|
The combination of fludarabine, cyclophosphamide, and rituximab is the most effective front-line therapy in chronic lymphocytic leukemia, based on 5-year follow-up data from a single-arm study.
Dr. Constantine S. Tam reported on 300 patients who received fludarabine, cyclophosphamide, and rituximab (FCR) as initial therapy for chronic lymphocytic leukemia. Median follow-up was 62 months for survivors. Preliminary data were reported previously (J. Clin. Oncol. 2005;23:4079-88).
Of the 300 patients, 72% achieved complete remission as confirmed by the absence of morphologic disease on bone marrow biopsy. Of these, 78% had no detectable disease on flow cytometry.
Partial response was reported in 12%, and nodular partial response in 10%. Only 4% were resistant to FCR. Time to progression for responders was 77 months.
When the analysis was limited to 190 patients with at least 5 years follow-up, actual 5-year-survival was 70%, said Dr. Tam, of the University of Texas M.D. Anderson Cancer Center in Houston.
In a multivariate analysis, independent risk factors for complete remission were age 70 years or greater (hazard ratio 2.1), and beta-2 microglobulin at least twice that of normal (HR 3.1).
A historical nonrandomized comparison of FCR with 190 patients who received fludarabine monotherapy and 140 patients who received fludarabine plus cyclophosphamide or mitoxantrone at M.D. Anderson indicates that FCR prolongs survival. At 5 years, patients receiving FCR have a 21% absolute improvement in survival as compared with fludarabine monotherapy.
"Compared with FC alone, FCR doubles the rate of complete remission to over 70% and doubles the time to progression to 6 and a half years," he said. "This has led to a significant improvement in survival for our patients."
The long-term data analysis gave some insight into late toxicities of FCR, which is intensely immunosuppressive in regard to CD4 T-cell suppression. The annual risk of infection was 10% in the first year and decreased to 4% in the second year before leveling off at 1%. Opportunistic infections during remission were restricted primarily to the first year. Five infections were fatal.
The 5-year risk of late cytopenias was 23%, and the 5-year risks of Richter transformation and myelodysplasia were 3%. There were two deaths within 3 months of initiating therapy.
Discussant Dr. Kanti Roop Rai of Long Island Jewish Medical Center in New York called the results encouraging, but questioned whether patients with persistent cytopenias should be classified separately from partial responders with residual disease, as suggested by the investigators, when the overall survival curves do not significantly differ.
Dr. Rai called the use of rituximab at a dose of 500 mg/m² "arbitrary," and suggested it is not worth pursuing without a controlled trial. There is convincing evidence of a synergy between chemotherapy agents and rituximab, "wherein 375 mg/m² rituximab seemed to be quite adequate and successful."
Dr. Tam has published results of a smaller phase II trial showing favorable results with a rituximab dose of 375 mg/m² (Cancer 2006;106:2412-20). Unpublished results from M.D. Anderson show dose-escalation of rituximab up to 1500 mg/m² per cycle did not achieve superior outcomes in FCR when compared with historical experience with 500 mg/m².
Tam C.S. et al. Seventy percent of complete responders remain in continuous remission: Five-year follow-up of 300 patients treated with fludarabine, cyclophosphamide, and rituximab (FCR) as initial therapy of CLL. Abstract 7008.
Commentary |
A highly regarded investigative team has developed a treatment regimen of fludarabine, cyclophosphamide, and rituximab (FCR) for chronic lymphocytic leukemia (CLL). Based on historic data, it appears that FCR is more effective than previous regimens in CLL. In the study by Tam et al., front-line FCR doubled the rate of complete remission and the time to progression. A critical issue to be delineated in future studies is whether FCR also prolongs survival when compared with other effective approaches. Randomized trials will be necessary to make this determination. These data are provocative, but the regimen cannot be considered the gold standard at present. The toxicity profile makes it critical that we determine this is the most appropriate regimen to use first-line in CLL before we universally embrace FCR as initial therapy. — Steven T. Rosen, M.D.
|