Chronic graft-versus-host disease (cGVHD) is a serious complication of allogeneic stem cell transplantation with few effective options available after failure of corticosteroids. B and T cells play a role in the pathophysiology of cGVHD. Ibrutinib inhibits Bruton tyrosine kinase in B cells and interleukin-2–inducible T-cell kinase in T cells. In preclinical models, ibrutinib reduced severity of cGVHD. This multicenter, open-label study evaluated the safety and efficacy of ibrutinib in patients with active cGVHD with inadequate response to corticosteroid-containing therapies. Forty-two patients who had failed 1 to 3 prior treatments received ibrutinib (420 mg) daily until cGVHD progression. The primary efficacy end point was cGVHD response based on 2005 National Institutes of Health criteria. At a median follow-up of 13.9 months, best overall response was 67%; 71% of responders showed a sustained response for ‡20 weeks. Responses were observed across involved organs evaluated. Most patients with multiple cGVHD organ involvement had a multiorgan response. Median corticosteroid dose in responders decreased from 0.29 mg/kg per day at baseline to 0.12 mg/kg per day at week 49; 5 responders discontinued corticosteroids. The most common adverse events were fatigue, diarrhea, muscle spasms, nausea, and bruising. Plasma levels of soluble factors associated with inflammation, fibrosis, and cGVHD significantly decreased over time with ibrutinib. Ibrutinib resulted in clinically meaningful responses with acceptable safety in patients with ‡1 prior treatments for cGVHD. Based on these results, ibrutinib was approved in the United States for treatment of adult patients with cGVHD after failure of 1 or more lines of systemic therapy. This trial was registered at www.clinicaltrials.gov as #NCT02195869.
Bibliographical noteFunding Information:
This study was supported by Pharmacyclics LLC, an AbbVie Company. Supriya Srinivasan, funded by Pharmacyclics LLC, an AbbVie Company, provided medical writing support in the preparation of the manuscript.
Conflict-of-interest disclosure: D.M. served in a consultancy/ advisory role for Pharmacyclics LLC, an AbbVie Company, Sanofi, Adaptive Biotechnologies, Kite, Genentech, and Velos; received research funding from Pharmacyclics LLC, an AbbVie Company; travel accommodations from Pharmacyclics LLC, an AbbVie Company, and Sanofi Oncology; and patents, royalties, and other intellectual property from Pharmacyclics LLC, an AbbVie Company. C.S.C. served in a consulting or advisory role with Pfizer, Kite, Bristol-Myers Squibb, Incyte, Astellas, and Pharmacyclics, an AbbVie Company. M.A. served in a consultancy/advisory role for Takeda Oncology. E.K.W. shared equity ownership with Cambium; received honoraria from Novartis; patents/royalties/other intellectual property and other relationship with Cambium Medical Technologies; received travel expenses with Novartis; served in a consulting/advisory role with Novartis, Alenon, Seattle Genetics, Mesoblast, and Aiye; and received research funding from Novartis and Sanofi. M.J. served in a consultancy/advisory role and received research funding from Theracos and Janssen. M.E.F. received research funding from Pharmacyclics LLC, an AbbVie Company. A.C.L. served in a consulting/advisory role with Amgen, Jazz, and Pharmacyclics LLC, an AbbVie Company, and received research funding from Astellas, Novartis, and Pharmacyclics LLC, an AbbVie Company. R.N. served in a consultancy/advisory role for Amgen and Seattle Genetics. B.R.B. served in a consultancy/advisory role with Tobira Therapeutics, Vulcan Capital, Idera Pharma, Sidley Austin LLP, Merck Sharpe & Dohme Corp, Merck Serono, Fate Therapeutics, Bristol-Myers Squibb, Sidley Austin, Kadmon Pharmaceuticals Inc, Kymab Scientific, Five Prime Therapeutics, Vitae Pharmaceuticals Inc, and Flx Bio; received research funding from Kadmon Corporation; and received patents/ royalties/other intellectual property as an individual (no company). Y.L. was employed with Pharmacyclics LLC, an AbbVie Company,