Ibrutinib as Treatment for Patients With Relapsed/Refractory Follicular Lymphoma: Results From the Open-Label, Multicenter, Phase II DAWN Study
- 9 August 2018
- journal article
- research article
- Published by American Society of Clinical Oncology (ASCO) in Journal of Clinical Oncology
- Vol. 36 (23), 2405-+
- https://doi.org/10.1200/JCO.2017.76.8853
Abstract
PurposeThe 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.MethodsDAWN 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.ResultsBetween 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- and interleukin-12 increased (P .035).ConclusionWith 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.Keywords
This publication has 30 references indexed in Scilit:
- Non‐Hodgkin lymphoma subtype distribution, geodemographic patterns, and survival in the US: A longitudinal analysis of the National Cancer Data Base from 1998 to 2011American Journal of Hematology, 2015
- Ibrutinib treatment ameliorates murine chronic graft-versus-host diseaseJCI Insight, 2014
- Ibrutinib versus Ofatumumab in Previously Treated Chronic Lymphoid LeukemiaThe New England Journal of Medicine, 2014
- Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytesBlood, 2013
- Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphomaHaematologica, 2013
- Bruton Tyrosine Kinase Inhibitor Ibrutinib (PCI-32765) Has Significant Activity in Patients With Relapsed/Refractory B-Cell MalignanciesJournal of Clinical Oncology, 2013
- B-cell signaling networks reveal a negative prognostic human lymphoma cell subset that emerges during tumor progressionProceedings of the National Academy of Sciences of the United States of America, 2010
- Revised Response Criteria for Malignant LymphomaJournal of Clinical Oncology, 2007
- Prediction of Survival in Follicular Lymphoma Based on Molecular Features of Tumor-Infiltrating Immune CellsThe New England Journal of Medicine, 2004
- Follicular Lymphoma International Prognostic IndexBlood, 2004