Purine analogs in chronic lymphocytic leukemia and Waldenström's macroglobulinemia

The observation of lymphopenia in children deficient in adenosine deaminase (ADA) led to exploration of an inhibitor of the enzyme in lymphoid malignancies; thus deoxycoformycin was the first purine nucleotide used in human trials. Fludarabine and 2-chlorodeoxyadenosine (2-CdA), agents resistant to deamination by ADA, have been utilized in the past decade. All of these drugs act as competitors for deoxyadenosine triphosphate at the A sites of the elongating DNA strand, terminating DNA synthesis. However, their remarkable efficacy in indolent lymphoid malignancies is not well explained by this mechanism of action. The induction of apoptosis and resultant cytotoxicity may be important in their activity. As a single agent, fludarabine has been associated with overall remission rates as high as 55% in previously treated patients and 79% in previously untreated patients. With this agent, a dosage regimen of 25-30 mg/m2 daily over 5 days seems to be the most effective to date. Fludarabine has shown more favorable remission rates than the traditional salvage regimens incorporating anthracyclines and alkylating agents. Regimens combining fludarabine with mitoxantrone and with doxorubicin have shown minimal therapeutic advantage in CLL, while combination with cyclophosphamide appears promising. Remission rates with deoxycoformycin have been lower than with fludarabine, but studies have been small in patient numbers. The agent 2-CdA, first successful in hairy-cell leukemia, has shown overall response rates in chronic lymphocytic leukemia similar to those seen with fludarabine. Whether or not cross-resistance occurs among the purine analogs has not been fully determined, but occasional patients with disease refractory to fludarabine have responded to 2-CdA. Cumulative myelosuppression and immunosuppression may be experienced however. In the B-cell neoplastic entity, Waldenström's macroglobulinemia, fludarabine therapy in patients previously treated with alkylating agents and/or steroids produced a 36% response rate. Only two previously untreated patients received fludarabine, and both responded. A similar response rate of 40% was seen when 2-CdA was administered to previously treated patients. This response rate increased to 85% in a study of 26 previously untreated patients, making this one of the most effective drugs yet investigated in this condition.