Cladribine, sold under the brand name Leustatin, among others, is a medication used to treat hairy cell leukemia (formally named leukemic reticuloendotheliosis) and B-cell chronic lymphocytic leukemia. Cladribine, sold under the brand name Mavenclad, is used for the treatment of adults with highly active forms of relapsing-remitting multiple sclerosis. Cladribine is a purine analogue that selectively targets and suppresses lymphocytes implicated in the underlying pathogenesis of multiple sclerosis and B-cell leukaemia. Chemically, it mimics the nucleoside deoxyadenosine. However, unlike deoxyadenosine, it is relatively resistant to breakdown by the enzyme adenosine deaminase, which causes it to accumulate in targeted cells and interfere with the cell's ability to process DNA. Cladribine is taken up by cells via transporter proteins. Once inside a cell, cladribine undergoes phosphorylation by the enzyme deoxycytidine kinase (DCK) to produce mononucleotide 2-chlorodeoxyadenosine 5'monophosphate (2-CdAMP), which is subsequently phosphorylated to the triphosphorylated active compound 2-chlorodeoxyadenosine 5'triphosphate (2-CdATP). Activated cladribine is incorporated into cellular DNA, which triggers apoptosis. Accumulation of cladribine into cells is dependent on the ratio of DCK and 5'-nucleotidase (5'-NT), which breaks down and inactivates the compound. This ratio differs between cell types, with high levels in T and B lymphocytes, resulting in selective targeting of these cells. In contrast, DCK:5'NT is relatively low in other cell types, thus sparing numerous non-haematological cells. It is on the World Health Organization's List of Essential Medicines.
Medical uses Cladribine is used as a first- and second-line treatment for symptomatic hairy cell leukemia and for B-cell chronic lymphocytic leukaemia, and is administered by intravenous or subcutaneous infusion. Some investigators have used the parenteral formulation orally to treat patients with hairy cell leukemia. About 37–51% of oral cladribine is bioavailable orally. It is used, often in combination with other cytotoxic agents, to treat various kinds of histiocytosis, including Erdheim–Chester disease and Langerhans cell histiocytosis. Following EMA approval of cladribine tablets for the treatment of adult patients with highly active relapsing-remitting multiple sclerosis in 2017, as of July 2020, cladribine tablets have gained marketing authorisation in over 75 countries. In 2019, cladribine tablets were approved by the FDA for the treatment of relapsing forms of multiple sclerosis, to include relapsing-remitting disease and active secondary progressive disease, in adult patients who have had an inadequate response to, or are unable to tolerate, an alternate drug indicated for the treatment of multiple sclerosis. Cladribine may cause foetal harm when administered to a pregnant woman and is listed by the FDA as pregnancy category D; safety and efficacy in children has not been established.
Multiple sclerosis As per the EU label, cladribine tablets are indicated for the treatment of adult patients with highly active relapsing multiple sclerosis as defined by clinical or imaging features: (i) patients with a relapse in the previous year and at least one T1 Gd+ lesion or 9 or more T2 lesions, while on another disease-modifying therapies or (ii) patients with two or more relapses in the previous year, whether on disease-modifying treatment or not. Two main approaches to multiple sclerosis treatment maintenance therapy are used – immunomodulation and immunosuppression and alternatively, immune reconstitution therapy. Classified as the latter, cladribine tablets are administered intermittently as a short treatment course without continuous immunosuppression. In contrast to maintenance therapies, clinical efficacy extends beyond the dosing period. Cladribine tablets are administered as 2 courses separated by 1 year (a maximum of 20 days of treatment). The recommended cumulative dose is 3.5 mg/kg weight over 2 years, administered as 1 treatment course of 1.75 mg/kg per year. Each treatment course consists of 2 treatment weeks, one at the beginning of the first month and one at the beginning of the second month of the respective treatment year. Each treatment week consists of 4 or 5 days on which a patient receives 10 mg or 20 mg (1 or 2 tablets) as a single daily dose based on body weight. Before initiating treatment with cladribine tablets, blood tests, MRI and infection screening must be performed. Due to an increased risk of herpes zoster with cladribine tablets, patients who are antibody-negative for varicella zoster virus are recommended to be vaccinated before starting treatment. Treatment should not be initiated within 4 to 6 weeks of receiving a live or attenuated live vaccine because of a risk of active infection. Vaccination with live or attenuated live vaccines should also be avoided during and after treatment, but can be considered when lymphocyte counts have recovered to ≥1000 cells/mm3. Following completion of the two treatment courses, no further treatment or additional monitoring is required. The use of cladribine tablets is contraindicated in pregnant women, and women of childbearing potential must use effective contraception to prevent pregnancy during treatment and 6 months after receiving the last dose.
Side effects
In hairy cell leukemia Injectable cladribine suppresses the body's ability to make new lymphocytes, natural killer cells, and neutrophils (called myelosuppression); data from hairy cell leukemia studies showed that about 70% of people taking the drug developed dangerously low levels of white blood cells and about 30% developed infections and some of those progressed to septic shock; about 40% of people taking the drug had fewer red blood cells and became severely anaemic; and about 10% of people had too few platelets. At the dosage used to treat hairy cell leukemia in two clinical trials, 16% of people had rashes and 22% had nausea, the nausea generally did not lead to vomiting.
… excerpt ends here. Continue reading the full article.
