Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712)

Abstract

Recent studies have suggested that ritux- imab has clinical activity and modulates antiapoptotic proteins associated with drug resistance in chronic lymphocytic leukemia (CLL). We performed a random- ized phase 2 study to determine the effi- cacy, safety, and optimal administration schedule of rituximab with fludarabine in previously untreated CLL patients. Pa- tients were randomized to receive either 6 monthly courses of fludarabine concur- rently with rituximab followed 2 months later by 4 weekly doses of rituximab for consolidation therapy or sequential flu- darabine alone followed 2 months later by rituximab consolidation therapy. A total of 104 patients were randomized to the concurrent (n 51) and sequential (n 53) regimens. During the induction portion of treatment, patients receiving the concurrent regimen experienced more grade 3 or 4 neutropenia (74% versus 41%) and grade 3 or 4 infusion-related toxicity (20% versus 0%) as compared with the sequential arm. The consolida- tion rituximab therapy was tolerated well in both arms. All other toxicities were similar in the 2 arms. The overall re- sponse rate with the concurrent regimen was 90% (47% complete response (CR), 43% partial response (PR); 95% confi- dence interval (CI), 0.82-0.98) compared with 77% (28% CR, 49% PR; 95% CI, 0.66-0.99) with the sequential regimen. With a median follow-up time of 23 months, the median response duration and survival have not been reached for either regimen. Rituximab administered concurrently with fludarabine in previ- ously untreated CLL patients demon- strates marked clinical efficacy and ac- ceptable toxicity. Phase 3 studies using this combination approach for patients with CLL are warranted. (Blood. 2003;101: 6-14)