Leveraging gene expression subgroups to classify DLBCL patients and select for clinical benefit from a novel agent

Alberto Risueño, Patrick R. Hagner, Fadi Towfic, Celia Fontanillo, Amira Djebbari, Joel S. Parker, Clifton P. Drew, Grzegorz S. Nowakowski, Matthew J. Maurer, James R. Cerhan, Xin Wei, Yan Ren, Chung Wein Lee, Suzana Couto, Maria Wang, Michael Pourdehnad, Anita K. Gandhi, Matthew W.B. Trotter

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1008-1018
Number of pages11
JournalBlood
Volume135
Issue number13
DOIs
StatePublished - Mar 26 2020

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Risueño, A., Hagner, P. R., Towfic, F., Fontanillo, C., Djebbari, A., Parker, J. S., Drew, C. P., Nowakowski, G. S., Maurer, M. J., Cerhan, J. R., Wei, X., Ren, Y., Lee, C. W., Couto, S., Wang, M., Pourdehnad, M., Gandhi, A. K., & Trotter, M. W. B. (2020). Leveraging gene expression subgroups to classify DLBCL patients and select for clinical benefit from a novel agent. Blood, 135(13), 1008-1018. https://doi.org/10.1182/blood.2019002414