Cladribine, sold under the brand name Leustatin, among others, is a medication used to treat hairy cell leukemia (leukemic reticuloendotheliosis) and B-cell chronic lymphocytic leukemia.Cladribine, sold under the brand name Mavenclad, is indicated for the treatment of adult patients with highly active forms of relapsing-remitting multiple sclerosis.Cladribine (2-chloro-2-deoxyadenosine [2-CdA]) 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 adenosine. However, unlike adenosine, it is relatively resistant to breakdown by the enzyme adenosine deaminase, which causes it to accumulate in targeted cells and interfere with the cells 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 2-CdATP 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, CdATP:5NT is relatively low in other cell types, thus sparing numerous non-haematological cells. 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.
This reduction correlated with a reduced risk in disability progression in a retrospective analysis.In clinical trials, higher cumulative doses of cladribine tablets did not result in further improvement in efficacy nor did additional courses after the 2-year treatment period, but was associated with a higher incidence of Grade 3 and Grade 4 lymphopenia. Safety profile of cladribine tablets in multiple sclerosis
Cladribine tablets target the cells of the adaptive immune system with minimal impact on innate immune cells. Although the exact mechanism by which cladribine exerts its therapeutic effect is not fully elucidated, it is proposed to have a transient effect on B and T lymphocyte depletion, interrupting the cascade of immune events central to multiple sclerosis. As a result, a reduction in lymphocyte count (lymphopenia) may be reported following treatment. In clinical trials, lymphocyte levels above Grade 0 (≥1000 cells/mm3) and Grade 1 (<1000–800 cells/mm3) were maintained in most patients, with levels continuing to improve after the 2-year dosing period. Less than 1% of patients developed Grade 4 lymphopenia (<200 cells/mm3). It is important that patients with lymphocyte counts below 500 cells/mm3 should be actively monitored for signs suggestive of infection and that anti-infective treatments are given to at-risk patients.Despite the initial reduction in lymphocyte counts following treatment, studies showed the overall risk of infection in patients receiving cladribine tablets was comparable to those who received placebo, except for herpes zoster infection.