Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemia

Abstract

Long-term results of chemoimmunotherapy with low-dose fludarabine, cyclophosphamide and high-dose rituximab as initial treatment for patients with chronic lymphocytic leukemiaChemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) is currently considered the gold standard first-line therapy for chronic lymphocytic leukemia (CLL). 1 In an attempt to reduce the neutropenia and maintain the high response rate of standard-dose FCR, we conducted a prospective phase 2 clinical trial in untreated CLL patients using lower doses of FC and higher dose of R followed by R maintenance until progression or up to 2 years (FCR-Lite). Details of the study were previously described. (73%) achieved complete response (CR), 2 (3%) achieved nodular partial remission (nPR), 11 (17%) achieved partial remission (PR), and 4 (6%) did not respond. Among the 50 patients with Rai stage I-II there were 38 (76%) CRs and 10 (20%) PRs and among the 13 patients with Rai stage III-IV there were 8 (62%) CRs and 3 (23%) PRs. For patients Ͻ 60 years there were 35 (81%) CRs and 5 (12%) PRs, for patients between 60-69 years there were 6 (55%) CRs and 4 (36%) PRs, and for patients Ն 70 years there were 5 (56%) CRs and 4 (44%) PRs. For the 40 patients with normal cytogenetics, del13q or ϩ12 there were 31 (78%) CRs, 7 (17%) PRs, and 2 (5%) NRs. Eight of 9 (89%) patients with del11q had a CR and 1 (11%) had a PR. Three of 3 patients with del17p had PRs.The median overall survival has not been reached and the median progression-free survival was 5.8 years and the 3-and 5-year progression-free survival probability is shown in Table 1. This compares favorably with the MD Anderson Cancer Center (MDACC) phase 2 FCR trial where the 6-year actuarial OS and failure-free survival were 77% and 51%, respectively, as well as the FCR arm of the German CLL Study Group GCLLSG) where the PFS was 4.4 years. [4][5][6] Fifty-five patients (85%) completed all 6 courses of FCR-Lite with dose reduction in 2% of total cycles. Grade 3-4 neutropenia occurred in 11% of total cycles of FCR-Lite and grade 3-4 infections were seen in 6% of patients. Three patients developed myelodysplastic syndromes and 2 patients developed B-cell lymphomas after FCR-Lite therapy.In summary, the FCR-Lite regimen represents an active frontline treatment with excellent responses and duration of response with a favorable toxicity profile. Interpretation of these data and comparisons with the MDACC and GCLLSG trials should be viewed in light of the relatively low numbers of patients, relatively early Rai stages of the patients, use of prophylactic growth factors, and maintenance rituximab in the FCR-Lite trial. Further studies with FCR-Lite will include combination therapies with promising new agents.

Impact of dose intensity on outcome of fludarabine, cyclophosphamide, and rituximab regimen given in the first-line therapy for chronic lymphocytic leukemia

“…Furthermore, these patients benefited from two years of rituximab maintenance and this makes it difficult to interpret the impact of altered RDI on the recently published long-term PFS results. 7,8 Two French randomized studies have now incorporated the concept of high-dose rituximab associated with FC: i) the CLL-2010 FMP study (500 mg To conclude, our study shows that the efficiency of FCR depends on precise modalities of administration. Outside the setting of clinical trials, FCR dose adjustments are frequent because of objective considerations (e.g.…”

“…5,6 More recently, Foon and coworkers have developed the FCR-Lite schedule using low doses of FC in combination with high-dose rituximab. 7,8 Finally, the French CLL study group is currently promoting FCR combination in young or fit elderly patients with oral F 40 mg/m 2 Days 1-3 + C 250 mg/m 2 Days 1-3 + R 375-500 mg/m 2 . From all these studies, it seems that toxicity is more related to the dose rather than to the route of administration.…”

Chlorambucil plus rituximab with or without maintenance rituximab as first‐line treatment for elderly chronic lymphocytic leukemia patients

“…As in other chronic B-cell malignancies, the use of R after induction chemotherapy suggests a benefit in sustaining the response duration in CLL patients [28][29][30][31]. Most of the published studies used R after fludarabine-based regimens; the most recent one after FCR plus mitoxantrone, with a remarkable efficacy but a relevant hematologic Only AE judged clinically relevant and/or more frequent within safety population were selected.…”

Chronic lymphocytic leukemia (CLL)—Then and now

“…and FCRlite regimens [71]. Of further interest, patients who relapse after initial remission duration 3 years after frontline FCR were considered suitable to receive FCR again as the first salvage therapy [72].…”