Leveraging Gene Expression Subgroups to Classify DLBCL Patients and Enrich for Clinical Benefit to a Novel Agent

• DOI: 10.1182/blood.2019002414
• Publication Date: 2020-01-24T10:02:07Z
• Authors: Alberto Risueno; Patrick Ryan Hagner; Fadi Towfic; Celia Fontanillo; Amira Djebbari; Joel S. Parker; Clifton Drew; Grzegorz S. Nowak...; Matthew J. Maurer; James R. Cerhan; Xin Wei; Yan Ren; Chung-Wein Lee; Suzana Couto; Maria Wang; Michael Pourdehnad; Anita Krithivas G...; Matthew William B...
• Keywords: Adult; Male; 0301 basic medicine; Biopsy; Gene Expression Profiling; Computational Biology; Fluorescent Antibody Technique; Reproducibility of Results; Antineoplastic Agents; Middle Aged; 3. Good health; Gene Expression Regulation, Neoplastic; 03 medical and health sciences; Antineoplastic Combined Chemotherapy Protocols; Humans; Female; Gene Regulatory Networks; Lymphoma, Large B-Cell, Diffuse; Transcriptome; Aged

Diffuse large B-cell lymphoma 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 two 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 and 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 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 demonstrated an enrichment in response rate and progression-free survival of 44% and 6.2 months versus 19% and 1.6 months for classifier-negative patients (HR=0.49 [0.280, 0.86]; P=.0096). The classifier was not prognostic for R-CHOP or salvage immunochemotherapy. The classifier described here discriminates DLBCL tumors based on tumor and non-tumor composition and has potential utility to enrich for clinical response to immunomodulatory agents including avadomide.