Immune reconstitution therapy (IRT) is an emerging management concept for relapsing multiple sclerosis (RMS), whereby a short course of treatment provides long-lasting suppression of disease activity. |
“Cladribine tablets 10 mg” refers to a total cumulative dose of cladribine given over 2 years (henceforth referred to as cladribine tablets 3.5 mg/kg); it is a relatively new treatment option, hypothesised to act as an IRT acting preferentially on the adaptive immune system. |
Results from randomised trials and from extensions to these trials have shown reductions in relapse rates that clearly outlasted the period of drug administration, consistent with an IRT-like mechanism. |
Treatment with cladribine tablets 10 mg is associated with a low rate of serious infections. |
The monitoring burden associated with the treatment is also low compared with other high-efficacy disease-modifying drugs for RMS. |
We describe the therapeutic profile of cladribine tablets 3.5 mg/kg and provide practical information on initiating this treatment in the most appropriate patients. |
Introduction
Brief Overview of Immune Reconstitution Therapy
Therapeutic Profile of Cladribine Tablets 3.5 mg/kg in Relapsing–Remitting Multiple Sclerosis
Effects on the Immune System
Clinical Efficacy
Parameter | Main finding (for cladribine tablets 3.5 mg/kg except where stated)a |
---|---|
Randomised phase | |
Annualised relapse rate [10] | Lower for cladribine tablets 3.5 mg/kg (0.14) vs. placebo (0.33) (p < 0.001) |
% Relapse free [10] | Higher for cladribine tablets 3.5 mg/kg (79.7%) vs. placebo (60.9%) (p < 0.001) |
Disability progression [10]b | Hazard rate 0.67 (95% CI 0.48–0.93) (p = 0.02) for sustained 3-month EDSS progression for cladribine tablets 3.5 mg/kg vs. placebo |
Extension phase | |
Relapse rates [15] | Maintained efficacy in the 2-year extension phase for patients continuing on cladribine tablets 3.5 mg/kg or re-randomised to placebo—efficacy persisted after recovery of lymphocytes |
About 75% re-randomised from cladribine tablets 3.5 mg/kg to placebo for 2 years remained relapse free | |
Disability progression [15] | No difference in 3-month confirmed EDSS progression between groups irrespective of order of cladribine tablets 3.5 mg/kg or placebo administration |
MRI activity [16]c | 90.4% relative reduction in T1 Gd + lesions at the end of the extension compared with the end of the randomised phase for patients re-randomised from placebo to cladribine tablets 3.5 mg/kg for the extension phase |
There was some reactivation of MRI activity mainly associated with longer gaps between the randomised and extension phases of the study | |
Post hoc and subgroup analyses | |
Sustained NEDA [11]d | Cladribine tablets 3.5 mg/kg vs. placebo (all comparisons are p < 0.001) |
24 weeks: 67% vs. 39%; OR 3.31 (95% CI 92.46–4.46) | |
48 weeks: 54% vs. 24%; OR 3.80 (95% CI 2.77–5.22) | |
96 weeks: 44% vs. 16%; OR 4.25 (95% CI 3.05–6.02) | |
Patient subgroups [12] | Consistent reductions in risk of relapse in patients stratified for gender, gender; age; MS duration; prior DMD treatment (or not); relapses in prior year; EDSS; baseline MRI lesions (all p ≤ 0.05) |
High baseline disease activity [13]e | 47% reduction in the risk of 6-month EDSS progression in a subgroup with high disease activity at baseline |
Health economics [14] | Reduced need with cladribine tablets 3.5 mg/kg vs. placebo for inpatient treatment (difference – 3.19 days, emergency room visits (– 0.09) or clinic visits (–0.68) (all p ≤ 0.01) |
Safety and Tolerability
Practical use of Cladribine Tablets 3.5 mg/kg in the Management of Multiple Sclerosis
Initiation—Who?
Therapeutic indication |
Highly active relapsing–remitting multiple sclerosis (on clinical or imaging features) |
Contraindications |
Infection with human immunodeficiency virus |
Active tuberculosis or hepatitis infection |
Immunocompromised patients (including iatrogenic causes) |
Moderate or severe renal impairment (creatinine clearance < 60 mL/min)a |
Active malignancy |
Pregnancy and breastfeeding |
Not recommended |
Moderate or severe hepatic impairmenta |
Prescribe with caution |
Elderly (> 65 years)a |
Before first prescription |
Measure lymphocyte count (must be normal) |
Screen for/treat latent infections, especially tuberculosis, hepatitis B and C, varicella zoster |
Check for/treat acute infections |
Vaccination recommended for varicella-zoster antibody-negative patients |
Baseline magnetic resonance imaging (≤ 3 months after treatment initiation) |
Compiled from Mavenclad® 10 mg tablets European Summary of Product Characteristics [5]. Information is paraphrased for brevity: local full labelling should be checked before prescribing |
aDue to insufficient clinical trial data available for unrestricted indication in these populations |
Contraception |
Counsel women of childbearing potential and men who could potentially father a child on the need for effective contraception during, and for at least 6 months after, administration of cladribine tablets 3.5 mg/kg |
Women using systemic hormonal contraception should add a barrier method during, and for 4 weeks after, administration of cladribine tablets 3.5 mg/kg |
Pregnancya |
Pregnancy must be excluded before initiation of treatment with cladribine tablets 3.5 mg/kg |
Stop treatment immediately if pregnancy occurs during administration of cladribine tablets 3.5 mg/kg |
Breastfeedinga |
Women should not breastfeed during treatment with, and for 1 week after, administration of cladribine tablets 3.5 mg/kg |
Compiled from Mavenclad® 10 mg tablets European Summary of Product Characteristics [5]. Information is paraphrased for brevity: local full labelling should be checked before prescribing |
aRequirements for avoidance of pregnancy and breastfeeding apply to both treatment years 1 and 2 |
Initiation—How?
Measure lymphocyte counts immediately before each treatment course, and at 2 and 6 months after each treatment course |
Lymphocyte count must be > 800 cells/mm3 before the year 2 treatment course of cladribine tablets 3.5 mg/kga |
Initiate prophylactic treatment for herpes (varicella) zoster lymphocyte if count drops to < 200 cells/mm3 |
Monitor for infections if lymphocyte count falls to < 500 cells/mm3 (especially herpes zoster) and monitor lymphocyte count actively until it recovers |
Compiled from Mavenclad® European Summary of Product Characteristics [5]. Information is paraphrased for brevity: local full labelling should be check before prescribing |
aThe second treatment course can be delayed for up to 6 months before the second treatment course is started; withdraw treatment if lymphocyte count remains insufficient |
Prior treatment | Suggested time to wait before switching from prior treatment to cladribine tablets |
---|---|
Glatiramer acetatea | None, or until remission of treatment-specific effects |
Interferon-β
1a
b
| None, or until remission of treatment-specific effects |
Interferon-β1b | None, or until remission of treatment-specific effects |
Dimethyl fumarate | None, or until remission of treatment-specific effects |
Teriflunomide | ≥ 4 weeks, or until remission of treatment-specific effects |
Fingolimod | ≥ 4 weeks, or until remission of treatment-specific effects |
Natalizumab | ≥ 6–8 weeks, or until remission of treatment-specific effects |
Alemtuzumab | ≥ 6–12 months, or until remission of treatment-specific effects |