Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia

Abstract

Early results of the fludarabine, cyclophosphamide, and rituximab (FCR) regimen in 224 patients showed that it was highly active as initial therapy of chronic lymphocytic leukemia. In this report, we present the final results of all 300 study patients at a median follow up of 6 years. The overall response rate was 95%, with complete remission in 72%, nodular partial remission in 10%, partial remission due to cytopenia in 7%, and partial remission due to residual disease in 6%. Two patients (< 1%) died within 3 months of starting therapy. Six-year overall and failure-free survival were 77% and 51%, respectively. Median time to progression was 80 months. Pretreatment characteristics independently associated with inferior response were age 70 years or older, beta2-microglobulin twice the upper limit of normal (2N) or more, white cell count 150 x 10(9)/L or more, abnormal chromosome 17, and lactate dehydrogenase 2N or more. No pretreatment characteristic was independently associated with decreased complete remission duration. The risk of late infection was 10% and 4% for the first and second years of remission, respectively, and less than 1.5% per year for the third year onward. In a multivariate analysis of patients receiving fludarabine-based therapy at our center, FCR therapy emerged as the strongest independent determinant of survival.

Figures

Figure 1

Overall survival (OS) and time to progression (TTP). (A) OS by treatment response. Patients in complete remission (CR) and nodular partial response (PR-nod) had similarly favorable survival (6-year OS 88% and 77% respectively, P = .12). Survival for other categories was as follows: partial response due to incomplete recovery (PR-i), 6-year OS 42%; partial remission due to residual disease (PR-d), 5-year OS 24%; and resistant disease, 5-year OS 15%. (B) TTP by treatment response. Median TTP was longest in CR patients (85 months), followed by PR-nod and PR-i (71 months and 50 months, respectively), and was only 19 months for patients in PR-d. (C) Impact of flow cytometry (FL-C) status on TTP. Patients with less than 1% CD5/19 coexpressing cells in the bone marrow at the end of therapy had a significantly longer TTP (median 85 vs 49 months for FL-C negative vs positive, P < .001). (D) Impact of PCR status on TTP. PCR-negative patients had longer TTP than low positive patients (median 89 vs 80 months, respectively, P = .06), who in turn had longer TTP than PCR-positive patients (median 40 months, P = .001 compared with low positive patients).

Figure 2

The risk of late infections during remission. Bars represent the risk of serious (grade ≥ 3, viral, or opportunistic) infections for each year of ongoing remission. The infection risk was highest in the first year and rapidly declined to a baseline risk of less than 1.5% per year from the third year onward. The colored dots represent individual episodes per year; crosses, infection episodes that were fatal. The occurrence of opportunistic infections was limited to the first year, and varicella-zoster reactivation was limited predominantly to the first 2 years.

Figure 3

Survival of patients receiving fludarabine (F), fludarabine and cyclophosphamide or mitoxantrone (FC/M), and FCR as initial therapy of CLL at the M. D. Anderson Cancer Center. Six-year overall survivals were 54%, 59%, and 77%, respectively.