Ibrutinib as treatment for patients with relapsed/refractory follicular lymphoma: Results from the open-label, multicenter, phase II DAWN study

Ajay K. Gopal, Stephen J. Schuster, Nathan H. Fowler, Judith Trotman, Georg Hess, Jing Zhou Hou, Abdulraheem Yacoub, Michael Lill, Peter Martin, Umberto Vitolo, Andrew Spencer, John Radford, Wojciech Jurczak, James Morton, Dolores Caballero, Sanjay Deshpande, Gary J. Gartenberg, Shean Sheng Wang, Rajendra N. Damle, Michael SchafferSriram Balasubramanian, Jessica Vermeulen, Bruce D. Cheson, Gilles Salles

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Purpose The Bruton’s tyrosine kinase inhibitor ibrutinib has demonstrated clinical activity in B-cell malignancies. The DAWN study assessed the efficacy and safety of single-agent ibrutinib in chemoimmunotherapy relapsed/refractory follicular lymphoma (FL) patients. Methods DAWN was an open-label, single-arm, phase II study of ibrutinib in patients with FL with two or more prior lines of therapy. Patients received ibrutinib 560 mg daily until progressive disease/unacceptable toxicity. The primary objective was independent review committee–assessed overall response rate (ORR; complete response plus partial response). Exploratory analyses of T-cell subsets in peripheral blood (baseline/cycle 3) and cytokines/chemokines (baseline/cycle 2) were performed for available samples. Results Between March 2013 and May 2016, 110 patients with a median of three prior lines of therapy were enrolled. At median follow-up of 27.7 months, ORR was 20.9% (95% CI, 13.7% to 29.7%, which did not meet the 18% lower-bound threshold for the primary end point). Twelve patients achieved a complete response (11%; 95% CI, 5.8% to 18.3%). Median duration of response was 19.4 months (range, 1 to ≥ 33 months), with a median progression-free survival of 4.6 months and a 30-month overall survival of 61% (95% CI, 0.51% to 0.70%). Lymphoma symptoms resolved in 67%. Seven of 32 patients who experienced initial radiologic progression responded upon continuing therapy (pseudoprogression). The most common adverse events were diarrhea, fatigue, cough, and muscle spasms; 48.2% of patients reported serious adverse events. In patients who experienced a response, regulatory T cells were downregulated at C3D1 (P = .02), and Th1-promoting (antitumor) cytokines interferon-g and interleukin-12 increased (P ≤ .035). Conclusion With an ORR of 20.9%, ibrutinib failed to meet its primary efficacy end point in chemoimmunotherapy in patients with relapsed/refractory FL, although responses were durable and associated with a reduction in regulatory T cells and increases in proinflammatory cytokines.

Original languageEnglish
Pages (from-to)2405-2412
Number of pages8
JournalJournal of Clinical Oncology
Issue number23
Publication statusPublished - 10 Aug 2018

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