Ibrutinib for chronic graft-versus-host disease after failure of prior therapy

David Miklos, Corey S. Cutler, Mukta Arora, Edmund K. Waller, Madan Jagasia, Iskra Pusic, Mary E. Flowers, Aaron C. Logan, Ryotaro Nakamura, Bruce R. Blazar, Yunfeng Li, Stephen Chang, Indu Lal, Jason Dubovsky, Danelle F. James, Lori Styles and Samantha Jaglowski

Key points

  • Ibrutinib induced a high rate of sustained responses (ORR 67%) in patients with cGVHD that had failed 1 or more lines of systemic therapy.

  • This trial supported FDA approval of ibrutinib for treatment of adult patients with cGVHD after failure of ≥ 1 lines of systemic therapy.


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's 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 NIH 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/day at baseline to 0.12 mg/kg/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 US for treatment of adult patients with cGVHD after failure of one or more lines of systemic therapy. The study is registered to as NCT02195869.

  • Submitted July 7, 2017.
  • Accepted September 6, 2017.