Hématologie, Hospices Civils de Lyon and University Lyon 1, Lyon, France.
Clin Cancer Res. 2013 May 1;19(9):2551-61. doi: 10.1158/1078-0432.CCR-12-3069. Epub 2013 Apr 2.
Identify subgroups of patients with relapsed/refractory follicular lymphoma deriving substantial progression-free survival (PFS) benefit with bortezomib-rituximab versus rituximab in the phase III LYM-3001 study.
A total of 676 patients were randomized to five 5-week cycles of bortezomib-rituximab or rituximab. The primary end point was PFS; this prespecified analysis of candidate protein biomarkers and genes was an exploratory objective. Archived tumor tissue and whole blood samples were collected at baseline. Immunohistochemistry and genetic analyses were completed for 4 proteins and 8 genes.
In initial pairwise analyses, using individual single-nucleotide polymorphism genotypes, one biomarker pair (PSMB1 P11A C/G heterozygote, low CD68 expression) was associated with a significant PFS benefit with bortezomib-rituximab versus rituximab, controlling for multiple comparison corrections. The pair was analyzed under dominant, recessive, and additive genetic models, with significant association with PFS seen under the dominant model (G/G+C/G). In patients carrying this biomarker pair [PSMB1 P11A G allele, low CD68 expression (≤50 CD68-positive cells), population frequency: 43.6%], median PFS was 14.2 months with bortezomib-rituximab versus 9.1 months with rituximab (HR 0.47, P < 0.0001), and there was a significant overall survival benefit (HR 0.49, P = 0.0461). Response rates were higher and time to next antilymphoma therapy was longer in the bortezomib-rituximab group. In biomarker-negative patients, no significant efficacy differences were seen between treatment groups. Similar proportions of patients had high-risk features in the biomarker-positive and biomarker-negative subsets.
Patients with PSMB1 P11A (G allele) and low CD68 expression seemed to have significantly longer PFS and greater clinical benefit with bortezomib-rituximab versus rituximab.
在 III 期 LYM-3001 研究中，确定与利妥昔单抗相比，硼替佐米-利妥昔单抗治疗复发性/难治性滤泡淋巴瘤患者亚组人群的无进展生存期（PFS）有显著获益。
共 676 例患者被随机分配至硼替佐米-利妥昔单抗或利妥昔单抗的五个 5 周周期。主要终点为 PFS；这是对候选蛋白生物标志物和基因的预先指定分析，是一个探索性的目标。在基线时收集存档的肿瘤组织和全血样本。对 4 种蛋白和 8 种基因进行了免疫组织化学和基因分析。
在初始的两两分析中，使用单个单核苷酸多态性基因型，一个生物标志物对（PSMB1 P11A C/G 杂合子，低 CD68 表达）与硼替佐米-利妥昔单抗相比，利妥昔单抗的 PFS 获益有显著相关性，校正了多重比较校正。该对在显性、隐性和加性遗传模型下进行了分析，在显性模型（G/G+C/G）下观察到与 PFS 的显著关联。在携带该生物标志物对的患者中（PSMB1 P11A G 等位基因，低 CD68 表达（≤50 个 CD68 阳性细胞），人群频率：43.6%），硼替佐米-利妥昔单抗组的中位 PFS 为 14.2 个月，而利妥昔单抗组为 9.1 个月（HR 0.47，P < 0.0001），总生存获益有显著意义（HR 0.49，P = 0.0461）。硼替佐米-利妥昔单抗组的缓解率更高，下一阶段抗淋巴瘤治疗的时间更长。在生物标志物阴性患者中，两组之间的疗效无显著差异。生物标志物阳性和阴性亚组患者的高危特征比例相似。
PSMB1 P11A（G 等位基因）和低 CD68 表达的患者似乎具有更长的 PFS 和更大的临床获益，与硼替佐米-利妥昔单抗相比，利妥昔单抗治疗效果更好。
