IBRUTINIB DECREASES OBINUTUZUMAB‐INDUCED SECRETION OF CYTOKINES ASSOCIATED WITH INFUSION‐RELATED REACTIONS IN PATIENTS WITH CLL: ANALYSIS FROM THE ILLUMINATE STUDY (2019)

Introduction: Infusion-related reactions (IRRs) are potentially serious complications resulting from release of inflammatory cytokines in response to administration of certain drugs, including obinutuzumab (G), an anti-CD20 antibody (Freeman, Blood2015). In the phase 3 iLLUMINATE study of first-line ibrutinib-G (ibr-G) vs chlorambucil-G (clb-G) in patients (pts) with chronic lymphocytic leukemia (CLL), IRRs were decreased with ibr-G vs clb-G (any grade: 25% vs 58%; grade ≥3 or serious: 3% vs 9%) (Moreno, Lancet Oncol 2019). As IRR results from the release of inflammatory cytokines, we prospectively analyzed cytokines thought to be associated with IRRs in pts from iLLUMINATE to evaluate the impact of ibr on secretion of cytokines following G infusion. Methods: Pts with previously untreated CLL/small lymphocytic lymphoma were randomized to ibr-G or clb-G. Ibr or clb was given approximately 30-120 min before the first G infusion. Plasma samples were collected at 4 timepoints (before ibr/clb, immediately before G infusion, and 2h and 4h post-G infusion) on day 1. Cytokines evaluated were IFNγ, IL6, IL8, IL10, IL18, MCP1, MIP1α, MIP1β, and TNFα. Changes from baseline (immediately before G infusion) to post-G infusion peak cytokine levels were compared between arms and between pts with vs without IRRs using Wilcoxon rank sum test. A 2-sided P value of <0.05 was considered significant with no adjustments for multiplicity. Results: Of 229 randomized pts, 95 pts on ibr-G (15 with IRR; 80 without IRR) and 88 pts on clb-G (45 with IRR; 43 without IRR) had cytokine data and were included in the analysis population. Baseline characteristics were similar between arms, except for lower platelets in ibr-G pts and higher baseline MCP1 levels in clb-G pts. As expected, all cytokine levels increased after infusion of G. Analysis of cytokine levels by treatment arm (ibr-G vs clb-G), irrespective of IRR occurrence, revealed that the median increase in cytokines was lower in ibr-G vs clb-G pts for all cytokines (P<0.01) except MIP1β (Figure). When analyzing pts with and without IRR, the median increase in post-G peak from baseline was greater in pts with vs without IRR for all cytokines (P<0.001) except MIP1β. Analysis of cytokine levels in pts with and without IRR within each treatment arm showed that IL6 and IL8 elevations were associated with IRRs in both treatment arms. In ibr-G arm, pts with IRR had increases in post-G levels of IL6, IL8, IL18, MCP1, MIP1α, and TNFα (P<0.04); in clb-G arm, pts with IRR had increases in IFNγ, IL6, IL8, and IL10 (P<0.03). Among the pts with IRR, ibr-G pts had lower post-G increases in IL6, IL8, IL10, and MCP1 levels (P<0.04) than clb-G pts. Keywords: cytokines; ibrutinib; obinutuzumab. Disclosures: Greil, R: Employment Leadership Position: Celgene, Roche, Merck, AstraZeneca, Novartis, Amgen, BMS, MSD, Takeda, Sandoz; Consultant Advisory Role: Celgene, Novartis, Roche, BMS, Abbvie, AstraZeneca, Janssen, Takeda; Research Funding: Celgene, Roche, Merck, AstraZeneca, Novartis, Amgen, BMS, MSD, Takeda, Sandoz; Other Remuneration: Travel, Accomodations, Expenses: Roche, Amgen, Janssen, AstraZeneca. Tedeschi, A: Consultant Advisory Role: Janssen spa, Gilead, AbbVie, SUNESIS; Other Remuneration: Speaker's Bureau: Janssen. Moreno, C: Consultant Advisory Role: Janssen, Pharmacyclics, AbbVie. Larratt, L: Consultant Advisory Role: Abbvie, Janssen. Simkovic, M: Consultant Advisory Role: Abbvie, Roche, Gilead; Honoraria: Abbvie, Janssen-Cilag, Roche, Gilead; Other Remuneration: Speaker's Bureau: Abbvie, Roche, Janssen-Cilag, Gilead; Travel, Accomodations, Expenses: Roche, Janssen-Cilag, Gilead. Gill, D: Consultant Advisory Role: Janssen Cilag; Honoraria: Janssen-Cilag. Gribben, J: Consultant Advisory Role: Pharmacyclics, Janssen; Honoraria: Pharmacyclics LLC, an AbbVie Company, Janssen; Research Funding: Janssen. Flinn, I: Research Funding: Agios, ArQule, Beigene, Calithera, Celgene, Constellation, Curis, Forma, Forty Seven, Genentech, Gilead, Incyte, infinity, Janssen, KITE, Merck, Novartis, Pfizer, Pharmamcyclics, Portola, Seattle genetics, Takeda, TG Therapeutics, Trillium, Verastem. Wang, Z: Employment Leadership Position: Pharmacyclics LLC, an AbbVie Company; Stock Ownership: Abbvie, Anaptysbio. Cheung, L: Employment Leadership Position: Pharmacyclics LLC, an AbbVie Company; Stock Ownership: AbbVie & Eli Lilly and Company; Other Remuneration: Patents, Royalties: Pharmacyclics LLC, an AbbVie Company. Nguyen, A: Employment Leadership Position: Pharmacyclics, an AbbVie Company; Stock Ownership: Abbvie; Other Remuneration: Travel, Accomodations, Expenses: AbbVie. Zhou, C: Employment Leadership Position: Pharmacyclics LLC, an AbbVie Company; Stock Ownership: Abbvie. Styles, L: Employment Leadership Position: Pharmacyclics LLC, an AbbVie Company; Stock Ownership: Abbvie. Demirkan, F: Consultant Advisory Role: Amgen, Abbvie; Research Funding: Janssen, Abbvie; Other Remuneration: Travel, Accomodations, or Other Expenses: Abbvie, Pfizer, Janssen, Amgen.