Berinstein N L, Grillo-López A J, White C A, Bence-Bruckler I, Maloney D, Czuczman M, Green D, Rosenberg J, McLaughlin P, Shen D
Department of Medicine, Toronto-Sunnybrook Regional Cancer Centre, Ontario, Canada.
Ann Oncol. 1998 Sep;9(9):995-1001. doi: 10.1023/A:1008416911099.
Monoclonal antibodies are being utilized for treatment of patients with low-grade non-Hodgkin's lymphoma as well as other cancers. Results from phase I and II clinical studies has shown that the chimeric monoclonal antibody Rituximab has minimal toxicity and significant therapeutic activity in low grade non-Hodgkin's lymphoma.
We have recently reported on a multicentre pivotal phase III clinical trial involving 166 patients with recurrent low-grade lymphoma who were treated with four infusions of Rituximab. Eighty patients (48%) achieved objective responses including 10 patients (6%) with complete responses. Overall, 126 patients (76%) had a > or = 20% reduction in overall tumor size. The median response duration and time to progression are 11.6 and 13.2 months, respectively. The infusional and long term toxicities were limited.
In this report we describe the pharmacokinetic data obtained on these patients. Measurable concentrations of Rituximab were detected in all patients after the first infusion and increased throughout the treatment course. The half-life of the monoclonal antibody increased from 76.3 hours after the first infusion to 205.8 hours after the fourth infusion and was concomitant with a four-fold decrease in the antibody clearance. At three months and six months post-treatment, the median Rituximab serum levels were 20.3 micrograms/ml (range 0.0 to 96.8 micrograms/ml in 104 patients) and 1.3 micrograms/ml (range 0.0-28.7 micrograms/ml in 13 patients), respectively. A statistically significant correlation was found between the median antibody concentration and response for multiple time points during the treatment and followup. The mean serum antibody concentration was also inversely correlated with measurements of tumor bulk and with the number of circulating B cells at baseline.
We conclude that Rituximab is therapeutically effective against B-cell lymphoma. Pharmacokinetic data suggests that certain subsets of patients may possibly benefit from increased dosing and studies to address this are currently underway.
单克隆抗体正被用于治疗低度非霍奇金淋巴瘤患者以及其他癌症患者。I期和II期临床研究结果表明，嵌合单克隆抗体利妥昔单抗在低度非霍奇金淋巴瘤中具有最小的毒性和显著的治疗活性。
我们最近报道了一项多中心关键III期临床试验，该试验涉及166例复发性低度淋巴瘤患者，他们接受了4次利妥昔单抗输注治疗。80例患者（48%）获得了客观缓解，其中10例患者（6%）完全缓解。总体而言，126例患者（76%）的总体肿瘤大小缩小了≥20%。中位缓解持续时间和疾病进展时间分别为11.6个月和13.2个月。输注毒性和长期毒性均有限。
在本报告中，我们描述了在这些患者身上获得的药代动力学数据。首次输注后，所有患者均检测到可测量的利妥昔单抗浓度，且在整个治疗过程中浓度不断升高。单克隆抗体的半衰期从首次输注后的76.3小时增加到第四次输注后的205.8小时，同时抗体清除率下降了四倍。治疗后3个月和6个月时，利妥昔单抗血清中位水平分别为20.3微克/毫升（104例患者中范围为0.0至96.8微克/毫升）和1.3微克/毫升（13例患者中范围为0.0至28.7微克/毫升）。在治疗和随访期间的多个时间点，中位抗体浓度与缓解之间存在统计学显著相关性。平均血清抗体浓度也与基线时的肿瘤体积测量值以及循环B细胞数量呈负相关。
我们得出结论，利妥昔单抗对B细胞淋巴瘤具有治疗效果。药代动力学数据表明，某些患者亚组可能会从增加剂量中获益，目前正在开展相关研究以解决这一问题。
