TO THE EDITOR:
DeFilipp et al published a phase 2, multicenter, trial treating bronchiolitis obliterans syndrome (BOS) after hematopoietic cell transplantation with ruxolitinib,1 a therapy for other chronic graft-versus-host diseases (cGVHDs).2 The authors should be lauded for undertaking an interventional BOS trial, a rare complication of hematopoietic cell transplantation.3 However, the trial incorporated an atypical definition of BOS, which pertained to 33% of those accrued, our point of discussion.1
Before 2005, 10 distinct BOS definitions confounded the literature.4 The landscape was transformed by the 2005 cGVHD diagnostic criteria,5 refined in 2014, and accepted.6 Multiple trials used these criteria, permitting comparison of response and tolerability.7, 8, 9, 10 However, recent trials included differing atypical BOS definitions (see table).1,11, 12, 13 Because 33% of this cohort lack National Institutes of Health-BOS, it is unclear how to interpret the aggregate 34.7% response rate.1
Recent lung cGVHD prospective interventional trials
| Trial intervention | Non-NIH BOS definition | NIH BOS definition % | Non-NIH BOS definition % | N | Trial design | Response definition | Year |
|---|---|---|---|---|---|---|---|
| Etanercept9 | FEV1/FVC <0.75; trial amended after NIH criteria published | 88 (22/25 obstructive) | 22 | 34 | Single arm | FEV1% | 2012 |
| Montelukast7 | N/A | 100 | 25 | Single arm vs historical | Slope & FEV1% | 2022 | |
| FAM-inhaled fluticasone, azithromycin, montelukast8 | N/A | 100 | 36 | Single arm vs historical | Slope & FEV1% | 2016 | |
| Pirfenidone11 | CT with air trapping >28% or clinical improvement after treatment | 90.9 | 9.1 | 30 | Single arm | Slope of FEV1% | 2022 |
| Belumosudil12 | FEV1 ≤79%, clinician attribution to BOS | Unknown | 100 | 59 | Single arm | FEV1% | 2022 |
| Inhaled corticosteroid and long-acting beta agonist13 | FEV1 <80%, FEV1/FVC <5th percentile of CI, TLC ≥80% | Unknown | 100 | 32 | Randomized controlled | FEV1 (mL) | 2015 |
| Axatilimab10 | N/A | 100 | 16 | Single arm | FEV1% in 1 of 5 responders Symptoms in 4 of 5 responders |
2023 | |
| Ruxolitinib1 | FEV1 <80%, >10% decrease in <2 years, VC <80%, FEV1/VC >0.7, absence of infection | 66 | 33 | 49 | Single arm | FEV1 (mL) | 2024 |
The non-NIH BOS patients accrued in the etanercept trial were accrued prior to the development of the 2005 NIH BOS consensus criteria. Of note, the axatilimab trial included patients with other cGVHD manifestations (not just BOS). For the belumosudil and inhaled corticosteroid and long-acting beta agonist trials, all patients met the atypical BOS definition; what is unknown is how many of these patients would also have met the NIH-BOS definition at study entry.
CI, confidence interval; CT, computed tomography; FAM, fluticasone, azithromcyin, montelukast therapy; FEV1, forced expiratory volume at 1 second; N, total number of patients with BOS enrolled; N/A, not applicable; NIH, National Institutes of Health; TLC, total lung capacity; VC, vital capacity.
These results diverge from the prior ruxolitinib study showing an 8.6% response in BOS,2 although pulmonary function tests were not captured, relying upon the Lee Symptom Scale metric. However, other studies have shown concordance between these tests.1,7,8,11,12 It is thus possible that atypical BOS patients inflated the response, possibly reflecting responses to restrictive lung GVHD.3,14, 15, 16 Alternatively, atypical BOS patients could obscure a higher response, diluting the cohort with poorly responsive myositis, myalgia, or infections.2
A control group could mitigate these factors, as shown in 1 study.13 Established patients are more likely to skew the results toward stability, with 27% exhibiting prolonged stable disease.1 In addition, cotreatment with other BOS-directed therapies at diagnostic onset complicates response assessments in this study, affecting the majority of patients.8,13
We request details regarding the atypical-BOS pulmonary function test response in this trial. Although it may be time to use data to refine the National Institutes of Health’s definition of BOS, we plead with our community to report the number and details of non-BOS lung cGVHD separately to enhance our understanding of responses, pathogenesis, and phenotypes.17
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Acknowledgments
Acknowledgment: Funding for this study was provided in part by the National Institutes of Health, National Heart, Lung, and Blood Institute grant R01HL162661.
Contribution: K.M.W. wrote and designed the manuscript; and V.L., K.R.C., K.M.W., and G.A.Y. edited the manuscript.
References
- 1.DeFilipp Z, Kim HT, Cheng GS, et al. A phase 2 multicenter trial of ruxolitinib to treat bronchiolitis obliterans syndrome after allogeneic HCT. Blood Adv. 2025;9(2):244–253. doi: 10.1182/bloodadvances.2024014000. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Zeiser R, Polverelli N, Ram R, et al. Ruxolitinib for glucocorticoid-refractory chronic graft-versus-host disease. N Engl J Med. 2021;385(3):228–238. doi: 10.1056/NEJMoa2033122. [DOI] [PubMed] [Google Scholar]
- 3.Williams KM. How I treat bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation. Blood. 2017;129(4):448–455. doi: 10.1182/blood-2016-08-693507. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Williams KM, Chien JW, Gladwin MT, Pavletic SZ. Bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation. JAMA. 2009;302(3):306–314. doi: 10.1001/jama.2009.1018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and Staging Working Group report. Biol Blood Marrow Transpl. 2005;11(12):945–956. doi: 10.1016/j.bbmt.2005.09.004. [DOI] [PubMed] [Google Scholar]
- 6.Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transpl. 2015;21(3):389–401.e1. doi: 10.1016/j.bbmt.2014.12.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Williams KM, Pavletic SZ, Lee SJ, et al. Prospective phase II trial of montelukast to treat bronchiolitis obliterans syndrome after hematopoietic cell transplantation and investigation into bronchiolitis obliterans syndrome pathogenesis. Transpl Cell Ther. 2022;28(5):264.e1–264.e9. doi: 10.1016/j.jtct.2022.01.021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Williams KM, Cheng GS, Pusic I, et al. Fluticasone, azithromycin, and montelukast treatment for new-onset bronchiolitis obliterans syndrome after hematopoietic cell transplantation. Biol Blood Marrow Transpl. 2016;22(4):710–716. doi: 10.1016/j.bbmt.2015.10.009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Yanik GA, Mineishi S, Levine JE, et al. Soluble tumor necrosis factor receptor: enbrel (etanercept) for subacute pulmonary dysfunction following allogeneic stem cell transplantation. Biol Blood Marrow Transpl. 2012;18(7):1044–1054. doi: 10.1016/j.bbmt.2011.11.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Kitko CL, Arora M, DeFilipp Z, et al. Axatilimab for chronic graft-versus-host disease after failure of at least two prior systemic therapies: results of a phase I/II study. J Clin Oncol. 2023;41(10):1864–1875. doi: 10.1200/JCO.22.00958. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Matthaiou EI, 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 Transpl. 2022;57(8):1319–1326. doi: 10.1038/s41409-022-01716-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.DeFilipp Z, Kim HT, Yang Z, et al. Clinical response to belumosudil in bronchiolitis obliterans syndrome: a combined analysis from 2 prospective trials. Blood Adv. 2022;6(24):6263–6270. doi: 10.1182/bloodadvances.2022008095. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Bergeron A, Chevret S, Chagnon K, et al. Budesonide/formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation. Am J Respir Crit Care Med. 2015;191(11):1242–1249. doi: 10.1164/rccm.201410-1818OC. [DOI] [PubMed] [Google Scholar]
- 14.Namkoong H, Ishii M, Mori T, et al. Clinical and radiological characteristics of patients with late-onset severe restrictive lung defect after hematopoietic stem cell transplantation. BMC Pulm Med. 2017;17(1):123. doi: 10.1186/s12890-017-0466-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.L'Excellent S, Yakouben K, Delclaux C, Dalle JH, Houdouin V. Lung evaluation in 10 year survivors of pediatric allogeneic hematopoietic stem cell transplantation. Eur J Pediatr. 2019;178(12):1833–1839. doi: 10.1007/s00431-019-03447-z. [DOI] [PubMed] [Google Scholar]
- 16.Yang JY, Oh SY, Song JW, et al. Restrictive chronic lung function decline after haematopoietic stem cell transplantation. Eur Respir J. 2016;47(1):336–339. doi: 10.1183/13993003.00180-2015. [DOI] [PubMed] [Google Scholar]
- 17.Kitko CL, Pidala J, Schoemans HM, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IIa. The 2020 Clinical Implementation and Early Diagnosis Working Group report. Transpl Cell Ther. 2021;27(7):545–557. doi: 10.1016/j.jtct.2021.03.033. [DOI] [PMC free article] [PubMed] [Google Scholar]