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Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic cell transplantation (HCT) is associated with high mortality. We hypothesized that inhaled fluticasone, azithromycin, and montelukast (FAM) with a brief steroid pulse could avert progression of new-onset BOS. We tested this in a phase II, single-arm, open-label, multicenter study (NCT01307462). Thirty-six patients were enrolled within 6 months of BOS diagnosis. The primary endpoint was treatment failure, defined as 10% or greater forced expiratory volume in 1 second decline at 3 months. At 3 months, 6% (2 of 36, 95% confidence interval, 1% to 19%) had treatment failure (versus 40% in historical controls, P < .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 Short-Form 36 social functioning score and mental component score, Functional Assessment of Cancer Therapies 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% confidence interval, 21% to 54%, n = 13 of 36, with 6 documented failures, 7 missing pulmonary function tests). Overall survival was 97% (95% confidence interval, 84% to 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., (Copyright © 2016 American Society for Blood and Marrow Transplantation. All rights reserved.)

Several distinct graft-versus-host disease (GVHD)-related syndromes have been defined by the National Institutes of Health Consensus Conference. We enrolled a prospective cohort of 911 hematopoietic cell transplantation (HCT) recipients at 13 centers between March 2011 and May 2014 to evaluate 4 GVHD syndromes: late acute GVHD (aGVHD), chronic GVHD (cGVHD), bronchiolitis obliterans syndrome, and cutaneous sclerosis. The median age at HCT was 53.7 years. The majority of patients received a peripheral blood stem cell transplant (81%) following nonmyeloablative or reduced-intensity conditioning (55%). Pediatric age group and use of bone marrow and umbilical cord blood grafts were underrepresented in our cohort (≤11%). The cumulative incidence of late aGVHD (late onset and recurrent) was 10% at a median of 5.5 months post-HCT, that of cGVHD was 47% at a median of 7.4 months, that of bronchiolitis obliterans was 3% at a median of 12.2 months, and that of cutaneous sclerosis was 8% at a median onset of 14.0 months. Late aGVHD and bronchiolitis obliterans had particularly high nonrelapse mortality of 23% and 32%, respectively, by 2 years after diagnosis. The probability of late aGVHD- and cGVHD-free, relapse-free survival was 38% at 1 year post-HCT and 26% at 2 years post-HCT. This multicenter prospective study confirms the high rate of late aGVHD and cGVHD syndromes and supports the need for continuous close monitoring and development of more effective GVHD treatment strategies to improve HCT success., (Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

To examine safety and efficacy of bandage soft contact lenses (BSCLs) for ocular chronic graft-versus host disease (GVHD), we conducted a phase II clinical trial. Extended-wear BSCLs were applied under daily topical antibiotic prophylaxis. Patients completed standardized symptom questionnaires at enrollment and at 2 weeks, 4 weeks, and 3 months afterward. Ophthalmologic assessment was performed at enrollment, at 2 weeks, and afterward as medically needed. Assessments at follow-up were compared with baseline by paired t-test. Nineteen patients with ocular GVHD who remained symptomatic despite conventional treatments were studied. The mean Lee eye subscale score was 75.4 at enrollment and improved significantly to 63.2 at 2 weeks (P = .01), to 61.8 at 4 weeks (P = .005), and to 56.3 at 3 months (P = .02). The ocular surface disease index score and 11-point eye symptom ratings also improved significantly. According to the Lee eye subscale, clinically meaningful improvement was observed in 9 patients (47%) at 2 weeks, in 11 patients (58%) at 4 weeks, and in 9 patients (47%) at 3 months. Visual acuity improved significantly at 2 weeks compared with enrollment values. Based on slit lamp exam at 2 weeks, punctate epithelial erosions improved in 58% of the patients, showed stability in 16%, and worsened in 5%. No corneal ulceration or ocular infection occurred. BSCLs are a widely available, safe, and effective treatment option that improves manifestations of ocular GVHD in approximately 50% of patients. This study was registered at www.clinicaltrials.gov as NCT01616056., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Ocular involvement can be quite symptomatic in patients with chronic graft-versus-host disease (GVHD). The prevalence of and risk factors for ocular GVHD and its impact on quality of life (QOL) in patients with chronic GVHD were studied in a prospective, multicenter, longitudinal, observational study. This study enrolled 342 patients with 1483 follow-up visits after allogeneic hematopoietic cell transplantation. All patients in this analysis were diagnosed with chronic GVHD requiring systemic treatment and enrolled within 3 months of chronic GVHD diagnosis. The symptom burden of ocular GVHD was based on the degree of dry eye symptoms, frequency of artificial tear usage, and impact on activities of daily living. Patients' QOL was measured by self-administered questionnaires. Variables associated with ocular GVHD at enrollment and subsequent new-onset ocular GVHD and the associations with QOL were studied. Of the 284 chronic GVHD patients, 116 (41%) had ocular GVHD within 3 months of chronic GVHD diagnosis ("early ocular GVHD"). Late ocular GVHD (new onset > 3 months after chronic GVHD diagnosis) occurred in 64 patients. Overall cumulative incidence at 2 years was 57%. Female gender (P = .005), higher acute GVHD grade (P = .04), and higher prednisone dose at study entry (P = .04) were associated with early ocular GVHD. For patients who did not have ocular GVHD within 3 months of chronic GVHD diagnosis, presence of prior grades I to IV acute GVHD (HR 1.78, P = .04) was associated with shorter time to late ocular GVHD, whereas female donor-male recipient (HR .53, P = .05) was associated with longer time to late ocular GVHD onset. Using all visit data, patients with ocular GVHD had worse QOL, as measured by Functional Assessment of Cancer Therapy Bone Marrow Transplantation (P = .002), and greater chronic GVHD symptom burden, as measured by the Lee symptom overall score excluding the eye component (P < .001), compared with patients without ocular GVHD. In conclusion, this large, multicenter, prospective study shows that ocular GVHD affects 57% of patients within 2 years of chronic GVHD diagnosis. Women, patients on higher doses of prednisone at study entry, and those with a history of acute GVHD were at higher risk for ocular GVHD. Strong evidence suggests that ocular GVHD is associated with worse overall health-related QOL., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Although older patients undergoing allogeneic hematopoietic stem cell transplantation (HCT) may experience higher morbidity, the impact of chronic graft-versus-host disease (GVHD) on quality of life (QOL) and survival outcomes for older compared with younger patients is currently unknown. We utilized data of patients with moderate or severe chronic GVHD (N = 522, 1661 follow-up visits, a total of 2183 visits) from the Chronic GVHD Consortium, a prospective observational multicenter cohort. We examined the relationship between age group (adolescent and young adult, "AYA," 18 to 40 years; "middle-aged," 41 to 59 years; and "older," ≥ 60 years) and QOL (Functional Assessment of Cancer Therapy-Bone Marrow Transplantation [FACT-BMT]), physical functioning (Human Activity Profile [HAP]), functional status (2-minute walk test [2MWT]), nonrelapse mortality, and overall survival. Because of multiple testing, P values < .01 were considered significant. This study included 115 (22%) AYA, 279 (53%) middle-aged, and 128 (25%) older patients with moderate (58%) or severe (42%) chronic GVHD. Despite more physical limitations in older patients as measured by worse functional status (shorter 2MWT [P < .001] and lower HAP scores [P < .001]) relative to AYA and middle-aged patients, older patients reported better QOL (FACT-BMT, P = .004) compared with middle-aged patients and similar to AYA patients (P = .99). Nonrelapse mortality and overall survival were similar between the age groups. Therefore, despite higher physical and functional limitations, older patients who are selected to undergo HSCT and survive long enough to develop moderate or severe chronic GVHD have preserved QOL and similar overall survival and nonrelapse mortality when compared with younger patients. Therefore, we did not find evidence that older age is associated with worse outcomes in patients with moderate or severe chronic GVHD., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The 2005 National Institutes of Health (NIH) Consensus Conference recommended assessment of lung function in patients with chronic graft-versus-host disease (GVHD) by both pulmonary function tests (PFTs) and assessment of pulmonary symptoms. We tested whether pulmonary measures were associated with nonrelapse mortality (NRM), overall survival (OS), and patient-reported outcomes (PRO). Clinician and patient-reported data were collected serially in a prospective, multicenter, observational study. Available PFT data were abstracted. Cox regression models were fit for outcomes using a time-varying covariate model for lung function measures and adjusting for patient and transplantation characteristics and nonlung chronic GVHD severity. A total of 1591 visits (496 patients) were used in this analysis. The NIH symptom-based lung score was associated with NRM (P = .02), OS (P = .02), patient-reported symptoms (P < .001) and functional status (P < .001). Worsening of NIH symptom-based lung score over time was associated with higher NRM and lower survival. All other measures were not associated with OS or NRM; although, some were associated with patient-reported lung symptoms. In conclusion, the NIH symptom-based lung symptom score of 0 to 3 is associated with NRM, OS, and PRO measures in patients with chronic GVHD. Worsening of the NIH symptom-based lung score was associated with increased mortality., (Copyright © 2014 American Society for Blood and Marrow Transplantation. All rights reserved.)

Hand grip strength (HGS) and the 2-minute walk test (2MWT) have been proposed as elements of chronic graft-versus-host disease (GVHD) assessment in clinical trials. Using all available data (n = 584 enrollment visits, 1689 follow-up visits, total of 2273 visits) from a prospective observational cohort study, we explored the relationship between HGS and 2MWT and patient-reported measures (Lee symptom scale, MOS 36-Item Short-Form Health Survey [SF-36], and Functional Assessment of Cancer Therapy [FACT]-Bone Marrow Transplantation quality of life instruments and Human Activity Profile [HAP]), chronic GVHD global severity (National Institutes of Health global score, clinician global score, and patient-reported global score), calculated and clinician-reported chronic GVHD response, and mortality (overall survival, nonrelapse mortality, and failure-free survival) in multivariable analyses adjusted for significant covariates. 2MWT was significantly associated with intuitive domains of the Lee Symptom Scale (overall, skin, lung, energy), SF-36 domain and summary scores, FACT summary and domain scores, and HAP scores (all P < .001). Fewer associations were detected with the HGS. The 2MWT and HGS both had significant association with global chronic GVHD severity. In multivariable analysis, 2MWT was significantly associated with overall survival, nonrelapse mortality, and failure-free survival, whereas no association was found for HGS. 2MWT and HGS were not sensitive to National Institutes of Health or clinician-reported response. Based on independent association with mortality, these data support the importance of the 2MWT for identification of high-risk chronic GVHD patients. However, change in 2MWT is not sensitive to chronic GVHD response, limiting its usefulness in clinical trials., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Although data support adverse prognosis of overlap subtype of chronic grant-versus-host disease (GVHD), the importance of site of gastrointestinal (GI) and type of hepatic involvement is not known. Using data from the Chronic GVHD Consortium observational cohort study (N = 567, total of 2115 visits), we examined whether the site of GI (esophageal, upper GI, or lower GI) and type of hepatic (bilirubin, alkaline phosphatase, alanine aminotransferase) involvement are associated with overall survival (OS) and nonrelapse mortality (NRM), symptoms, quality of life (QOL) and functional status measures. In multivariate analysis utilizing data from enrollment visits only, lower GI involvement (HR, 1.67; P = .05) and elevated bilirubin (HR, 2.46; P = .001) were associated with OS; both were also associated with NRM. In multivariable analysis using all visits (time-dependent covariates), GI score greater than zero (HR, 1.69; P = .02) and elevated bilirubin (HR, 3.73; P < .001) were associated with OS; results were similar for NRM. Any esophageal involvement and GI score greater than zero were associated with both symptoms and QOL, whereas elevated bilirubin was associated with QOL. We found no consistent evidence that upper GI involvement, alkaline phosphatase, alanine aminotransferase, or NIH liver score add prognostic value for survival, overall symptom burden, or QOL. These data support important differences in patient-reported outcomes according to GI and hepatic involvement among chronic GVHD-affected patients and identify those with elevated bilirubin or higher GI score at any time, or lower GI involvement at cohort enrollment, as patients at greater risk for mortality under current treatment approaches., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

In 2005, a National Institutes of Health consensus conference was held to refine methods for research in patients with chronic graft-versus-host disease, including proposed objective response measures and a provisional algorithm for calculating organ-specific and overall response. In this study, we used weighted kappa statistics to evaluate the level of agreement between clinician response ratings and calculated response categories in patients with chronic graft-versus-host disease. The study included 290 patients who had paired enrollment and follow-up visits. Based on a set of objective measures, 37% of the patients had an overall complete or partial response, whereas clinicians reported an overall complete or partial response rate of 71% (slight to fair agreement, weighted kappa 0.20). Agreement rates between calculated organ-specific responses and clinician-reported changes in skin, mouth, and eyes were fair to moderate (weighted kappa, 0.28-0.54). We conclude that for both overall and organ-specific comparisons, clinician response ratings did not agree well with calculated response categories. Possible reasons for this discrepancy include a high clinical sensitivity for detecting response, a clinical predisposition to recognize selective improvements as overall response, the large change in objective measures proposed to define response, and the high incidence of progressive disease based on new manifestations. Conclusions from prior literature reporting high overall response rates based on clinician judgment would not be supported if the provisional algorithm had been applied to calculate response. Our analysis also highlights the need to define an overall response measure that incorporates both patient-reported and objective measures and accurately reflects the outcome in patients with a mixed response in which one organ or site improves, whereas another shows new involvement., (Copyright © 2012 American Society for Blood and Marrow Transplantation. All rights reserved.)

To determine whether changes in objective response measures proposed by the National Institutes of Health correlate with clinical benefit, such as symptom burden, quality of life, and survival outcomes, we analyzed data from a multicenter prospective cohort of 283 patients with chronic graft-versus-host disease requiring systemic treatment. The median follow-up time of survivors was 25.1 months (range, 5.4-47.7 months) after enrollment. Symptom measures included the Lee symptom scale and 10-point patient-reported symptoms. Quality-of-life measures included the Short Form-36, Functional Assessment of Cancer Therapy-Bone Marrow Transplantation, and Human Activities Profile. Overall and organ-specific responses were calculated by comparing manifestations at the 6-month visit and those at the enrollment visit using a provisional algorithm. Complete or partial responses were considered "response," and stable or progressive disease was considered "no response." Overall response rate at 6 months was 32%. Organ-specific response rates were 45% for skin, 23% for eyes, 32% for mouth, and 51% for gastrointestinal tract. Response at 6 months, as calculated according to the provisional response algorithm, was correlated with changes in symptom burden in patients with newly diagnosed chronic graft-versus-host disease, but not with changes in quality of life or survival outcomes. Modification of the algorithm or validation of other more meaningful clinical endpoints is warranted for future clinical trials of treatment for chronic graft-versus-host disease., (Copyright © 2012 American Society for Blood and Marrow Transplantation. All rights reserved.)