Time to Explore Preventive and Novel Therapies for Bronchiolitis Obliterans Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation

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Summary Chronic graft-versus-host disease (GVHD) is the leading cause of late, non-relapse, mortality and disability in allogeneic hematopoietic cell transplantation (HCT) patients and a major obstacle to improving outcomes. Chronic GVHD biology remains enigmatic, but understanding the underpinnings of the immunologic mechanisms responsible for the initiation and progression of disease is fundamental to developing effective prevention and treatment strategies. The goals of this task force review are as follows: Summarize the current “state-of-the-science” regarding pathogenic mechanisms of chronic GVHD and critical knowledge gaps.Develop working hypotheses/overriding concepts for chronic GVHD development.Define the usefulness of current preclinical models to test working hypotheses and ultimately discover and develop new therapeutic strategies.Identify shortcomings of preclinical models, and define criteria for the creation of additional models to address these limitations. This document is intended as a review of our understanding of chronic GVHD biology and therapies resulting from preclinical studies, and as a platform for developing innovative clinical strategies to prevent and treat chronic GVHD.

Section: A Three Phase Model For Chronic Gvhd Biologymentioning

confidence: 99%

The Biology of Chronic Graft-versus-Host Disease: A Task Force Report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease

Cooke

Luznik

Sarantopoulos

et al. 2017

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“…1,2 While BOS is rare, affecting only 5–12% of HCT recipients, it is a significant problem after HCT because of the high attributed morbidity and mortality. 1,3–7 Patients with early BOS are often asymptomatic, with symptoms developing later in the course of the disease such as dyspnea on exertion or a chronic cough, followed by dyspnea at rest, and finally inability to accomplish activities of daily living due to progressive pulmonary compromise and attributed weakness. 4 Bronchiolitis obliterans is caused by an immune response to antigens expressed by bronchiolar epithelia, causing inflammation and epithelial disruption, followed by progressive intraluminal fibrosis of the small terminal airways.…”

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

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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.

“…Several potential therapies have been investigated including systemic steroids, inhaled steroids 14 , long-acting beta agonists (LABA) 14, 15 , leukotriene receptor antagonists (LTRA) 16,27 , extracorporeal photophoresis (ECP) 17, 18 and macrolides 27, 16, 19, 20 . Macrolides, and azithromycin in particular, have been studied for the treatment of OB in patients who have undergone HSCT and lung transplantation.…”

Section: Introductionmentioning

confidence: 99%

Azithromycin for the Treatment of Obliterative Bronchiolitis after Hematopoietic Stem Cell Transplantation: A Systematic Review and Meta-Analysis

Yadav

Peters

Keogh

et al. 2016

Obliterative bronchiolitis (OB) is a major cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). Our objective was to perform a systematic review and meta-analysis of the impact of azithromycin on change in forced expiratory volume in 1 second (FEV1). We searched MEDLINE, EMBASE, Web of Science, Cochrane CENTRAL and Scopus databases. We included studies that compared azithromycin to placebo or no intervention in the treatment of OB or BOS in patients who had undergone allogeneic HSCT. 91 unique publications were identified. 4 studies met inclusion criteria, with a total of 90 patients. Changes in FEV1 were measured between 12 weeks and 24 weeks after initiation of treatment. The meta-analysis demonstrated a mean increase in FEV1 of 30 ml (95% Confidence Interval: -260 to +330 ml, p = 0.82) following initiation of azithromycin. One patient death was reported, but not attributed to azithromycin therapy. In conclusion, current evidence can neither support nor refute the use of azithromycin in the treatment of patients who develop OB/BOS following HSCT. Further studies are needed to determine whether azithromycin is beneficial for the treatment of OB/BOS in this setting.