Celgene Institute for Translational Research Europe, a Bristol-Myers Squibb Company, Seville, Spain.
Bristol-Myers Squibb, Summit, NJ.
Blood. 2020 Mar 26;135(13):1008-1018. doi: 10.1182/blood.2019002414.
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, commonly described by cell-of-origin (COO) molecular subtypes. We sought to identify novel patient subgroups through an unsupervised analysis of a large public dataset of gene expression profiles from newly diagnosed de novo DLBCL patients, yielding 2 biologically distinct subgroups characterized by differences in the tumor microenvironment. Pathway analysis and immune deconvolution algorithms identified higher B-cell content and a strong proliferative signal in subgroup A and enriched T-cell, macrophage, and immune/inflammatory signals in subgroup B, reflecting similar biology to published DLBCL stratification research. A gene expression classifier, featuring 26 gene expression scores, was derived from the public dataset to discriminate subgroup A (classifier-negative, immune-low) and subgroup B (classifier-positive, immune-high) patients. Subsequent application to an independent series of diagnostic biopsies replicated the subgroups, with immune cell composition confirmed via immunohistochemistry. Avadomide, a CRL4CRBN E3 ubiquitin ligase modulator, demonstrated clinical activity in relapsed/refractory DLBCL patients, independent of COO subtypes. Given the immunomodulatory activity of avadomide and the need for a patient-selection strategy, we applied the gene expression classifier to pretreatment biopsies from relapsed/refractory DLBCL patients receiving avadomide (NCT01421524). Classifier-positive patients exhibited an enrichment in response rate and progression-free survival of 44% and 6.2 months vs 19% and 1.6 months for classifier-negative patients (hazard ratio, 0.49; 95% confidence interval, 0.280-0.86; P = .0096). The classifier was not prognostic for rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone or salvage immunochemotherapy. The classifier described here discriminates DLBCL tumors based on tumor and nontumor composition and has potential utility to enrich for clinical response to immunomodulatory agents, including avadomide.
弥漫性大 B 细胞淋巴瘤（DLBCL）是一种异质性疾病，通常通过细胞起源（COO）分子亚型来描述。我们通过对新诊断的初发性弥漫性大 B 细胞淋巴瘤患者的基因表达谱进行大规模公共数据集的无监督分析，试图识别新的患者亚组，得出 2 个具有不同肿瘤微环境特征的生物学上明显不同的亚组。途径分析和免疫去卷积算法在亚组 A 中鉴定出更高的 B 细胞含量和强烈的增殖信号，在亚组 B 中鉴定出丰富的 T 细胞、巨噬细胞和免疫/炎症信号，反映了与已发表的 DLBCL 分层研究相似的生物学。从公共数据集导出的基因表达分类器，具有 26 个基因表达评分，用于区分亚组 A（分类器阴性，免疫低）和亚组 B（分类器阳性，免疫高）患者。随后将其应用于独立的诊断性活检系列，复制了亚组，通过免疫组织化学证实了免疫细胞组成。阿维鲁单抗是一种 CRL4CRBN E3 泛素连接酶调节剂，在复发/难治性弥漫性大 B 细胞淋巴瘤患者中显示出临床活性，与 COO 亚型无关。鉴于阿维鲁单抗的免疫调节活性和患者选择策略的需要，我们将基因表达分类器应用于接受阿维鲁单抗治疗的复发/难治性弥漫性大 B 细胞淋巴瘤患者的预处理活检（NCT01421524）。分类器阳性患者的反应率和无进展生存期分别为 44%和 6.2 个月，而分类器阴性患者分别为 19%和 1.6 个月（危险比，0.49；95%置信区间，0.280-0.86；P =.0096）。该分类器对利妥昔单抗、环磷酰胺、多柔比星、长春新碱、泼尼松或挽救性免疫化疗没有预后作用。这里描述的分类器根据肿瘤和非肿瘤成分区分 DLBCL 肿瘤，具有潜在的效用，可以富集对免疫调节剂的临床反应，包括阿维鲁单抗。
