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The safety and tolerability of pirfenidone for bronchiolitis obliterans syndrome after hematopoietic cell transplant (STOP-BOS) trial

Bone Marrow Transplantation volume 57, pages 1319–1326 (2022)Cite this article

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Abstract

Bronchiolitis obliterans syndrome (BOS) is the most morbid form of chronic graft-versus-host disease (cGVHD) after hematopoietic cell transplantation (HCT). Progressive airway fibrosis leads to a 5-year survival of 40%. Treatment options for BOS are limited. A single arm, 52-week, Phase I study of pirfenidone was conducted. The primary outcome was tolerability defined as maintaining the recommended dose of pirfenidone (2403 mg/day) without a dose reduction totaling more than 21 days, due to adverse events (AEs) or severe AEs (SAEs). Secondary outcomes included pulmonary function tests (PFTs) and patient reported outcomes (PROs). Among 22 participants treated for 1 year, 13 (59%) tolerated the recommended dose, with an average daily tolerated dose of 2325.6 mg/day. Twenty-two SAEs were observed, with 90.9% related to infections, none were attributed to pirfenidone. There was an increase in the average percent predicted forced expiratory volume in 1 s (FEV1%) of 7 percentage points annually and improvements in PROs related to symptoms of cGVHD. In this Phase I study, treatment with pirfenidone was safe. The stabilization in PFTs and improvements in PROs suggest the potential of pirfenidone for BOS treatment and support the value of a randomized controlled trial to evaluate the efficacy of pirfenidone in BOS after HCT. The study is registered in ClinicalTrials.gov (NCT03315741).

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Fig. 1
Fig. 2: Pulmonary function trajectory for pirfenidone responders and non-responders.
Fig. 3: Medical Outcomes Study Short-Form 36 (SF-36) Health Survey Questionnaire at baseline, 6 and 12 months during STOP-BOS trial.
Fig. 4: Lee graft versus host disease summary score during STOP-BOS trial.
Fig. 5: Biomarkers identified from a random forest model are associated with response to pirfenidone.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files. Additional study data generated for the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to thank all patients for their willingness to participate in the study. We would also like to thank Dr. Sally Glaser for her critical read of the manuscript and Mr. Guy Livneh for his advocacy for patients with BOS and support of the Stanford Lung GVHD clinic.

Funding

JH is funded by K08HL122528-01A1-NIH/NHLBI, and R01HL157414-01-NIH/NHLBI. GSC is funded by R01HL161037-01-NIH/NHLBI, P30 CA015704-NIH/NCI and a V Foundation grant. Genentech provided drug support for the trial. The Blood and Marrow Transplant database is funded by P01 CA049605-NIH, and P01 HL075462-NIH.

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Author notes

  1. These authors contributed equally: Efthymia Iliana Matthaiou, Husham Sharifi.

Authors and Affiliations

  1. Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Efthymia Iliana Matthaiou, Husham Sharifi, Wayland Chiu, Paulami Chatterjee, Ihsan Turk, Theresa Brondstetter, Karen Morris & Joe L. Hsu

  2. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Christian O’Donnell

  3. Department of Medicine, Division of Pulmonary and Critical Care Medicine, New York-Presbyterian Hospital/Weill Cornell Medical Center, New York, NY, USA

    Clark Owyang

  4. Department of Medicine, Division of Blood and Marrow Transplantation, Stanford University School of Medicine, Stanford, CA, USA

    Laura Johnston & Theresa Brondstetter

  5. Clinical Research Division, Section of Pulmonary and Critical Care, Fred Hutchinson Cancer Research Center, Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WA, USA

    Guang-Shing Cheng

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Contributions

JH conceived and designed the study, he had full access to all the data and is the guarantor for the integrity of the data and its analysis. EIM, HS, CO’D, WC, CO, PC, TB, KM, IT, LJ, and JH collected the data. EIM, HS, CO’D, PC, IT, GSC, and JH did the data analysis and interpretation. EIM, HS, CO’D, GSC, and JH drafted the manuscript. HS, CO’D, IT, KM, PC, GSC, and JH verified the data. All authors contributed to revisions of the manuscript. The final version of the manuscript was read and approved by all authors.

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Correspondence to Joe L. Hsu.

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Competing interests

JH was supported by the National Institutes of Health (NIH) during the period that the study was conducted. GSC reports grants from NIH and the V Foundation during the study period. All other authors declare no competing interests.

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Matthaiou, E.I., Sharifi, H., O’Donnell, C. et al. The safety and tolerability of pirfenidone for bronchiolitis obliterans syndrome after hematopoietic cell transplant (STOP-BOS) trial. Bone Marrow Transplant 57, 1319–1326 (2022). https://doi.org/10.1038/s41409-022-01716-4

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