Abstract
Cladribine is currently registered as a 10-milligram tablet formulation with a fixed cumulative dosage of 3.5 mg/kg over 2 years. It is important to investigate if an increased dosage may lead to further clinical stability with preserved safety. This study used an off-label subcutaneous (s.c.) formulation of cladribine and compared outcomes (Expanded Disability Status Scale (EDSS) scores and disease progression) between 52 relapsing multiple sclerosis (RMS) patients receiving different s.c. dosing regimens with up to 20 years of follow-up. The study group received induction therapy with s.c. cladribine (1.8 mg/kg cumulative dose; consistent with 3.5 mg/kg of cladribine tablets). Patients were subsequently offered maintenance therapy (repeated courses of 0.3 mg/kg s.c. cladribine during 5–20-year follow-up). Forty-one patients received an increased cumulative dose (higher than the induction dose of 1.8 mg/kg); 11 received the standard induction dose. Risk of progression on the EDSS correlated with lower cumulative dose (p < 0.05) and more advanced disability at treatment initiation (p < 0.05) as assessed by EDSS change between year 1 and years 5 and 10 as the last follow-up. Maintenance treatment was safe and well-tolerated, based on limited source data. Subcutaneous cladribine with increased cumulative maintenance dosage was associated with disease stability and favorable safety over a prolonged period of follow-up (up to 20 years) in RMS patients.
Highlights
There has been substantial progress in understanding the pathogenesis of multiple sclerosis, which has led to the introduction of many successful disease-modifying drugs targeting different molecular pathways [1]
After intracellular activation by kinases, activated cladribine is cytotoxic to dividing and non-dividing lymphocytes due to its interference at several stages in nucleotide metabolism [3]. It has been extensively studied in different formulations [4,5,6], which led to the formal registration of a tablet formulation for the treatment of relapsing multiple sclerosis (RMS) [7,8]
Cladribine is currently registered as 10-milligram tablets (MAVENCLAD® ) with a fixed cumulative dose of 3.5 mg/kg body weight divided into two treatment cycles with a 1-year interval
Summary
There has been substantial progress in understanding the pathogenesis of multiple sclerosis, which has led to the introduction of many successful disease-modifying drugs targeting different molecular pathways [1]. After intracellular activation by kinases, activated cladribine is cytotoxic to dividing and non-dividing lymphocytes due to its interference at several stages in nucleotide metabolism [3]. It has been extensively studied in different formulations [4,5,6], which led to the formal registration of a tablet formulation for the treatment of relapsing multiple sclerosis (RMS) [7,8]. Despite previous studies including higher doses of cladribine, there is no consensus on whether it is safe to use repeated courses of treatment with a higher cumulative dose than the approved treatment regimen (3.5 mg/kg) to retain long-term clinical efficacy. It is important to investigate if increased dosage of cladribine might lead to further clinical stability with preserved safety following long-term observation
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