Risk Factors for Bronchiolitis Obliterans in Allogeneic Hematopoietic Stem-Cell Transplantation for Leukemia

doi:10.1378/chest.128.1.153

Chest

Volume 128, Issue 1, July 2005, Pages 153-161

https://doi.org/10.1378/chest.128.1.153 Get rights and content

Study objectives

Reported risk factors for bronchiolitis obliterans (BO) in allogeneic hematopoietic stem-cell transplant recipients come from modest-sized studies and are limited to experiences of single institutions. We sought to identify risk factors for BO using data from the International Bone Marrow Transplant Registry.

Methods

Registry data on 6,275 adult patients with leukemia who received human leukocyte antigen-identical sibling transplants from 1989 to 1997 and survived at least 100 days after transplantation were evaluated for the study. Risk factors for BO were analyzed using proportional hazards regression.

Results

Seventy-six patients were found to have BO, with an incidence rate of 1.7% at 2 years after transplantation. The Kaplan-Meier estimate of median time to onset of BO was 431 days. Histologic evaluation was performed in 36 patients (47%). In 28 patients (37%), diagnosis was based on pulmonary function tests, CT scans of the chest, or a combination of both. On multivariate analysis, the factors that were associated with an increased risk for BO included the following: peripheral blood-derived stem cell, a busulfan-based conditioning regimen, interval from diagnosis to transplant ≥ 14 months, female donor to male recipient sex match, prior interstitial pneumonitis, and an episode of moderate-to-severe acute graft-vs-host disease (GVHD).

Conclusion

In addition to corroborating previously reported risk factors, such as acute GVHD and a busulfan-based conditioning regimen, we found that peripheral blood stem-cell transplantation, long duration to transplant, female donor to male recipient, and a prior episode of interstitial pneumonitis are associated with an increased risk for BO.

Section snippets

IBMTR Database

The IBMTR is a voluntary working group of > 350 transplantation centers worldwide that contribute detailed data on consecutive allogeneic HSCTs to a statistical center at the Health Policy Institute of the Medical College of Wisconsin in Milwaukee. Based on data collected in the Centers for Disease Control Hospital Surveys and the US Government Accounting Office and worldwide surveys of transplant activity, approximately 40% of allogeneic transplants worldwide are registered with the IBMTR.

Cohort Characteristics

A total of 8,276 patients receiving HLA-identical sibling transplants for leukemia between 1989 and 1997 were identified based on the inclusion criteria. Excluding those who survived < 100 days after transplant, 6,341 patients remained. Another 66 patients were excluded because of preexisting obstructive lung disease prior to transplant. Eight patients with a diagnosis of BO were excluded: five patients who survived < 100 days, and three patients with preexisting obstructive lung disease. The

Discussion

In this study of 6,275 adult recipients of HLA-identical sibling matched HSCT for leukemia we found several factors associated with an increased risk for the development of BO. Aside from validating previously described risk factors such as GVHD and type of conditioning regimen, our analysis indicates that, PBSCT, a long interval from diagnosis to transplant, female donor to male recipient, and a prior episode of interstitial pneumonitis are risk factors. The large number of patients reported

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Bronchiolitis obliterans (BO) is a form of graft-versus-host disease (GVHD) in the lung and manifests as moderate to severe airflow obstruction after hematopoietic stem cell transplantation (HCT). New-onset airflow obstruction on spirometry is considered diagnostic of bronchiolitis obliterans syndrome (BOS). BOS affects about 5% of all HCT recipients. In general, BO is thought of as a late complication of HCT, usually occurring after day 100 post-transplantation. However, the onset of airflow obstruction can be rapid and is most often irreversible even with treatment. We describe a patient who rapidly developed severe airflow obstruction less than one month after transplantation following the development of upper airway symptoms. Despite aggressive immunosuppression, the patient had no improvement in airflow obstruction. We hypothesize that early screening and treatment may help prevent BOS after HCT.
Efficacy of inhaled tiotropium add-on to budesonide/formoterol in patients with bronchiolitis obliterans developing after hematopoietic stem cell transplantation
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Bronchiolitis obliterans syndrome (BOS) is the lung manifestation of chronic graft-versus-host disease after hematopoietic stem cell transplantation (HSCT). We assessed whether inhaled tiotropium add-on to the combination regimen including budesonide/formoterol improve pulmonary function and the chronic obstructive pulmonary disease assessment test (CAT) scores in patients with BOS.
Post-HSCT patients diagnosed as BOS in Seoul St. Mary's Hospital were reviewed retrospectively. Patients defined as BOS and treated with budesonide/formoterol/tiotropium combination therapy after budesonide/formoterol therapy from January 2011 to June 2019 were enrolled.
Total of 86 patients were evaluated. After tiotropium add-on, the absolute FEV1 increased significantly from 1.47 ± 0.49 to 1.53 ± 0.57 L (p = 0.023) and the % predicted FEV1 from 45.0 ± 12.8 to 46.8 ± 14.5% (p = 0.031). The % predicted DLCO increased significantly after tiotropium add-on (from 61.6 ± 16.7 to 64.3 ± 16.3%, p = 0.028). Among 56 patients with complete CAT scores, no significant change was present in total CAT scores. In all, 30 of the 72 patients (41.7%) evidenced FEV1 increases > 100 mL, and 20 of 56 patients (35.7%) had CAT score decreases of ≥ 2 points. When the FEV1 and CAT scores were combined, the overall response rate to tiotropium add-on was 56.2% (41/73). The response group evidenced a significantly greater FVC increase, and a significant decrease in the RV/TLC ratio compared to the no-response group.
Inhaled tiotropium add-on to combination budesonide/formoterol significantly improved lung function, but not respiratory symptoms, in patients with post-HSCT BOS.
Risk Factors for Bronchiolitis Obliterans Syndrome after Initial Detection of Pulmonary Impairment after Hematopoietic Cell Transplantation
2023, Transplantation and Cellular Therapy
Pulmonary chronic graft-versus-host-disease (cGVHD), or bronchiolitis obliterans syndrome (BOS), is a highly morbid complication of hematopoietic cell transplantation (HCT). The clinical significance of a single instance of pulmonary decline not meeting the criteria for BOS is unclear. We conducted a retrospective analysis in a cohort of patients who had an initial post-HCT decline in the absolute value of forced expiratory volume in 1 second (FEV₁) of ≥10% or mid-expiratory flow rate of ≥25% but not meeting the criteria for BOS (pre-BOS). We examined the impact of clinical variables in patients with pre-BOS on the risk for subsequent BOS. Pre-BOS developed in 1325 of 3170 patients (42%), of whom 72 (5%) later developed BOS. Eighty-four patients developed BOS without detection of pre-BOS by routine screening. Among patients with pre-BOS, after adjusting for other significant variables, airflow obstruction (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.1 to 3.7; P = .02), percent-predicted FEV₁ on decline (HR, .98; 95% CI, .97 to 1.0; P = .02), active cGVHD (HR, 7.7; 95% CI, 3.1 to 19.3; P < .001), peripheral blood stem cell source (HR, 3.8; 95% CI, 1.7 to 8.6; P = .001), and myeloablative conditioning (HR, 2.0; 95% CI, 1.1 to 3.5; P = .02) were associated with subsequent BOS. The absence of airflow obstruction and cGVHD had a negative predictive value of 100% at 6 months for subsequent BOS, but the positive predictive value of both factors was low (cGVHD, 3%; any obstruction, 4%; combined, 6%). Several clinical factors at the time of pre-BOS, particularly active cGVHD and airflow obstruction, increase the risk for subsequent BOS. These factors merit consideration to be included in screening practices to improve the detection of BOS, with the caveat that the predictive utility of these factors is limited by the overall low incidence of BOS among patients with pre-BOS.
Noninfectious Pulmonary Complications after Hematopoietic Stem Cell Transplantation
2023, Transplantation and Cellular Therapy
Citation Excerpt :
BOS usually develops after day +100 and typically within 2 years post-transplantation, at a median of 273 to 547 days [35,53]. Currently identified risk factors include cyclophosphamide dose, absence of ATG in conditioning, busulfan-based conditioning, presence of cGVHD, peripheral blood stem cell transplantation, female donor to male recipient transplantation, prior interstitial pneumonitis, prior viral and/or bacterial pneumonia, and lower pretransplantation forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio [54–57]. In particular, the use of myeloablative conditioning has been shown to increase the cumulative risk of BOS compared to RIC or nonmyeloablative conditioning [58,59].
Pulmonary complications after hematopoietic stem cell transplantation (HSCT) are important sources of morbidity and mortality. Improvements in infection-related complications have made noninfectious pulmonary complications an increasingly significant driver of transplantation-related mortality. Broadly, these complications can be characterized as either early or late complications, with idiopathic pneumonia syndrome and bronchiolitis obliterans syndrome the most prevalent early and late complications, respectively. Outcomes with historical treatment consisting mainly of corticosteroids are often poor, highlighting the need for a deeper understanding of these complications’ underlying disease biology to guide the adoption of novel therapies that are being increasingly used in the modern era.
Prospective Phase II Trial of Montelukast to Treat Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation and Investigation into Bronchiolitis Obliterans Syndrome Pathogenesis
2022, Transplantation and Cellular Therapy
Bronchiolitis obliterans syndrome (BOS) is a severe manifestation of chronic graft-versus-host disease (cGVHD) following hematopoietic cell transplantation (HCT). Montelukast interrupts cysteinyl leukotriene (CysLT) activity and may diminish the activation and homing of cells to bronchioles and subsequent fibrosis. We performed a prospective phase II trial to test whether montelukast altered lung decline for patients with BOS after HCT. In this single-arm, open-label, multi-institutional study, the primary endpoints were stability or improvement (<15% decline) in forced expiratory volume in 1 second (FEV1) and a <1-point decline in the slope of FEV1 after 6 months of treatment. Secondary endpoints included symptom and functional responses and immune correlates investigating the role of leukotrienes in BOS progression. The study enrolled 25 patients with moderate to severe lung disease after 3 months of stable cGVHD therapy. Montelukast was well tolerated, and no patient required escalation of BOS-directed therapy. At the primary endpoint, all 23 evaluable patients met the criteria for treatment success using FEV1% predicted, and all but 1 patient had stable or improved FEV1 slope. In those with a >5% improvement in FEV1, clinically meaningful improvements were seen in the Lee scores of breathing, energy, and mood. Improvements in the Human Activity Profile and 6-minute-walk test were observed in those with a <5% decline in FEV1. Overall survival was 87% at 2 years. Immune correlates showed elevated leukotriene receptor levels on blood eosinophils and monocytes versus healthy controls, elevated urine leukotrienes in 45% of the cohort, and CysLT receptors in bronchoalveolar lavage subsets and a predominance of Th2 cells, all pretreatment. These data suggest that montelukast may safely halt the progression of BOS after HCT, and that leukotrienes may play a role in the biology of BOS.
A case of imatinib-related obstructive bronchiolitis followed long term
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Obstructive bronchiolitis (OB) is an intractable disease causing stenosis in the surrounding bronchiolar region and bronchiolar lumen obstruction. Causes of OB are lung and hematopoietic stem-cell transplantation, collagen diseases, infections, and foods, but there are very few reports of drug-induced OB [1]. Imatinib is a drug used for the treatment of leukemia, gastrointestinal stromal tumors, etc. Although there are some reports of imatinib-induced lung injury as a complication (Ohnishi et al., 2006; Ma et al., 2003; Yamasawa et al., 2008; Koide et al., 2011) [[2], [3], [4], [5]], OB has not been reported. We have encountered a patient with OB related to imatinib administered for chronic myelogenous leukemia, who we have followed for 10 years. Drug-induced OB is very rare, but our case demonstrates the importance of considering the possibility of airway lesions by evaluating pulmonary function and expiratory computed tomography in patients with respiratory symptoms despite no shading on imaging.

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Chest

Clinical InvestigationsTransplantationRisk Factors for Bronchiolitis Obliterans in Allogeneic Hematopoietic Stem-Cell Transplantation for Leukemia

Study objectives

Methods

Results

Conclusion

Section snippets

IBMTR Database

Cohort Characteristics

Discussion

Chest

Mayo Clin Proc

Biol Blood Marrow Transplant

Clin Chest Med

Blood

Blood

Blood

Blood

Blood

Clin Chest Med

Blood

Blood

Blood

Blood

Chest

Clin Radiol

J Heart Lung Transplant

Mayo Clin Proc

J Heart Lung Transplant

Report from the International Bone Marrow Transplant Registry and Autologous Blood and Marrow Transplant Registry–North America

Clin Transplant

The lung as a critical organ in marrow transplantation

Bone Marrow Transplant

Pulmonary complications of bone marrow transplantation

Respir Med

Late pulmonary impairment following allogeneic bone marrow transplantation

Eur J Med Res

Long-term survival and late deaths after allogeneic bone marrow transplantation: Late Effects Working Committee of the International Bone Marrow Transplant Registry

N Engl J Med

Late-onset noninfectious pulmonary complications after allogeneic bone marrow transplantation

Br J Haematol

Fatal airway disease in an adult with chronic graft-versus-host disease

Thorax

Airflow obstruction after myeloablative allogeneic hematopoietic stem cell transplantation

Am J Respir Crit Care Med

Small-airways disease in recipients of allogeneic bone marrow transplants: an analysis of 11 cases and a review of the literature

Medicine

Idiopathic small airways pathology in patients with graft-versus-host disease following allogeneic bone marrow transplantation

Am J Surg Pathol

Obstructive lung disease after allogeneic marrow transplantation: clinical presentation and course

Ann Intern Med

Risk factors for airflow obstruction in recipients of bone marrow transplants

Ann Intern Med

Clinical Investigations
Transplantation
Risk Factors for Bronchiolitis Obliterans in Allogeneic Hematopoietic Stem-Cell Transplantation for Leukemia