Review: Purine nucleoside analogues: Fludarabine, pentostatin, and cladribine: Part 1: Fludarabine

Purpose. An introductory template for an extensive discussion of the pharmacology, pharmacokinetics, clinical use and adverse effects of the currently ap proved adenosine analogues: fludarabine, pentostatin, and cladribine is profiled. This is part one of a three-part series. Data Sources. We reviewed the literature through a MEDLINE search from 1986 to 1996. Relevant articles cited in literature obtained by MEDLINE searching were also considered. We searched the following terms: fludarabine, cladribine, pentostatin, apoptosis and adenosine ana logues. The search was restricted to the English language. We have incorporated pricing information from our prac tice sites as well as the average wholesale price for the purpose of cost comparison. Data Extraction. We have reviewed the current literature with regard to the chemistry, mechanisms of action and pharmacology, pharmacokinetics, clinical use, adverse effects, drug interactions, indications, formulation, dosage, administration, pharmaceutical issues and a cost comparison of the currently approved adenosine ana logues, fludarabine, pentostatin, and cladribine. Data Synthesis. The adenosine analogues are struc turally similar agents used in the management of hemato logical malignancies. Fludarabine and cladribine exhibit significant activity in CLL (chronic lymphocytic leukemia) and NHL (non-Hodgkin's lymphoma) and pentostatin and cladribine are both active in the treatment of hairy cell leukemia. There are no comparative clinical trials between the agents and we have provided comparisons based on pharmacology, clinical experience, adverse effects and cost as well as reviewing the clinical use of these agents. Conclusion. The adenosine analogues, fludarabine, pentostatin, and cladribine, represent an important ad vance in the treatment of indolent lymphoid malignancies. Although response rates for fludarabine and cladribine in chronic lymphocytic leukemia and for pentostatin and cladribine in hairy cell leuemia are improved over standard therapy, the true clinical impact of these agents has not yet been realized. Additional studies in larger populations of both previously treated and untreated patients, as well as comparative trials between the deoxyadenosine analogues themselves need to be carried out. Moreover, combination chemotherapy trials with deoxyadenosine analogues and other cytotoxic agents need to be performed to determine the efficacy and toxicity of these combinations in various lymphoid malignancies.