利妥昔单抗联合氟达拉滨和环磷酰胺治疗慢性淋巴细胞白血病患者的随机、开放标签、3 期临床试验。
Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial.
机构信息
Department I of Internal Medicine and Centre for Integrated Oncology, University of Cologne, Cologne, Germany.
出版信息
Lancet. 2010 Oct 2;376(9747):1164-74. doi: 10.1016/S0140-6736(10)61381-5.
BACKGROUND
On the basis of promising results that were reported in several phase 2 trials, we investigated whether the addition of the monoclonal antibody rituximab to first-line chemotherapy with fludarabine and cyclophosphamide would improve the outcome of patients with chronic lymphocytic leukaemia.
METHODS
Treatment-naive, physically fit patients (aged 30-81 years) with CD20-positive chronic lymphocytic leukaemia were randomly assigned in a one-to-one ratio to receive six courses of intravenous fludarabine (25 mg/m(2) per day) and cyclophosphamide (250 mg/m(2) per day) for the first 3 days of each 28-day treatment course with or without rituximab (375 mg/m(2) on day 0 of first course, and 500 mg/m(2) on day 1 of second to sixth courses) in 190 centres in 11 countries. Investigators and patients were not masked to the computer-generated treatment assignment. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00281918.
FINDINGS
408 patients were assigned to fludarabine, cyclophosphamide, and rituximab (chemoimmunotherapy group) and 409 to fludarabine and cyclophosphamide (chemotherapy group); all patients were analysed. At 3 years after randomisation, 65% of patients in the chemoimmunotherapy group were free of progression compared with 45% in the chemotherapy group (hazard ratio 0·56 [95% CI 0·46-0·69], p<0·0001); 87% were alive versus 83%, respectively (0·67 [0·48-0·92]; p=0·01). Chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (136 [34%] of 404 vs 83 [21%] of 396; p<0·0001) and leucocytopenia (97 [24%] vs 48 [12%]; p<0·0001). Other side-effects, including severe infections, were not increased. There were eight (2%) treatment-related deaths in the chemoimmunotherapy group compared with ten (3%) in the chemotherapy group.
INTERPRETATION
Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab improves progression-free survival and overall survival in patients with chronic lymphocytic leukaemia. Moreover, the results suggest that the choice of a specific first-line treatment changes the natural course of chronic lymphocytic leukaemia.
FUNDING
F Hoffmann-La Roche.
背景
基于几项 2 期试验报告的有希望的结果，我们研究了在氟达拉滨和环磷酰胺的一线化疗中添加单克隆抗体利妥昔单抗是否会改善慢性淋巴细胞白血病患者的预后。
方法
30-81 岁的初治、身体状况良好的 CD20 阳性慢性淋巴细胞白血病患者以 1:1 的比例随机分配，接受六周期静脉注射氟达拉滨（每天 25mg/m2）和环磷酰胺（每天 250mg/m2），在 28 天的每个治疗周期的前 3 天，或在 11 个国家的 190 个中心接受或不接受利妥昔单抗（第一周期的第 0 天为 375mg/m2，第二至第六周期的第 1 天为 500mg/m2）。研究者和患者对计算机生成的治疗方案不知情。主要终点是无进展生存期（PFS）。分析采用意向治疗。这项研究在 ClinicalTrials.gov 注册，编号为 NCT00281918。
结果
408 名患者被分配至氟达拉滨、环磷酰胺和利妥昔单抗（化疗免疫组），409 名患者被分配至氟达拉滨和环磷酰胺（化疗组）；所有患者均接受了分析。随机分组后 3 年，化疗免疫组 65%的患者无进展，而化疗组为 45%（风险比 0.56[95%CI 0.46-0.69]，p<0.0001）；分别有 87%和 83%的患者存活（0.67[0.48-0.92]；p=0.01）。化疗免疫组更常发生 3 级和 4 级中性粒细胞减少症（136[34%] vs 83[21%]，p<0.0001）和白细胞减少症（97[24%] vs 48[12%]，p<0.0001）。其他副作用，包括严重感染，并未增加。化疗免疫组有 8 例（2%）与治疗相关的死亡，化疗组有 10 例（3%）。
结论
氟达拉滨、环磷酰胺和利妥昔单抗的化疗免疫治疗可改善慢性淋巴细胞白血病患者的无进展生存期和总生存期。此外，结果表明，特定的一线治疗选择改变了慢性淋巴细胞白血病的自然病程。
资金来源
罗氏制药公司。
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