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Safety and efficacy of single‐agent ibrutinib in patients with relapsed/refractory (R/R) marginal zone lymphoma (MZL): A multicenter, open‐label, phase 2 study

1 (Th1) cells (Dubovsky, et al. Blood 2013). We describe the effect of ibr treatment on T‐cells and cytokines in pts in the DAWN study. Methods: This was a multicenter, single‐arm, phase 2 study of ibr in FL pts with ≥2 prior lines of therapy and progressive disease (PD) ≤ 12 months after CIT regimen. Pts received ibr (560 mg QD) on a 21‐day cycle until PD or toxicity. A protocol amendment allowed continued ibr treatment in clinically stable/improving pts with radiological evidence of PD (new lesion/increase ≥50%) to account for “pseudo‐PD”. The primary end point was the overall response rate (ORR) (complete response [CR] + partial response). Flow cytometry assessed T‐cell subsets in peripheral blood at baseline (C1D1) and at cycle 3 (C3D1) for 57 pts (14 responders, 43 nonresponders); cytokine and chemokine analyses were performed at C1D1 and at cycle 2 (C2D1) for 50 pts (21 responders, 29 nonresponders). Results: The DAWN study results have been presented (Gopal A, et al. ASH 2016); ibr achieved an ORR of 20.9% (CR rate, 10.9%). Flow cytometry analysis revealed CD4 + CD25 + CD127− Tregs were downregulated at C3D1 in responders (CR + PR, mean decrease 17 to 12.9% CD4, p = 0.02) but not in nonresponders (11.5 to 10.4% CD4, p = 0.17). There were no differences between responders and nonresponders in a large panel of inflammation‐related cytokines and chemokines at C1D1, confirmed by gene expression profiling in the tumor. After 21 days, Th1 cytokines interferon (IFN)‐γ and interleukin (IL)‐12 were increased in responders but decreased in nonresponders (p = 0.0025 and p = 0.035, respectively; Figure). The chemokines IFN‐γ‐induced protein 10 and monocyte‐chemotactic protein 3 were decreased in responders but increased in nonresponders (p = 0.022 and 0.016, respectively). Available data in pseudo‐PD pts showed a similar trend of decreased Tregs at C3D1 as responders, but the cytokines showed a similar trend as nonresponders. Conclusions: In ibr‐responding pts at early time points, Tregs were downregulated and Th1‐associated cytokines IFN‐γ and IL‐12 were increased. This shift inT‐cell population may be linked to the antitumor response; in nonresponders, these cytokines were decreased but Tregs were not. Chemokine changes suggest variation in chemoattraction. These data suggest that immunomodulatory effects of ibr could play a role in its antitumor activity in FL; combinations with other therapies may prove beneficial.