Racila Emilian, Link Brian K, Weng Wen-Kai, Witzig Thomas E, Ansell Stephen, Maurer Matthew J, Huang Jian, Dahle Christopher, Halwani Ahmad, Levy Ronald, Weiner George J
Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa 52242, USA.
Clin Cancer Res. 2008 Oct 15;14(20):6697-703. doi: 10.1158/1078-0432.CCR-08-0745.
Complement may play a role in the clinical response to rituximab and other monoclonal antibody-based therapies of cancer. The purpose of this study was to explore the relationship between the C1qA([276]) polymorphism and the clinical response to rituximab in patients with follicular lymphoma.
Genotyping for C1qA([276A/G]) was done in 133 subjects with follicular lymphoma treated with single-agent rituximab, and correlation with clinical response was done using Cox regression analysis.
Prolonged remission was observed among subjects that responded clinically to rituximab therapy and were carriers of the A allele compared with homozygous G subjects. Homozygous G subjects had a time to progression of 282 days, whereas A-allele carriers had a time to progression of 708 days [hazard ratio, (HR), 2.5; 95% confidence interval (95% CI), 2.0-3.1; P = 0.02]. Among subjects who achieved complete remission, homozygous G subjects had a time to progression of 250 days, whereas A-allele carriers had a time to progression of 1,118 days (HR, 4.5; 95% CI, 4.1-4.8, P = 0.04). The difference persisted after controlling for CD32 and CD16 polymorphisms. In patients who responded to rituximab used as first-line agent, a linear trend was observed among the C1qA([276]) genotypes, with homozygous A subjects achieving complete response at a higher rate compared with heterozygous or homozygous G subjects.
Our findings indicate that polymorphisms in the C1qA gene may affect the clinical response and duration of response to rituximab therapy of follicular lymphoma. These results could have direct implications on designing antibodies with improved efficiency and enhance our understanding of the role of complement in monoclonal antibody therapy.
补体可能在利妥昔单抗及其他基于单克隆抗体的癌症治疗的临床反应中发挥作用。本研究旨在探讨C1qA([276])基因多态性与滤泡性淋巴瘤患者对利妥昔单抗临床反应之间的关系。
对133例接受单药利妥昔单抗治疗的滤泡性淋巴瘤患者进行C1qA([276A/G])基因分型，并使用Cox回归分析其与临床反应的相关性。
与纯合G型患者相比，临床对利妥昔单抗治疗有反应且为A等位基因携带者的患者缓解期延长。纯合G型患者的疾病进展时间为282天，而A等位基因携带者的疾病进展时间为708天[风险比(HR)为2.5；95%置信区间(95%CI)为2.0 - 3.1；P = 0.02]。在达到完全缓解的患者中，纯合G型患者的疾病进展时间为250天，而A等位基因携带者的疾病进展时间为1118天(HR为4.5；95%CI为4.1 - 4.8，P = 0.04)。在控制CD32和CD16基因多态性后，差异仍然存在。在将利妥昔单抗用作一线药物有反应的患者中，C1qA([276])基因型之间观察到线性趋势，纯合A基因型患者的完全缓解率高于杂合或纯合G基因型患者。
我们的研究结果表明，C1qA基因的多态性可能影响滤泡性淋巴瘤患者对利妥昔单抗治疗的临床反应及反应持续时间。这些结果可能对设计效率更高的抗体有直接影响，并增进我们对补体在单克隆抗体治疗中作用的理解。
