Ibrutinib for Chronic Graft-versus-Host Disease After Failure of Prior Therapy: 1-Year Update of a Phase 1b/2 Study

Edmund K. Waller, David Miklos, Corey Cutler, Mukta Arora, Madan H. Jagasia, Iskra Pusic, Mary E.D. Flowers, Aaron C. Logan, Ryotaro Nakamura, Stephen Chang, Fong Clow, Indu D. Lal, Lori Styles, Samantha Jaglowski

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

Chronic graft-versus-host disease (cGVHD) is a life-threatening complication of allogeneic stem cell transplantation. In a Phase 1b/2, open-label study (PCYC-1129; ClinicalTrials.gov identifier NCT02195869) involving 42 patients with active cGVHD who were steroid-dependent or -refractory, the activity and safety of ibrutinib, a once-daily inhibitor of Bruton's tyrosine kinase, was demonstrated. Here we report extended follow-up for patients in this study. After a median follow-up of 26 months (range,.53 to 36.7 months), best overall response rate in the all treated population was 69% (29 of 42), with 13 patients (31%) achieving a complete response and 16 patients (38%) achieving a partial response. Sustained responses of ≥20, ≥32, and ≥44 weeks were seen in 20 (69%), 18 (62%), and 16 (55%) of the 29 responders, respectively. Of 26 patients with ≥2 involved organs, 19 (73%) showed responses in ≥2 organs. Six of 10 patients (60%) with ≥3 involved organs showed responses in ≥3 organs. Eleven of 18 patients (61%) who had sclerosis at baseline showed a sclerotic response (39% with complete response, 22% with partial response). Twenty-seven of 42 patients (64%) reached a corticosteroid dose of <.15 mg/kg/day during the study; 8 discontinued corticosteroid treatment and remained off corticosteroid at study closure. Safety findings for this updated analysis were consistent with the safety profile seen at the time of the original analysis. Common grade ≥3 adverse events (AEs) were pneumonia (n = 6), fatigue (n = 5), and diarrhea (n = 4). The onset of new grade ≥3 AEs decreased from 71% in the first year of treatment to 25% in the second year (n = 12). AEs leading to discontinuation occurred in 18 patients (43%). At a median follow-up of >2 years, ibrutinib continued to produce durable responses in patients with cGVHD who had failed previous systemic therapy. In this pretreated, high-risk population, clinically meaningful benefit and an acceptable safety profile were observed with additional follow-up for ibrutinib. These results demonstrate a substantial advance in the therapeutic management of patients with cGVHD.

Original languageEnglish (US)
Pages (from-to)2002-2007
Number of pages6
JournalBiology of Blood and Marrow Transplantation
Volume25
Issue number10
DOIs
StatePublished - Oct 2019

Bibliographical note

Funding Information:
Financial disclosure: Medical writing support was provided by Lauren D'Angelo, PhD, and funded by Pharmacyclics LLC, an AbbVie Company, Sunnyvale, California, USA, and Janssen Research and Development, Titusville, New Jersey, USA.

Funding Information:
The authors thank all of the patients who participated in this trial and their families. Financial disclosure: Medical writing support was provided by Lauren D'Angelo, PhD, and funded by Pharmacyclics LLC, an AbbVie Company, Sunnyvale, California, USA, and Janssen Research and Development, Titusville, New Jersey, USA. Conflict of interest statement: E.K.W.: leadership role for and patents, royalties, or other intellectual properties from Cambium Medical Technologies; consultancy/advisory role and honoraria for Novartis, Amgen, Celldex, and CSL Behring; patents, royalties, or other intellectual properties from Cambium Medical Technologies; research funding from Celldex and Novartis; stock or other ownership in Cerus, Chimerix, Cambium Medical Technologies, and Cambium Oncology; and travel, accommodations, or expenses from Pharmacyclics LLC, an AbbVie Company. D.M.: consultancy/advisory role for Pharmacyclics LLC, an AbbVie Company, Janssen, Adaptive Biotechnologies, Kite-Gilead, Novartis, and Juno; speakers bureau for Pharmacyclics LLC, an AbbVie Company, Adaptive Biotechnologies, and Kite-Gilead; and patent for ibrutinib therapy of chronic graft-versus-host disease with Pharmacyclics LLC, an AbbVie Company. C.C.: consultancy/advisory role for Pharmacyclics LLC, an AbbVie Company, Genentech, Pfizer, Kite, Jazz, Sandoz, Bristol-Myers Squibb, Incyte, Astellas, and Kadmon; and expert testimony for Pharmacyclics LLC, an AbbVie Company. M.A.: nothing to disclose. M.H.J.: honoraria from Mallinckrodt and Kadmon; consultancy/advisory role for Incyte and Kadmon; and research funding from Janssen and Mallinckrodt. I.P.: travel, accommodations, or expenses from Pharmacyclics LLC, an AbbVie Company. M.E.D.F.: honoraria, speakers bureau, and travel, accommodations, or expenses from Astellas and Mallinckrodt; consultancy/advisory role for Pharmacyclics LLC, an AbbVie Company, and CSL Behring; and research funding from Pharmacyclics, LLC, an AbbVie Company, and Incyte/Novartis; A.C.L.: consultancy/advisory role for Amgen, Adaptive Biotechnologies, Agios, Jazz, Shire, and Pfizer; and research. Funding from Pharmacyclics LLC, an AbbVie Company, Astellas, Novartis, Kite, and Jazz. R.N.: consultancy/advisory role for Merck. S.C.: employed by Pharmacyclics LLC, an AbbVie Company, and stock or other ownership in AbbVie, Johnson and Johnson, Portola, Abbott, and Ipsen. F.C.: employed by, leadership role for, and travel, accommodations, or expenses from Pharmacyclics LLC, an AbbVie Company; and stock or other ownership in AbbVie. I.D.L.: employed by Pharmacyclics LLC, an AbbVie Company and spouse employment with The Permanente Medical Group; and stock or other ownership in AbbVie, Gilead Sciences, Clovis, Infinity, The Permanente Medical Group, and Reviva Pharmaceuticals. L.S.: employed by Pharmacyclics LLC, an AbbVie Company, and stock or other ownership in AbbVie. S.J.: consultancy/advisory role for Pharmacyclics LLC, an AbbVie Company, Kite, Novartis, and Juno; research funding from Pharmacyclics LLC, an AbbVie Company, Kite, Unum, Novartis, Janssen, and Amgen; and travel, accommodations, or expenses from Kite, Novartis, and Juno.

Funding Information:
Conflict of interest statement: E.K.W.: leadership role for and patents, royalties, or other intellectual properties from Cambium Medical Technologies; consultancy/advisory role and honoraria for Novartis, Amgen, Celldex, and CSL Behring; patents, royalties, or other intellectual properties from Cambium Medical Technologies; research funding from Celldex and Novartis; stock or other ownership in Cerus, Chimerix, Cambium Medical Technologies, and Cambium Oncology; and travel, accommodations, or expenses from Pharmacyclics LLC, an AbbVie Company. D.M.: consultancy/advisory role for Pharmacyclics LLC, an AbbVie Company, Janssen, Adaptive Biotechnologies, Kite-Gilead, Novartis, and Juno; speakers bureau for Pharmacyclics LLC, an AbbVie Company, Adaptive Biotechnologies, and Kite-Gilead; and patent for ibrutinib therapy of chronic graft-versus-host disease with Pharmacyclics LLC, an AbbVie Company. C.C.: consultancy/advisory role for Pharmacyclics LLC, an AbbVie Company, Genentech, Pfizer, Kite, Jazz, Sandoz, Bristol-Myers Squibb, Incyte, Astellas, and Kadmon; and expert. Testimony for Pharmacyclics LLC, an AbbVie Company. M.A.: nothing to disclose. M.H.J.: honoraria from Mallinckrodt and Kadmon; consultancy/advisory role for Incyte and Kadmon; and research. Funding from Janssen and Mallinckrodt. I.P.: travel, accommodations, or expenses from Pharmacyclics LLC, an AbbVie Company. M.E.D.F.: honoraria, speakers bureau, and travel, accommodations, or expenses from Astellas and Mallinckrodt; consultancy/advisory role for Pharmacyclics LLC, an AbbVie Company, and CSL Behring; and research funding from Pharmacyclics, LLC, an AbbVie Company, and Incyte/Novartis; A.C.L.: consultancy/advisory role for Amgen, Adaptive Biotechnologies, Agios, Jazz, Shire, and Pfizer; and research. Funding from Pharmacyclics LLC, an AbbVie Company, Astellas, Novartis, Kite, and Jazz. R.N.: consultancy/advisory role for Merck. S.C.: employed by Pharmacyclics LLC, an AbbVie Company, and stock or other ownership in AbbVie, Johnson and Johnson, Portola, Abbott, and Ipsen. F.C.: employed by, leadership role for, and travel, accommodations, or expenses from Pharmacyclics LLC, an AbbVie Company; and stock. Or other ownership in AbbVie. I.D.L.: employed by Pharmacyclics LLC, an AbbVie Company and spouse employment with The Permanente Medical Group; and stock. Or other ownership in AbbVie, Gilead Sciences, Clovis, Infinity, The Permanente Medical Group, and Reviva Pharmaceuticals. L.S.: employed by Pharmacyclics LLC, an AbbVie Company, and stock or other ownership in AbbVie. S.J.: consultancy/advisory role for Pharmacyclics LLC, an AbbVie Company, Kite, Novartis, and Juno; research funding from Pharmacyclics LLC, an AbbVie Company, Kite, Unum, Novartis, Janssen, and Amgen; and travel, accommodations, or expenses from Kite, Novartis, and Juno.

Publisher Copyright:
© 2019 American Society for Transplantation and Cellular Therapy

Keywords

  • Bruton's tyrosine kinase inhibitor
  • Chronic graft-versus-host disease
  • Ibrutinib
  • Steroid-dependent chronic graft-versus-host disease
  • Steroid-refractory chronic graft versus host disease

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