Alkylating agents and nucleoside analogues in the treatment of B cell chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the Western world. The natural clinical course is highly variable and chemotherapy is usually not indicated in early and stable disease. Treatment is needed in the progressive form of this leukemia. Chlorambucil, with or without steroids, has been for many years the drug of choice in the treatment of CLL. More recently, treatment approaches have included nucleoside analogues, (NA) fludarabine (FAMP) and cladribine (2-CdA, 2-chlorodeoxyadenosine), which seem to be the treatment of choice for patients failing standard therapies. Their role as first line therapy is being investigated in randomized trials and the results have recently been published. These studies have shown a higher overall response and complete remission (CR) rate and longer response duration in patients treated initially with NA than with chlorambucil or cyclophosphamide-based combination regimens. In contrast, overall survival is similar in patients treated with NA and alkylating agents. However, the randomized trials were designed as crossover studies which may influence survival. Combined use of NA with other cytotoxic drugs, cytokines, monoclonal antibodies and other agents may increase the CR and prolong survival time. However, the results of randomized trials comparing combination treatment with NA alone are not yet available. In conclusion, alkylating agents still have an important place in the routine management of the majority of CLL patients. NA should be routinely used as second line treatment and possibly as first line therapy in younger patients, who are candidates for potentially curative treatment such as stem cell transplantation and/or monoclonal antibodies.