Biomarkers of response to ibrutinib plus nivolumab in relapsed diffuse large B-cell lymphoma, follicular lymphoma, or Richter's transformation

• Published in: Translational oncology Vol. 14; no. 1; p. 100977
• Main Authors: Hodkinson, Brendan P., Schaffer, Michael, Brody, Joshua D., Jurczak, Wojciech, Carpio, Cecilia, Ben-Yehuda, Dina, Avivi, Irit, Forslund, Ann, Özcan, Muhit, Alvarez, John, Ceulemans, Rob, Fourneau, Nele, Younes, Anas, Balasubramanian, Sriram
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2021; Neoplasia Press; Elsevier
• Subjects: Biomarkers; Ibrutinib; Nivolumab; Non-hodgkin's lymphoma; Original article; Phase I/II trial; Non-hodgkin's lymphoma; Biomarkers; Phase I/II trial; Nivolumab; Ibrutinib
• ISSN: 1936-5233; 1936-5233
• DOI: 10.1016/j.tranon.2020.100977

•Biomarkers of response to ibrutinib + nivolumab were analyzed in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma and Richter transformation.•DLBCL patients with elevated PD-L1 by immunohistochemistry tended to have better response and survival.•Whole exome sequencing identified gene mutations in alternate B-cell receptor pathways linked to response in DLBCL.•Enriched pathways by gene expression profiling were related to immune activation in responders and proliferation/replication in nonresponders.•This preliminary work may help to generate hypotheses on genetically defined subsets of patients most likely to benefit from ibrutinib + nivolumab.
We analyzed potential biomarkers of response to ibrutinib plus nivolumab in biopsies from patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and Richter's transformation (RT) from the LYM1002 phase I/IIa study, using programmed death ligand 1 (PD-L1) immunohistochemistry, whole exome sequencing (WES), and gene expression profiling (GEP). In DLBCL, PD-L1 elevation was more frequent in responders versus nonresponders (5/8 [62.5%] vs. 3/16 [18.8%]; p = 0.065; complete response 37.5% vs. 0%; p = 0.028). Overall response rates for patients with WES and GEP data, respectively, were: DLBCL (38.5% and 29.6%); FL (46.2% and 43.5%); RT (76.5% and 81.3%). In DLBCL, WES analyses demonstrated that mutations in RNF213 (40.0% vs. 6.2%; p = 0.055), KLHL14 (30.0% vs. 0%; p = 0.046), and LRP1B (30.0% vs. 6.2%; p = 0.264) were more frequent in responders. No responders had mutations in EBF1, ADAMTS20, AKAP9, TP53, MYD88, or TNFRSF14, while the frequency of these mutations in nonresponders ranged from 12.5% to 18.8%. In FL and RT, genes with different mutation frequencies in responders versus nonresponders were: BCL2 (75.0% vs. 28.6%; p = 0.047) and ROS1 (0% vs. 50.0%; p = 0.044), respectively. Per GEP, the most upregulated genes in responders were LEF1 and BTLA (overall), and CRTAM (germinal center B-cell–like DLBCL). Enriched pathways were related to immune activation in responders and resistance-associated proliferation/replication in nonresponders. This preliminary work may help to generate hypotheses regarding genetically defined subsets of DLBCL, FL, and RT patients most likely to benefit from ibrutinib plus nivolumab.