Cladribine

Mechanism of Action

Cladribine is an analog of deoxyadenosine that contains a substitution of a chlorine atom for a hydrogen atom at position 2 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.

T-cell and B-cell lymphocytes play a complex role in the immunopathology of multiple sclerosis, 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 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, multiple sclerosis 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 multiple sclerosis.[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 multiple sclerosis.[11]

Administration

Cladribine for multiple sclerosis is an orally administered drug. The FDA-approved dose is 3.5 mg/kg over 2 years, administered as 1.75 mg/kg per year. Two treatment courses are separated by 12 months. The first course is given over 4 to 5 consecutive days in the first month, followed by an equivalent dose over 4 to 5 consecutive days in the second month.

The second course of cladribine follows 12 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 the drug's approval in Europe and the USA. In a retrospective data analysis 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 with a normal absolute lymphocyte count at CLARITY baseline and recovered to grade 0 or 1 lymphocyte counts before retreatment with cladribine tablets. 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 multiple sclerosis, 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]

Contraindications

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.

Monitoring

Laboratory studies that require checking before considering oral cladribine as a multiple sclerosis 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 multiple sclerosis start taking cladribine, they need complete blood counts with differential cell counts monitored at months 3 and 7 following each cladribine course over the following 2 years. If the drug is well-tolerated, routine monitoring of blood tests may not be necessary after the first 2 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 multiple sclerosis 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 healthcare outcomes for adults living with multiple sclerosis. However, one must still address the role of comprehensive multiple sclerosis care centers in administering complex immunosuppressive medications and other aspects of multiple sclerosis care.

The Kurtzke Expanded Disability Status Scale (EDSS) is a commonly used quantitative measure of multiple sclerosis-related disability. Developed by the late neuroepidemiologist John F. Kurtzke, MD in 1983, the EDSS compiles disability ratings in 8 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 multiple sclerosis).[15] EDSS scores have served as a key outcome measure in many clinical trials, including the oral cladribine trials for multiple sclerosis. 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 multiple sclerosis (N=1326).[12] Participants with relapsing multiple sclerosis were randomly allocated to 1 of 3 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] 

Lower-dose and higher-dose oral cladribine reduced the risk of disability progression as measured by EDSS change scores at 3 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 3.5 mg/kg of cladribine tablets. Former CLARITY intervention-group patients (who had received either active doses in the original CLARITY trial) were re-randomized 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 2 years resulted in a durable clinical response that lasted at least 4 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 3.5 mg/kg of cladribine tablets reduced MRI markers of disease activity in patients with highly active relapsing multiple sclerosis. Cladribine conferred a 47% risk reduction for worsening EDSS scores 6 months post-treatment compared to placebo. A published subgroup analysis found that patients with the highest level of multiple sclerosis 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]

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 multiple sclerosis, 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 multiple sclerosis diagnostic criteria was published in 2017 and upheld cladribine’s efficacy in early multiple sclerosis. 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, multicenter, 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 a multiple sclerosis 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.[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 multiple sclerosis 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]

Together, these data from the oral cladribine trials show an impressive potential to improve a range of healthcare outcomes for adults with multiple sclerosis. Potential concerns regarding the use of cladribine include patient safety issues, such as lymphopenia, and the need for extended monitoring for the effects of prolonged immunosuppression. For these reasons, the manufacturer recommends that clinicians reserve cladribine for adults who had an inadequate response to or did not tolerate other multiple sclerosis 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 multiple sclerosis 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 multiple sclerosis care centers offer a cross-disciplinary team approach to delivering state-of-the-art multiple sclerosis disease-modifying therapy and symptom management while serving as centers for multiple sclerosis research.

Staff typically include multiple sclerosis specialist neurologists, researchers, physiatrists, clinical psychologists, neuropsychologists, multiple sclerosis nurses skilled in administering specialized infusions, physical and occupational therapists, speech and language pathologists, pharmacists, nutritionists, social workers, and other multiple sclerosis professionals. Team members collaborate to provide a systematic approach to diagnosis and disease monitoring, administering immunosuppressive therapies, monitoring for adverse effects, treatment sequencing, and coordinated management of multiple sclerosis 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 and the Multiple Sclerosis Association of America.[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 multiple sclerosis, all these disciplines must work and communicate collaboratively to effectively use cladribine to treat these patients and achieve optimal outcomes.

With help from multiple sclerosis comprehensive care centers, cladribine, and other cutting-edge multiple sclerosis disease-modifying therapies, it will be more likely to benefit a broader population of people living with multiple sclerosis. All clinicians tasked with caring for people with multiple sclerosis 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.