Rituximab (Rituxan), a chimeric anti-CD20 antibody, is effective as a single agent in chronic lymphocytic leukemia (CLL), down-regulates antiapoptotic proteins in CLL cells in vivo, and is minimally immunosuppressive. To further improve outcomes of previously untreated CLL patients receiving fludarabine (Fludara), the Cancer and Leukemia Group B (CALGB) conducted a randomized phase II trial of sequential vs concurrent rituximab(Drug information on rituximab).
All patients fulfilled the National Cancer Institute (NCI) definition of CLL and were symptomatic. Patients on the sequential arm (fludarabine followed by rituximab) received fludarabine (25 mg/m² days 1-5 every month × 6) induction followed 2 months later by rituximab (375 mg/m² repeated weekly × 4). Patients on the concurrent arm (fludarabine with rituximab) received therapy identical to the sequential arm, except rituximab (375 mg/m²) was also administered (days 1 and 4 of cycle 1; day 1 of cycles 2-6) with induction therapy. A total of 104 patients were enrolled. Median age was 64 years (range: 36-86 years). Modified Rai stage class was 59% intermediate and 41% high risk. Fludarabine induction toxicity included neutropenia (grade 3, 11%; grade 4, 30%), thrombocytopenia (grade 3, 8%; grade 4, 4%), and infection (grade 3, 19%; grade 4, 2%).
Nine of the first 44 patients (20%) on the concurrent fludarabine and rituximab induction arm developed grade 3/4 dyspnea or hypotension with full-dose rituximab on day 1 of therapy, as compared to none of the last seven patients utilizing stepped-up dosing (50 mg/m² day 1, 325 mg/m² day 3, 375 mg/m² day 5 of cycle 1 only). Other toxicities included neutropenia (grade 3, 31%; grade 4, 43%), thrombocytopenia (grade 3, 14%; grade 4, 6%), and infection (grade 3, 18%). Consolidation was tolerated well in both arms; grade 3/4 neutropenia was more common in the concurrent arm vs the sequential arm (37% vs 18%). Opportunistic infections were noted in 8 patients on the concurrent arm and 14 patients on the sequential arm. Fifteen of these were varicella-zoster (n = 5) or herpes simplex 1/2 (n = 10).
Response data using the modified NCI criteria are summarized in the table above.
CONCLUSION: These data suggest that the concurrent combination of rituximab with fludarabine is feasible after management of initial infusion toxicity for which a stepped-up dosing schedule has been introduced. Overall, toxicity on the two arms was similar. Complete response was more frequent on the concurrent arm than on the sequential arm, and toxicities were similar and acceptable. We plan to test concurrent fludarabine and rituximab in a phase III trial.