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 the DNA synthesis pathway, where it disrupts DNA repair and synthesis, resulting in an accumulation of DNA strand breaks This is followed by the activation of transcription factor p53, the release of cytochrome c from mitochondria and eventual programmed cell death (apoptosis). This process occurs over approximately 2 months, with a peak level of cell depletion 4–8 weeks after treatment.Another family of enzymes, the 5-nucleotidase (5-NT) family, is also capable of dephosphorylating cladribine, making it inactive. The most important subtypes of this group appear to be cytosolic 5-NT, c-5NCT1A and c-NT1B, which are cytosolically active and specific for purine analogues.Accumulation of cladribine into cells is dependent on the ratio of 2-CdATP and 5-NT. This ratio differs between cell types, with high levels in T and B lymphocytes, making them particularly susceptible to cell death. The cells with the highest ratios are B cells, especially germinal centre and naïve B cells. This helps to explain which B cells are more vulnerable to cladribine-mediated apoptosis. DCK is the rate-limiting enzyme for conversion of the cladribine prodrug into its active triphosphate form, leading to the selective depletion of dividing and non-dividing T and B lymphocytes.
Due to this increased risk, it is recommended that patients are screened for varicella zoster virus and antibody-negative patients are vaccinated prior to receiving treatment. In an analysis of post-approval data, as of 2020, no new infection safety signals were observed in over 18,000 patients.Progressive multifocal leukoencephalopathy has been reported in patients with hairy cell leukemia treated with parenteral cladribine. However, in up to 10 years of follow-up of patients receiving cladribine tablets for multiple sclerosis, no cases of progressive multifocal leukoencephalopathy have been observed; baseline MRI must be performed prior to initiating treatment.In clinical trials, malignancies were observed more frequently in patients treated with cladribine tablets compared with patients who received placebo. Compared with a matched reference population from the Global Cancer Observatory  database, cladribine tablets had no increased risk of malignancy in long-term real-world evidence data. Research directions
Cladribine has been studied as part of a multidrug chemotherapy regimen for drug-resistant T-cell prolymphocytic leukaemia. References
External links
"Cladribine". Drug Information Portal. U.S. National Library of Medicine.