Pretreatment With Ibrutinib Reduced Obinutuzumab-Induced Cytokine Secretion and Infusion-Related Reactions in CLL/SLL

Patients with chronic lymphocytic leukemia/small lymphocytic lymphoma were pretreated with ibrutinib saw a reduction in obinutuzumab-induced infusion-related reactions as well as cytokines and chemokines.

Both the rate of clinically apparent obinutuzumab (Gazyva)-induced infusion-related reactions (IRRs) and levels of IRR-related cytokines and chemokines were reduced among patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) who were pretreated with ibrutinib (Imbruvica), according to results from the phase 3 iLLUMINATE trial (NCT02264574) published in Annals of Hematology.

Following obinutuzumab infusion, increases over baseline levels were observed for patients across all cytokines and chemokines analyzed. Moreover, the median change in baseline cytokine levels was statistically significantly lower among patients in the ibrutinib/obinutuzumab arm compared with patients in the chlorambucil/obinutuzumab arm (P < .01). Of note regarding change from baseline levels, MIP-1β was the only chemokine with no statistically significant difference between treatment arms (P = .7747).

“The current analysis demonstrates that ibrutinib suppresses obinutuzumab-induced increases in multiple cytokines and chemokines related to IRRs and suggests that the reduction in IRR events in ibrutinib-treated patients is the result of a reduction in the release of inflammatory cytokines and chemokines,” the study authors wrote.

A total of 228 patients were enrolled on the trial and treated, with 95 patients receiving ibrutinib/obinutuzumab arm and 88 patients receiving chlorambucil/obinutuzumab arm. These patients were included in the analysis population due to evaluable cytokine/chemokine results.

Patients were treated with either ibrutinib or chlorambucil approximately 30 to 120 minutes before the first obinutuzumab infusion. Investigators evaluated several cytokines including IFNγ, IL-6, IL-8, IL-10, IL-18, MCP-1, MIP-1α, MIP-1β, and TNFα. Eligible patients were aged 18 years or older with previously untreated CLL/SLL.

For patients with IRRs (n = 60), increases in median changes from baseline levels were significantly greater vs patients without IRRs (n = 123) across both treatment arms (P < .001) for all cytokines and chemokines accessed except for MIP-1β (P = .6290). After treatment with obinutuzumab, greater increases from baseline levels in IL-6 and IL-8 were significantly associated with IRRs for patients in both the ibrutinib/obinutuzumab (P = .0012 and P = .0126, respectively) and chlorambucil/obinutuzumab arms (P = .0097 and P = .0234, respectively).

When analyzing cytokine/chemokine patterns in patients across the differnet treatment arms, investigators identified that notable increases from baseline IL-6 and IL-8 levels following treatment with obinutuzumab had a significant association with IRRs in both the ibrutinib (P = .0012 and P = .0126) and chlorambucil arms (P = .0097 and P = .0234), respectively. Moreover, patients with IRRs in the ibrutinib/obinutuzumab arm underwent significant significantly higher increases in post-obinutuzumab levels of IL-18, TNFα, MCP-1, and MIP-1α than patients without IRRs (P < .04). A similar increase in post-obinutuzumab levels of IFNγ and IL-10 was observed for patients with IRRs in the chlorambucil/obinutuzumab arm compared with those without IRRs (P < .03).

The analysis of covariance focused on the factors associated with the “increase in absolute values from baseline of cytokine and chemokine levels.” In the ibrutinib/obinutuzumab arm, those factors included splenomegaly (IL-6, IL-8, MCP-1, MIP-1α, TNFα), lower hemoglobin levels (IL-8), higher absolute neutrophil count (IL-8, MCP-1, MIP-1α, TNFα), and higher absolute lymphocyte count (IFNγ, IL-6, IL-8, MCP-1, MIP-1α, TNFα). For the chlorambucil/obinutuzumab arm, those factors were Rai stage III/IV (IL-8, IL-18), bulky disease (≥ 5 cm: IL-10, TNFα) splenomegaly (IFNγ, IL-18, IL-6, IL-8, MIP-1α, TNFα), lower hemoglobin levels (IL-10, IL-8), lower platelet count (IL-18, MCP-1, MIP-1β), and higher absolute lymphocyte count (IFNγ, IL-10, IL-6, IL-8, MCP-1, MIP-1α, TNFα).

“These observations may have implications for immunotherapeutic approaches where the tuning of the inflammatory reaction may modify the type and degree of cytokine release patterns (activated or dampened) and their role in the treatment effect or safety profile of immunotherapies,” the investigators concluded.


Greil R, Tedeschi A, Moreno C, et al. 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. Ann Hematol. 2021;100(7):1733-1742. doi:10.1007/s00277-021-04536-6

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