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In the phase 3 iLLUMINATE study of ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab in first-line chronic lymphocytic leukemia\/small lymphocytic lymphoma, IRRs were substantially reduced with ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab. We prospectively analyzed inflammatory cytokines to evaluate the impact of ibrutinib on circulating cytokine levels following obinutuzumab infusion. In iLLUMINATE, ibrutinib or chlorambucil was given approximately 30\u2013120 min before the first obinutuzumab infusion. Cytokines evaluated were IFN\u03b3, IL-6, IL-8, IL-10, IL-18, MCP-1, MIP-1\u03b1, MIP-1\u03b2, and TNF\u03b1. Changes in peak cytokine levels from baseline (immediately before obinutuzumab) to post-obinutuzumab infusion were compared between arms and between patients with versus without IRRs using Wilcoxon rank sum test. Of 228 treated patients, 95 on ibrutinib-obinutuzumab (15 with IRRs, 80 without) and 88 on chlorambucil-obinutuzumab (45 with IRRs, 43 without) with cytokine data were included. Irrespective of IRR occurrence, median increase in cytokines was lower with ibrutinib-obinutuzumab versus chlorambucil-obinutuzumab for all cytokines (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.01) except MIP-1\u03b2. Across treatment arms, post-obinutuzumab median increase in all cytokines except MIP-1\u03b2 was greater in patients with versus without IRRs (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.001). IL-6 and IL-8 elevations were associated with IRRs in both treatment arms. Among patients with IRRs, those receiving ibrutinib-obinutuzumab had lower post-obinutuzumab increases in IL-6, IL-8, IL-10, and MCP-1 (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.04) than patients receiving chlorambucil-obinutuzumab. For patients in the ibrutinib-treatment arm, we observed a reduction in both the rate of clinically apparent IRRs and the levels of IRR-related cytokines and chemokines. This observation supports an immunomodulatory mechanism of action for ibrutinib. Clinical Trial Registration: NCT02264574\n                  <\/jats:p>","DOI":"10.1007\/s00277-021-04536-6","type":"journal-article","created":{"date-parts":[[2021,5,20]],"date-time":"2021-05-20T17:02:35Z","timestamp":1621530155000},"page":"1733-1742","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Pretreatment with ibrutinib reduces cytokine secretion and limits the risk of obinutuzumab-induced infusion-related reactions in patients with CLL: analysis from the iLLUMINATE study"],"prefix":"10.1007","volume":"100","author":[{"given":"Richard","family":"Greil","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"Tedeschi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Moreno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bertrand","family":"Anz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Loree","family":"Larratt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Simkovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devinder","family":"Gill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John G.","family":"Gribben","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian W.","family":"Flinn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengyuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leo W. 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AT: consulting\/advisory role: AbbVie, AstraZeneca, BeiGene, Janssen, and Sunesis; speakers bureau: AbbVie and Janssen. CM: consulting\/advisory role: AbbVie, AstraZeneca, Janssen, and Sunesis; research funding: AbbVie and Janssen; speakers bureau: Janssen. BA: nothing to disclose. LL: honoraria: AbbVie and Janssen. MS: honoraria: AbbVie, Gilead, Janssen-Cilag, Acerta Pharma, and Roche; consulting\/advisory role: AbbVie; speakers bureau: AbbVie, Janssen-Cilag, Gilead, and Roche; travel, accommodations, or expenses: AbbVie, Gilead, Janssen-Cilag, and Roche. DG: honoraria and consulting\/advisory role: Janssen-Cilag. JGG: honoraria: AbbVie, Bristol-Myers Squibb, AstraZeneca, Janssen, and Roche; consultancy\/advisory role: AbbVie, Janssen, Gilead; research funding: AstraZeneca, Celgene, and Janssen. IWF: consultancy\/advisory role: AbbVie, AstraZeneca, BeiGene, Genentech, Gilead, Great Point Partners, Iksuda Therapeutics, Janssen, Juno Therapeutics, Kite Pharma, MorphoSys, Nurix Therapeutics, Pharmacyclics LLC, an AbbVie Company, Roche, Seattle Genetics, Takeda, TG Therapeutics, Unum Therapeutics, Verastem, and Yingli Pharmaceuticals; research funding: AbbVie, Acerta Pharma, Agios, ArQule, AstraZeneca, BeiGene, Calithera, Celgene, Constellation, Curis, F. Hoffman-la Roche Ltd, Forma, Forty Seven, Genentech, Gilead, IGM Biosciences, Incyte, Infinity, Janssen, Juno, Karyopharm, Kite, Loxo, Merck, MorphoSys AG, Novartis, Pfizer, Pharmacyclics LLC, an AbbVie Company, Portola, Rhizen Pharmaceuticals, Roche, Seattle Genetics, Takeda, Teva, TG Therapeutics, Trillium, Triphase Research & Development Corp, Unum, and Verastem. ZW: employment: currently with Ambry Genetics; previously with Pharmacyclics LLC, an AbbVie Company; stock or other ownership: AbbVie, AnaptysBio, Bristol-Myers Squibb, and Luxvitae; travel, accommodations, or other expenses: Ambry Genetics. LWKC: employment: Pharmacyclics LLC, an AbbVie Company; stock or other ownership: AbbVie and Eli Lilly; patents, royalties, or other intellectual property: Pharmacyclics LLC, an AbbVie Company. ANN: employment: currently with SparcBio; previously with Celgene and Pharmacyclics LLC, an AbbVie Company; stock or other ownership: AbbVie, Celgene, and SparcBio; patents, royalties, or other intellectual property: Celgene; travel, accommodations, or other expenses: Celgene. CZ and LS: employment: Pharmacyclics LLC, an AbbVie Company; stock or other ownership: AbbVie. FD: consulting\/advisory role: AbbVie AstraZeneca, Amgen, and Roche; research funding: AbbVie, Janssen, Pharmacyclics LLC, an AbbVie Company, and AstraZeneca; speakers bureau: AbbVie, Amgen, and Janssen; travel, accommodations, or other expenses: AbbVie, Amgen, Pfizer, and Janssen.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}