Therapy of chronic lymphocytic leukaemia with purine nucleoside analogues: facts and controversies.

Chronic lymphocytic leukaemia (CLL) is a neoplastic disease of unknown aetiology characterised by an absolute lymphocytosis in peripheral blood and bone marrow. The disease is diagnosed most commonly in the elderly with the median age at diagnosis being about 65 years. The purine nucleoside analogues (PNAs) fludarabine, cladribine (2-chlorodeoxyadenosine) and pentostatin (2'-deoxycoformycin) are highly active in CLL, both in previously treated and in refractory or relapsed patients. These three agents share similar chemical structures and mechanisms of action such as induction of apoptosis. However, they also exhibit significant differences, especially in their interactions with enzymes involved in adenosine and deoxyadenosine metabolism. Recent randomised studies suggest that fludarabine and cladribine have similar activity in CLL. However, clinical observations indicate the existence of cross-resistance between fludarabine and cladribine. Patients who received PNAs as their initial therapy and achieved long-lasting response can be successfully retreated with the same agent. PNAs administered in combination with other chemotherapeutic agents and/or monoclonal antibodies may produce higher response rates, including complete response (CR) or molecular CR, compared with PNAs alone or other treatment regimens. Management decisions are more difficult in elderly patients because of the apparent increase in toxicity of PNAs in this population. In elderly patients, we recommend chlorambucil as the first-line treatment, with PNAs in lower doses in refractory or relapsed patients. Myelosuppression and infections, including opportunistic varieties, are the most frequent adverse effects in patients with CLL treated with PNAs. Therefore, some investigators recommend routine antibacterial and antiviral prophylaxis during and after PNA treatment. This review presents current results and treatment strategies with the use of PNAs in CLL, especially in elderly patients.