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Editor: Elizabeth H. Morrison Updated: 3/20/2023 12:06:35 AM


Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of the central nervous system that results in loss of oligodendrocytes, astroglial scarring, and axonal injury. Certain clinical features are typical of MS, but the disease has a highly variable presentation. Neurological symptoms present through time and space, making it a complex disorder with atypical forms. Major subtypes include relapsing MS, secondary progressive MS, and primary progressive MS.[1][2] Relapsing MS is the most common form, characterized by cycles of relapses (exacerbations with a sustained worsening of demyelinating symptoms compared to baseline) and remissions (no clinical evidence of disease activity), with variable frequency and duration. Secondary progressive MS presents as a steady decline in neurological function.[3][4] Primary progressive MS is less common and presents with an insidious onset of demyelinating symptoms followed by steady symptom progression with no discrete relapses. This activity considers cladribine, an oral drug recently approved by the FDA for relapsing MS.[5][6]

Cladribine (2-chlorodeoxyadenosine [2-CdA]) is a synthetic deoxyadenosine (purine) analog classified as an anti-metabolite and anti-pyrimidine agent.[1] Drs. Beutler and Carson, two scientists working in the Scripps Institute, discovered and synthesized the compound during the 1980s. They incidentally found that adenosine deaminase (ADA) deficiency led to the destruction of B-cell lymphocytes by causing deoxynucleotides to accumulate in the cells.[2][3] With this knowledge, they hypothesized that it would effectively treat lymphoma and hairy cell leukemia by targeting B-cell lymphocytes. They subsequently found cladribine highly effective for inducing remission in hairy cell leukemia. In 1991, Johnson and Johnson mass-manufactured and marketed cladribine for hairy cell leukemia after gaining FDA approval. Dr. Beutler collaborated with Dr. Sipe, a neurologist at Scripps, to test the drug for aggressive multiple sclerosis. Drs. Sipe, Beutler, Carson, and other key collaborators hypothesized that cladribine could treat MS by targeting subpopulations of B- and T-lymphocytes, acting as a selective immune reconstitution therapy (SIRT). Cladribine acts as a short-term immunosuppressant relative to other maintenance MS therapies that result in long-term immunosuppression.[4][5][7]

Cladribine went through several steps in regulatory approval before Merck-Serono released data from the Cladribine Tablets Treating MS Orally (CLARITY) trial in 2008. This study showed cladribine's gradual but steady acceptance in the European medical community as an effective and safe drug for MS. CLARITY was a randomized, double-blind, placebo-controlled trial treating 1326 patients with relapsing MS (defined by revised McDonald criteria) to receive either placebo, lower-dose cladribine or higher-dose cladribine. The trial showed a 58% reduction in annualized relapse rates at two years with a lower dose of cladribine and a 55% reduction with a higher dose. The European Medicines Agency (EMA) granted cladribine final approval in August of 2017 for relapsing MS. In 2019, the US FDA approved oral cladribine for relapsing MS after several landmark studies (CLARITY extension, ORACLE MS, and ONWARD trials) supported the results of the original CLARITY trial. These studies redemonstrated that cladribine reduced lesion activity on MRI increased the percentage of relapse-free patients, and decreased disability progression by 30%. This article will summarize cladribine's mechanism, administration, known adverse effects, monitoring, treatment regimen, and relevant clinical trials, and will also discuss interprofessional coordination of care related to MS management.[8]

Mechanism of Action

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Mechanism of Action

Cladribine is an analog of deoxyadenosine that contains a substitution of a chlorine atom for a hydrogen atom at position two of the purine ring, rendering it resistant to deamination by adenosine deaminase (ADA). It mimics severe immunodeficiency disorder by selectively disrupting T-cell (cell-targeting) and B-cell (humoral) immunity. Within cells, high cladribine concentrations increase the expression of deoxycytidine kinase (DCK), leading to lymphocyte apoptosis. The phosphorylated form of cladribine disrupts intracellular processes, inhibiting DNA synthesis/repair, ribonucleotide enzymes, and alternating endonuclease activity—low intracellular levels of cladribine increase phosphatase 5’-nucleotidase, which inactivates phosphorylated (active) cladribine.  

Both T-cell and B-cell lymphocytes play a complex role in the immunopathology of MS, activating a cascade of inflammatory cytokines and antibodies directed against various central nervous system components, including myelin autoreactive T-cells.[1][2] Activated T and B cells then augment other proinflammatory cytokines in the serum and cerebrospinal fluid, raising chemokine levels, adhesion molecule expression, and mononuclear cell migration.[3][4] In histopathological slides, MS brain slices stain concurrently with CD8+ and CD4+ lymphocytes, showing that B-cell activation correlates with the formation of oligoclonal immunoglobulin G bands. These oligoclonal bands are a clinically useful CSF marker for MS.[7][8][9][10] Cladribine dampens these immune responses by targeting active immunity. The drug, clinically and radiographically, reduces the disease burden in people living with MS.[11]


Cladribine for multiple sclerosis is an orally administered drug. The FDA-approved dose is 3.5 mg/kg given over two years, administered as 1.75 mg/kg per year. Two treatment courses are separated by twelve months. The first course is given over four to five consecutive days in the first month, followed by an equivalent dose over four to five consecutive days in the second month.

The second course of cladribine follows twelve months later with the same frequency and dosing. For an adult of average body weight, dosing is estimated at approximately 10 to 20 mg daily for 4 to 5 days. Prescribers need to follow the manufacturer's specific guidelines for weight-based dosing according to approved federal guidelines of the Risk Evaluation and Mitigation Strategies (REMS) program. Monitoring occurs as described below to assure safe remission of the disease without severe lymphopenia or other adverse events.[9]

Adverse Effects

In clinical trials, cladribine’s most serious adverse effects have included lymphopenia and infections. These side effects delayed approval of the drug in Europe and the USA. In a retrospective analysis of data from the CLARITY and CLARITY Extension trials, severe lymphopenia was unlikely to occur with an oral cladribine dose of 3.5 mg/kg. More than 85% of patients taking FDA-approved doses of oral cladribine recovered to Common Terminology Criteria for Adverse Events grade 0 or 1 lymphocyte counts, and no patients developed grade 4 lymphopenia.[12]

Severe lymphopenia did not occur in cladribine patients who had a normal absolute lymphocyte count at CLARITY baseline and recovered to grade 0 or 1 lymphocyte counts before retreatment with cladribine tablets. Additional side effects include headaches, increased risk for herpetic infections or complications, nasopharyngitis, rashes, and alopecia. Although CLARITY investigators and others expressed initial concern that oral cladribine might increase the risk of malignancy in people with MS, neither the landmark ORACLE nor follow-up safety registry data from the PREMIERE study found any evidence of this risk, when given according to FDA-approved dosing guidelines of 3.5 mg/kg.[9][13]


People with multiple sclerosis should not take cladribine if they have hepatic cirrhosis, chronic kidney disease, active malignancy, HIV, or tuberculosis. Other contraindications to cladribine include a history of use of other immunosuppressants, including cyclophosphamide, azathioprine, methotrexate, or mitoxantrone. Sexually active men and women should receive counseling about cladribine’s teratogenicity and its effects on sperm quality and viability. Patients must be urged to maintain strict adherence to effective contraception before, during, and after taking cladribine.[14][13] The effects of cladribine in patients under age 18 are unknown, and these young people should avoid taking this medication.


Laboratory studies that require checking before considering oral cladribine as an MS disease-modifying therapy include complete blood count with differential, comprehensive metabolic panel, HIV screen, viral hepatitis panel, pregnancy test, and interferon-gamma release assay (QuantiFERON-TB). Clinicians must also monitor the medication history carefully; patients should not take cladribine with other immunosuppressive agents. Once people with MS start taking cladribine, they will need complete blood counts with differential cell counts monitored at months 3 and 7 following each cladribine course over the following two years. If the drug is well-tolerated, routine monitoring of blood tests may not be necessary after the first two years.[13]

Enhancing Healthcare Team Outcomes

In the late 20th century, the discovery of cladribine led to a long journey to FDA approval. As an oral medication given once a year as a maintenance dose, cladribine is an attractive option for MS disease-modifying therapy with important implications for patient experience, enhanced quality of life outcomes in different patient populations, and reduced health care costs. Several studies have shown that cladribine can improve health care outcomes for adults living with MS. However, one must still address the role of comprehensive MS care centers to administer complex immunosuppressive medications and other aspects of MS care.

The Kurtzke Expanded Disability Status Scale (EDSS) is a commonly-used quantitative measure of MS-related disability. Developed by the late neuroepidemiologist John F. Kurtzke, MD in 1983, the EDSS compiles disability ratings in eight functional systems domains (pyramidal, cerebellar, brainstem, sensory, bowel, and bladder, visual, cerebral, and ambulation) to generate a global disability score ranging from 0 (normal) to 10 (death due to MS).[15] EDSS scores have served as a key outcome measure in many clinical trials, including the oral cladribine trials for MS. For instance, Cladribine Tablets Treating Multiple Sclerosis Orally (CLARITY) was a multi-center, randomized, double-blind, placebo-controlled study of cladribine versus placebo in patients with relapsing MS (N=1326).[12] Participants with relapsing MS were randomly allocated to one of three study groups: cladribine tablets 3.5 mg/kg over 96 weeks, cladribine tablets 5.25 mg/kg over 96 weeks, or placebo. Compared to placebo, both doses of cladribine tablets showed decreased annualized relapse rates (ARR) and higher proportions of patients remaining relapse-free (p<0.001).[12] 

Both lower-dose and higher-dose oral cladribine reduced the risk of disability progression as measured by EDSS change scores at three months, compared to placebo (p=0.03). Following the CLARITY trial, CLARITY Extension was a 96-week study of the safety and efficacy of cladribine tablets that enrolled participants from the original CLARITY trial, including the CLARITY placebo group.[16] In CLARITY Extension, former CLARITY placebo-group patients received treatment with cladribine tablets 3.5 mg/kg. Former CLARITY intervention-group patients (who had received either of the active doses in the original CLARITY trial) were re-randomized either to cladribine tablets 3.5 mg/kg or placebo.[16]  Both absolute risk reduction and the proportion of relapse-free patients were similar across all CLARITY Extension study arms – including the placebo arm - showing that oral cladribine administered over two years resulted in a durable clinical response that lasted at least four years, even without retreatment.[16]

The original CLARITY placebo group, however, entered CLARITY Extension with a higher mean EDSS score, reflecting an increased disability level that followed these study participants through the CLARITY Extension monitoring period, as manifested by higher mean ARR (p<0.0001) and shorter time to first relapse compared with those CLARITY participants who had received either dose of cladribine.[17][18] More recently, a posthoc analysis of CLARITY data found that cladribine tablets 3.5 mg/kg reduced MRI markers of disease activity in patients with highly active relapsing MS. Cladribine conferred a 47% risk reduction for worsening EDSS scores six months post-treatment compared to placebo. A published subgroup analysis found that patients with the highest level of MS disease activity experienced the same or greater risk reduction (82% compared to placebo) compared with the rest of the CLARITY cohort, with a comparable safety profile.[19][20][21]  [Level 1]

Oral Cladribine in Early Multiple Sclerosis (ORACLE MS) was another multi-center, double-blind, randomized, phase III study of oral cladribine which showed a significant risk reduction compared to placebo for time to conversion to clinically definite MS, as measured by magnetic resonance imaging (hazard ratio [HR] for 5.25 mg/kg = 0.38, 95% CI 0.25 - 0.58, p<0.0001; HR for 3.5 mg/kg = 0.33, 95% CI 0.21 - 0.51, p<0.0001), for adults who had experienced a first clinically-isolated demyelinating syndrome (CIS).[22] Investigators stopped the ORACLE MS trial early because 5% of patients in the high-dose cladribine group and 2% in the low-dose cladribine group developed severe lymphopenia. A follow-up reanalysis of the ORACLE MS data using modern MS diagnostic criteria was published in 2017 and upheld cladribine’s efficacy in early MS. Stuve and colleagues demonstrated that cladribine-induced lymphopenia is reversible and that the T-cell and B-cell populations can reconstitute.[16] More recently, a phase II, multi-center, randomized study of add-on cladribine with interferon-beta (the ONWARD trial) found that 124 participants who were randomly assigned to receive cladribine 3.5 mg/kg plus IFN-ß (N=124) were 63% less likely to have an MS relapse compared with participants assigned to the placebo plus IFN-ß group (p < 0.001). Cladribine also reduced the mean number of new T1 and T2 MRI lesions in the combined treatment arm compared to placebo plus IFN-ß (Level I).[23][24] 

Published health services research has demonstrated further benefits of cladribine for quality improvement outcomes. For example, an economic analysis of the CLARITY and CLARITY Extension data showed that cladribine 3.5 mg/kg was associated with nearly a 50% reduction in the mean number of hospital admission days per person with MS over 96 weeks, compared with placebo. The mean value for emergency room visits was significantly lower (p <0.01) in both cladribine groups compared with placebo, as was the mean number of clinic visits (p =0.01). Treatment with cladribine reduced the mean number of missed workdays by approximately 2.5 days compared to placebo (p > 0.01). Corticosteroid use was lower among participants in the cladribine groups.[25][26] [Level 1] 

Considered together, these data from the oral cladribine trials show an impressive potential to improve a range of health care outcomes for adults living with MS. Potential concerns regarding the use of cladribine include patient safety issues that include lymphopenia and the need for extended monitoring for effects of prolonged immunosuppression. For these reasons, the manufacturer recommends that clinicians reserve cladribine for adults who had an inadequate response to or who did not tolerate other MS disease-modifying therapies. Recommendations may include referring patients who are potential candidates for cladribine to a comprehensive multiple sclerosis care center when possible. A comprehensive MS care center, or multiple sclerosis unit, is a specialized program that offers an interprofessional and patient-centered approach to diagnosing, treating, and managing multiple sclerosis. Comprehensive MS care centers offer a cross-disciplinary team approach to delivering state-of-the-art MS disease-modifying therapy and symptom management while serving as centers for MS research.

Staff typically include MS specialist neurologists, researchers, physiatrists, clinical psychologists, neuropsychologists, MS nurses skilled in administering specialized infusions, physical and occupational therapists, speech and language pathologists, pharmacists, nutritionists, social workers, and other MS professionals. Team members work collaboratively to provide a systematic approach to diagnosis and disease monitoring, administering immunosuppressive therapies, monitoring for adverse effects, treatment sequencing, and coordinated management of MS symptoms (including bladder and bowel dysfunction, cognitive changes, gait impairment, fatigue, and vision problems). They also offer referrals to support programs administered by partner agencies, including the National Multiple Sclerosis Society the Multiple Sclerosis Association of America, among others.[27] These interventions can increase patient satisfaction and quality of life by routinely monitoring patients’ EDSS scores and other indices, including fall risk assessment, routine assessment of cognition and vision, and risk of mistreatment, with the goal of early identification and intervention.[27][28] As part of an overall strategy to manage and treat MS, all these disciplines need to work and communicate collaboratively to effectively use cladribine to treat these patients and achieve optimal outcomes. [Level 5]

With help from MS comprehensive care centers, cladribine, and other cutting-edge MS disease-modifying therapies will be more likely to benefit a broader population of people living with MS. All clinicians tasked with caring for people with MS to reach out to these centers as needed. Other interprofessional healthcare team members, such as pharmacists and nurses, need to understand the clinical use of cladribine, including its dosing, adverse effects, contraindications, and interactions. In this way, they can advise and counsel patients, interact with prescribers, and contribute to the safe use of the drug through open communication and collaboration with other team members, leading to improved patient outcomes. [Level 5]



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