙ If the person with MS or their partner becomes pregnant, it is important to contact the doctor as soon as possible to discuss any potential risks with the pregnancy [16, 21].

∙ Cladribine tablets taken within the 6 months before or during pregnancy may cause miscarriages or birth defects [16, 21].

∙ Cladribine tablets may affect semen, which could harm any unborn child conceived while on treatment [16, 21].

∙ It is important for individuals with childbearing potential to use effective contraception to avoid pregnancy or getting another individual pregnant during treatment with cladribine tablets and at least 6 months after the last cladribine tablet [16, 21].

    ◦ A person with MS should seek advice and guidance on appropriate contraceptive methods from their doctor [16, 21].

∙ In individuals with MS who became pregnant whilst taking cladribine tablets and gave birth, the child’s weight at birth and the total number of weeks of pregnancy were seen to be the same as data from the general population. This suggests no increased risk of giving birth early or the child being born underweight [45].

∙ Tests on the effects of cladribine tablets on fertility have only been done on animals.

    ◦ No effects on fertility (the ability to conceive a pregnancy) have been seen in animal studies [16, 21].

Use of Vaccines with Cladribine Tablets

Similar to other therapies that reduce lymphocyte counts, treatment with cladribine tablets should not be initiated within 4 to 6 weeks of vaccination with live or attenuated virus because of a risk of active vaccine infection [16, 21]. While most vaccinations can be administered alongside cladribine tablets, vaccination with live or attenuated live vaccines should be avoided during and after cladribine tablets treatment until the white blood cell counts of the person with MS return to within normal limits [16, 21]. A timeline of when live and attenuated vaccines should not be administered or should be avoided can be found in Fig. 10. Recent data found that the majority of PwMS who underwent vaccinations against seasonal influenza and chickenpox (varicella) while taking cladribine tablets gained additional protection from these diseases [46, 47]. Data from the 2023 study by Rolfes et al. showed an increase in seroprotective titers for all strains of influenza in the majority of cladribine patients who received the seasonal influenza vaccine [47]. This seroprotection occurred irrespective of when vaccination took place and total lymphocyte counts [47].

Fig. 10
figure 10

Vaccine safety during cladribine tablet treatment. A timeline showing that live or attenuated vaccines should not be taken within 3–4 weeks of treatment

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With regards to coronavirus-19 (COVID-19) vaccinations, a recent consensus found that all experts agreed that PwMS being treated with cladribine tablets should be vaccinated as soon as possible, unless they have contraindications. All experts also highlighted that there is no current evidence that the COVID-19 vaccination will lead to an MS relapse or permanent disease worsening in PwMS receiving cladribine tablets [48].

Box 9: Explaining How Cladribine Tablets Affect Vaccines to PwMS

∙ Most vaccinations can be taken alongside cladribine tablets [21].

    ◦ These types include vaccines that use a killed version of the virus or bacteria (inactivated vaccines) or by using specific pieces of the virus or bacteria. Please speak to your healthcare provider for further advice on specific vaccines [49].

∙ In scientific studies, the level of protection provided by vaccines against seasonal flu and chickenpox was not negatively affected by treatment with cladribine tablets, regardless of whether people were vaccinated within 6 months or around 9 months after cladribine tablets treatment [46, 47].

∙ Vaccines that include live or weakened forms of a virus or bacteria should not be taken 4–6 weeks before starting treatment with cladribine tablets [16, 21].

    ◦ Examples of this kind of vaccine are vaccines for measles, mumps , and rubella (MMR) [49].

    ◦ This type of vaccine should be avoided until the number of immune cells has returned back to normal, after treatment with cladribine tablets has ended.

    ◦ Speak to your healthcare provider if you are unsure about vaccines [16, 21].

COVID-19 Vaccines

∙ It is important to take a COVID-19 vaccine as soon as possible.

∙ Experts have agreed that the risks of getting a COVID-19 infection are greater than the risks of taking a vaccine for COVID-19 [48].

∙ Experts have highlighted that COVID-19 vaccines do not increase the risk of relapse or worsening symptoms in people receiving cladribine treatment [48].

Discussion

The cladribine tablets clinical development program reported the efficacy, including long-term follow-up data, safety, and tolerability of cladribine tablets [26, 27, 35, 39, 50]. Post-approval data are also available and continue to support the initial clinical trial findings [30, 51,52,53,54,55,56]. Recent real-world data has highlighted that cladribine tablets are associated with more favorable relapse outcomes and significantly greater treatment persistence than other oral disease-modifying therapies such as fingolimod and dimethyl fumarate [57].

Other oral MS medications require consistent and regular tablet taking, which can be a burden to PwMS, and may result in missed doses and potentially suboptimal outcomes. This issue may be ameliorated by short-course treatment with cladribine tablets, which requires 8–10 days of administration per year over 2 years, with one dose a day during this time, although there are currently no data assessing the impact of treatment burden on clinical outcomes in PwMS. High adherence to cladribine tablets at year 2 was supported by results gained from a recent multinational, nurse-/pharmacy-led, patient support program [58]. The requirement for long-term, frequent dosing of other oral treatments, and many MS treatments in general, can lead to questions from PwMS relating to the mechanism and outcomes of short-course treatments, such as cladribine tablets. It may, therefore, be helpful for HCPs to focus on how cladribine tablets work in terms of the immune system and the resultant clinical outcomes and potential safety issues related to this mechanism of action. This manuscript has been developed with this conversational framework in mind, alongside useful visual tools and language aids, should they be required.

Here we aim to facilitate better conversations between HCPs and PwMS around key topics relating to cladribine tablets and their use. We have provided this information to HCPs in a plain language format to assist in answering identified key questions during discussions between HCPs and PwMS.

Conclusions

Better understanding of health information can lead to better patient experiences. A group of HCPs and PwMS experts identified key topics of interest around cladribine tablet treatment and used these to help identify knowledge gaps PwMS may have relating to this treatment, which may need to be addressed in discussion during consultations. This manuscript was developed to provide clear and concise responses to patient feedback on the most important aspects of these topics, to facilitate conversations and increase the involvement of PwMS in decision-making on whether to take cladribine tablets. This also helps ensure treatment choices are appropriately tailored to individuals, which may lead to improved clinical outcomes.