Current Status of U.S. Clinical Trials in Chronic Lymphocytic Leukemia

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Abstract
Current therapies for chronic lymphocytic leukemia (CLL) have not substantially improved the survival of these patients (pts). As a result treatment has been primarily palliative. One major obstacle in designing innovative therapies has been a lack of new and effective agents. Recent interest in clinical trials has been stimulated by the impressive activity in pts with CLL of three unique purine analogues; fludarabine (FLUDARA), 2′-deoxycoformycin (DCF) and 2-chlorodeoxyadenosine (CDA). Of the three, the largest experience in CLL is with FLUDARA. More than 1200 CLL patients have received FLUDARA either on clinical trials or through the NCI-Group C protocol mechanism. In contrast to the published data, preliminary analysis of the first 87 evaluable Group-C patients revealed only 2% complete and 37% partial responses; this discrepancy can be explained by the fact that most patients were still receiving treatment at the time of the analysis, and many were continuing to respond (9 of 12 patients who received treatment for > 6 cycles responded); there was no central pathology review to confirm the diagnosis, 89% were Rai “high risk”, and most patients had received extensive prior therapy. An updated analysis of response in the first 300 cases is underway. Of 497 pts evaluable for toxicity, 41% developed infections which were serious in 17%, and there were episodes of serious neurotoxicity in 9%. Based on the high level of activity and relative tolerability of FLUDARA, a national U.S. phase III trial is underway comparing chlorambucil (CLB) vs FLUDARA vs CLB + FLUDARA in untreated patients with advanced disease. A comparison of FLUDARA vs CDA in relapsed/refractory pts is being planned. Combination regimens are being piloted in relapsed/refractory CLL including DCF + FLUDARA, DCF + CLB, FLUDARA + CDA, FLUDARA + interferon-alpha, FLUDARA + gallium, FLUDARA + cyclophosphamide. Since FLUDARA achieves true complete responses in a substantial number of previously untreated pts, it is being considered as part of an induction program prior to autologous bone marrow transplantation. FLUDARA has a high degree of bioavailability in dogs, and an oral preparation is being evaluated in clinical trials. Hopefully, new purine analogue-based combination regimens will improve the response rate and survival in patients with CLL.