Cladribine

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 to have 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]

The discovery of cladribine in the late 20th century 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 for the administration of 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 to 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. 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 of EDSS scores at 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.[17][18][19][20][21]  [Level I]

Oral Cladribine in Early Multiple Sclerosis (ORACLE MS) was another multicenter, 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 mean numbers of missed work days by approximately 2.5 days compared to placebo (p > 0.01). Corticosteroid use was lower among participants in the cladribine groups.[25][26] [Level I] 

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. We also recommend 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 units, is a specialized program that offers an interprofessional and patient-centered approach to the diagnosis, treatment, and management of 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 including 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, administration of 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, 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 various disciplines need to work and communicate collaboratively to effectively use cladribine in a regimen to treat these patients and achieve optimal outcomes. [Level V]

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 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 members of the team, leading to improved patient outcomes. [Level V]