The favorable outcome of two patients with hairy cell leukemia in the Northwestern University study [1] of 2-CdA who had received previous DCF treatment supports our conclusion that cross-resistance may not exist between 2-CdA and DCF [2]. However, the number of treated patients is small, and, because of the subtle distinction between DCF intolerance and resistance, many more patients should be studied to draw firm conclusions.

Although DCF is a tight-binding inhibitor of adenosine deaminase, 2-CdA does not inhibit the enzyme directly, but rather resists deamination because of its chlorine atom at the two position of the purine ring. 2-Chlorodeoxyadenosine is phosphorylated to its putative active form, 2-chlorodeoxyadenosine triphosphate, by deoxycytidine kinase and dephosphorylated by 5'-nucleotidase. Lymphocytes have favorable ratios of deoxycytidine kinase to 5'-nucleotidase, favoring 2-CdA activation. Mean deoxycytidine kinase levels were higher and the 5'-nucleotidase levels were lower in patients with hairy cell leukemia who responded to 2-CdA than those among nonresponders [3]. Although these observations do provide insight into the prediction of response, many confounding issues remain. For example, the levels of deoxycytidine kinase were lower in patients with hairy cell leukemia than in those with chronic lymphocytic leukemia. This is difficult to explain because although 2-CdA is active in both diseases, it is dramatically more active in hairy cell leukemia, inducing complete and long-term remissions in most patients with only a single infusion of therapy. In chronic lymphocytic leukemia, however, it induces more partial than complete responses and requires multiple cycles of therapy [4].

The possible lack of cross-resistance between 2-CdA and DCF in hairy cell leukemia is difficult to explain at the molecular level because significant structural homology exists between these two molecules, and, from structure-activity considerations, one might expect their spectrum of activity and toxicity to be similar. Further investigation is required to understand fully these and other emerging clinical data, which will have important ramifications in future protocol design.