Budesonide/Formoterol for Bronchiolitis Obliterans after Hematopoietic Stem Cell Transplantation

Bergeron, Anne; Chevret, Sylvie; Chagnon, Karine; Godet, C.; Bergot, Emmanuel; Latour, Régis Peffault de; Dominique, S.; Revel, Thierry de; Juvin, Karine; Maillard, Natacha; Reman, Oumédaly; Contentin, Nathalie; Robin, Marie; Buzyn, Agnès; Socié, Gérard; Tazi, Abdellatif

doi:10.1164/rccm.201410-1818oc

Cited by 102 publications

(66 citation statements)

References 25 publications

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“…The selection of three months for the primary endpoint and six months for study completion was based on data published with similar evaluation periods in lung dysfunction after HCT and preliminary data showing that this timeframe was predictive of changes for the subsequent 1.5 years. 22,23,38 If the 3-month PFT was missing, the 2 or 6-month PFT was used for endpoint assessment, with the worse test included in the analysis. If no 2 or 6-month test was available, the patient was considered a treatment failure in the primary analysis.…”

Section: Methodsmentioning

confidence: 99%

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Fluticasone, Azithromycin, and Montelukast Treatment for New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation

Williams

Cheng

Pusic

et al. 2016

Biology of Blood and Marrow Transplantation

173

123

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Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (HCT) is associated with high mortality. Purpose: We hypothesized that FAM (inhaled Fluticasone, Azithromycin, and Montelukast) with a brief steroid pulse could avert progression of new-onset BOS. Experimental design: We tested this in a phase II, single-arm, open label, multicenter study (NCT01307462). Results: Thirty-six patients were enrolled within 6 months of BOS diagnosis. The primary endpoint was treatment failure, defined as 10% or greater FEV1% decline at 3 months. At 3 months, 6% (2/36, 95% CI 1%–19%) had treatment failure (vs. 40% in historical controls, p<0.001). FAM was well tolerated. Steroid dose was reduced by 50% or more at 3 months in 48% of patients who could be evaluated (n=27). Patient-reported outcomes at 3 months were statistically significantly improved for SF-36 social functioning score and mental component score, FACT emotional well-being, and Lee symptom scores in lung, skin, mouth, and the overall summary score compared to enrollment (n=24). At 6 months, 36% had treatment failure (95% CI 21%–54%, n=13/36, with 6 documented failures, 7 missing pulmonary function tests). Overall survival was 97% (95% CI 84%–100%) at 6 months. These data suggest that FAM was well tolerated and that treatment with FAM and steroid pulse may halt pulmonary decline in new-onset BOS in the majority of patients and permit reductions in systemic steroid exposure, which collectively may improve quality of life. However, additional treatments are needed for progressive BOS despite FAM.

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Section: Methodsmentioning

confidence: 99%

“…However, only 56% completed the 6 month primary endpoint, and 37% required unblinding due to nonimprovement after 1 month of therapy. 22 …”

Section: Introductionmentioning

confidence: 99%

Fluticasone, Azithromycin, and Montelukast Treatment for New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation

Williams

Cheng

Pusic

et al. 2016

Biology of Blood and Marrow Transplantation

173

123

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“…[27][28][29] Treatment with budesonide/formoterol improved forced expiratory volume in 1 second compared with placebo in a small prospective study of patients with mild to severe BOS after HSCT. 30 Patients should receive antireflux measures and prophylactic therapy against Pneumocystis jiroveci, Fungi, and CMV. Lung transplant has been successful in selected patients.…”

Section: Bronchiolitis Obliterans Syndromementioning

confidence: 99%

“…Lung transplant has been successful in selected patients. 30 Other treatments for BOS have been reported in small series or are currently under investigation, including leukotriene receptor antagonists, extracorporeal photodynamic therapy, antitumor necrosis factor α monoclonal antibodies (such as infliximab), imatinib mesylate, alefacept, daclizumab, and rituximab. [31][32][33][34] In advanced cases, patients may benefit from supplemental oxygen therapy and pulmonary rehabilitation referral.…”

Section: Bronchiolitis Obliterans Syndromementioning

confidence: 99%

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Diab

ZazaDitYafawi

Soubani³

2016

Exp Clin Transplant

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Both autologous and allogeneic hematopoietic stem cell transplants are important therapeutic options for several benign and malignant disorders. Pulmonary complications, although they have become less frequent, remain a significant cause of morbidity and mortality after hematopoietic stem cell transplant. These complications range from bacterial, fungal, and viral pulmonary infections to noninfectious conditions such as diffuse alveolar hemorrhage and idiopathic pneumonia syndrome. Bronchiolitis obliterans syndrome is the primary chronic pulmonary complication, and treatment of this condition remains challenging. This report highlights the advances in the diagnosis and management of the major pulmonary complications after hematopoietic stem cell transplant. It also underscores the need for prospective and multicenter research to have a better understanding of the mechanisms behind these complications and to obtain more effective diagnostic tool and therapeutic options. Key words: Adverse effects, Lung diseases/etiology, Lung diseases/diagnosis, Respiratory tract infections/etiology, Graft versus host disease IntroductionHematopoietic stem cell transplant (HSCT) is increasingly being used for treatment of a wide range of benign and malignant diseases. About 50 000 to 60 000 HSCTs are done annually. 1 Hematopoietic stem cell transplant can be classified as autologous when the stem cells are harvested from the same patient and reinfused after high-dose chemotherapy, whereas, in allogeneic HSCT, the stem cells are donated by another person. Allogeneic HSCT can be related or unrelated and matched or mismatched. The hematopoietic stem cells might be derived from the bone marrow, umbilical cord, or peripheral blood.Hematopoietic stem cell transplant can be a lifesaving treatment of a wide range of neoplastic and nonneoplastic diseases; however, it is still limited by the development of serious complications. Advances in the preparative regimen using a nonmyeloablative preparative regimen, reduced-intensity conditioning transplants, and posttransplant supportive care have contributed to improved overall survival. Despite these advances, pulmonary complications still occur in about 37% of patient after HSCT 2 and are associated with significant morbidity and mortality. In 1 study, the hazard ratio for death due to pulmonary complications was 30. 1 However, there is evidence that the overall mortality and pulmonary complications after HSCT are improving. A recent review of allogeneic HSCT patients in a large transplant center from 1993 to 2007 showed that the risk of nonrelapse mortality decreased by 60% and overall mortality decreased by 41%. In addition, the risk of acute respiratory failure dropped by 36%, with risk of gram-negative bacterial and invasive mold infections decreasing by 39% and 51%. 3 In this study, we provide an update of the main pulmonary complications (both infectious and noninfectious) after HSCT, including an overview of the diagnostic approach and treatment of these complications. Noninfec...

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“…1 The pathogenesis is believed to be analogous with pulmonary graft-versus-host disease and is often treated with systemic corticosteroids despite the lack of evidence supporting their effectiveness. 2 Azithromycin has been shown to improve lung function after 3 months of therapy in BOS complicating lung transplantation; however, a similar effect on the forced expiratory volume in 1 second (FEV 1 ) is not observed in patients with BOS after HSCT. Despite this lack of efficacy, azithromycin is commonly used to treat this disorder.…”

mentioning

confidence: 99%

Budesonide/Formoterol Therapy Increases FEV1 in Stem Cell Transplant–associated Bronchiolitis Obliterans Syndrome

West¹,

Zappetti²

2015

Clinical Pulmonary Medicine

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to antibiotics in the treatment of community-acquired pneumonia did not show a benefit in clinically important outcomes such as all-cause mortality, in preventing ICU admission and hospital readmission, and in reducing recurrent pneumonia. Trials should evaluate these endpoints in the future. In addition, future trials should consider whether prednisone should be restricted to selected populations such as those with more severe illness and those with high levels of inflammation. REFERENCES1. Confalionieri M, Urbino R, Potena A, et al. Hydrocortisone infusion for severe community-acquired pneumonia: a preliminary randomized study. Am J Resp Crit Care Med. 2005;171:242-248. 2. Garcia-Viadal C, Calbo E, Pascual V, et al. Effects of systemic steroids in patient with severe community-acquired pneumonia. Eur Respir J. 2007;30:951-956. 3. Meijvis SC, Hardeman H, Remmelts HH, et al. Dexamethasone and length of hospital stay in patients with community-acquired pneumonia: randomized, double-blind, placebo-controlled trial. Lancet. 2011;377:2023-2030. 4. Snijders D, Daniels JM, De Graff SC, et al. Efficacy of corticosteroids in community-acquired pneumonia: a randomized, doubleblinded clinical trial. Am J Resp Crit Care Med. 2010;181: 975-982. 5. Torres A, Sibila O, Ferrer M, et al. Effect of corticosteroids on treatment failure among hospitalized patients with severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA. 2015;313:677-686. 6. Nie W, Zhang Y, Cheng J, et al. Corticosteroids in the treatment of community-acquired pneumonia in adults: a meta-analysis. PLoS One. 2010;7:e47926. 7. Lamontagne F, Briel M, Guyatt GH, et al. Corticosteroid therapyfor acute lung injury, acute respiratory distress syndrome, and severe pneumonia: a meta-analysis of randomized controlled trials. Synopsis:In patients with mild to severe bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation, the administration of inhaled budesonide\formoterol led to a significant improvement in FEV 1 .B ronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic stem cell transplantation (HSCT) is a clinical syndrome characterized by airflow obstruction, with a reported incidence as high as 30%. 1 The pathogenesis is believed to be analogous with pulmonary graft-versus-host disease and is often treated with systemic corticosteroids despite the lack of evidence supporting their effectiveness. 2 Azithromycin has been shown to improve lung function after 3 months of therapy in BOS complicating lung transplantation; however, a similar effect on the forced expiratory volume in 1 second (FEV 1 ) is not observed in patients with BOS after HSCT. Despite this lack of efficacy, azithromycin is commonly used to treat this disorder. 3,4 Motivated by the lack of effective therapeutic strategies, the aim of this study was to assess the effect of inhaled budesonide/formoterol on the pulmonary function test (PFT) results of patients with mild to severe BOS after allogeneic HSCT. This ...

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Budesonide/Formoterol for Bronchiolitis Obliterans after Hematopoietic Stem Cell Transplantation

Abstract: Budesonide/formoterol administration led to a significant improvement in the FEV1 in patients with mild/severe BOS after allogeneic HSCT. Clinical trial registered with www.clinicaltrials.gov (NCT00624754).

Cited by 102 publications

References 25 publications

Fluticasone, Azithromycin, and Montelukast Treatment for New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation

Fluticasone, Azithromycin, and Montelukast Treatment for New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation

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Budesonide/Formoterol Therapy Increases FEV1 in Stem Cell Transplant–associated Bronchiolitis Obliterans Syndrome

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