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S.J. Lee et al.
blood instead of bone marrow or cord blood, females donating to male patients, lack of in vivo or ex vivo T-cell depletion or post-transplant cyclosphosphamide, and HLA mismatching.2 Chronic GvHD may be mild, requiring only topical or local interventions or short-term systemic immunosuppression; it may also be moderate to severe and poorly controlled with available treatments, causing sub- stantial morbidity or even death.3 Overall, chronic GvHD has been associated with worse quality of life (QOL) and functional status, and a higher symptom burden.4 Interventions that prevent chronic GvHD have been associ- ated with a lower symptom burden and better functional status in randomized controlled trials.5,6 The impact of chronic GvHD on QOL as measured by the National Institutes of Health (NIH) Patient-Reported Outcomes Measurement Information System (PROMIS) instruments has not been reported7 and currently the PROMIS measures are not included in the list of recommended scales for chronic GvHD assessment in clinical trials.
Interest in preventing and treating chronic GvHD has increased in the last 5-10 years with a growing recognition of the impact that this complication has on the long-term health of survivors. There are better options to prevent6,8-12 and treat chronic GvHD,13,14 and an increasing number of reports about biomarkers and insights from animal and human studies on its pathophysiology.15-17 In August 2017, ibrutinib became the first drug approved by the Food and Drug Administration for the management of chronic GvHD that persists or progresses after treatment with steroids.18
The goal of this study was to describe the QOL scores and health status of patients with active chronic GvHD of differing severity compared to those with resolved chronic GvHD or those who had never had chronic GvHD. We also aimed to investigate the PROMIS measures in chronic GvHD relative to established measures of QOL in long- term HCT survivors.
Methods
Participants
Questionnaires are sent annually to transplant survivors as part of the Fred Hutchinson Cancer Research Center (FHCRC) long- term follow-up research program. Non-responders to the initial survey are sent a reminder letter 1 month later. All patients who underwent allogeneic transplantation from any graft source at FHCRC and who consented to allow their information to be used for research purposes were included. Patients were aged 18 or greater at the time of the survey. The analyzed data were from surveys administered by mail or online, according to the partici- pants’ choice, from July 1, 2015 to June 30, 2016. The dataset was sealed as of September 30, 2016. The Institutional Review Board of FHCRC approved the study, and all patients provided written informed consent at the time of their transplants.
Data collection instruments
The core survey includes questions about QOL, symptoms, medical complications, medications, work status and chronic GvHD. In the chronic GvHD section, patients report having never had chronic GvHD, having had chronic GvHD but it resolved, or having current mild, moderate or severe involvement. Definitions were not provided for these categories. Patients also report their work/school status, whether they have had certain medical com- plications, and whether they are taking medications for specified conditions. An abbreviated comorbidity score consists of self-
reported pulmonary disease, avascular necrosis, adrenal insuffi- ciency and diabetes since these co-morbid conditions were previ- ously associated with QOL.19 The core survey also includes the Medical Outcomes Study Short Form-36 (SF-36) health survey. The SF-36 is a 36-item multidimensional QOL instrument with population norms.20,21 Two summary scales, the physical compo- nent score (PCS) and mental component score (MCS), are normal- ized to a T score of 50 with a standard deviation of 10. Higher scores indicate better QOL. A clinically meaningful difference is 0.5 times the standard deviation, so scores <45 or >55 are consid- ered to have clinical significance. There are also eight subscales: physical functioning, role physical functioning, emotional func- tioning, role emotional functioning, fatigue, social functioning, pain and general health.
Each year, a different module is added to the long-term follow- up core survey and, for this analysis, included the PROMIS Global Health 10, PROMIS-29 v2.0, and the Lee chronic GvHD symptom scale (LSS). The PROMIS Global Health 10 measure comprises ten items with two summary scores for physical and mental function- ing. The PROMIS-29 contains 29 scored items and seven sub- scales: for the physical and social functioning scales, higher scores indicate better functioning; for fatigue, pain, anxiety, depression, and sleep scales, higher scores indicate a greater symptom burden.22 Similar to the SF-36, scores are normalized to 50 with a standard deviation of 10 with higher scores indicating better func- tioning, and scores greater than 0.5 times the standard deviation (i.e., <45 or >55, compared to the general population) are consid- ered clinically meaningful.
The LSS is a 30-item measure with one summary score and seven domains: skin, mouth, eye, lung, psycho-emotional, vitality and nutrition.23,24 Higher scores indicate greater symptom burden. Half of the cases received the LSS with a 1-month recall period and half received a 1-week version; results were combined for analysis because there was no statistical difference between the aggregate scores for the two versions (data not shown). Scores may be calcu- lated if more than half of the items in a subscale are answered. Scores range from 0-100 with higher scores indicating greater symptom burden. A difference of 6-7 points on the summary score is considered clinically meaningful but since this scale meas- ures chronic GvHD symptoms, general population norms are not available.
Clinical and transplant variables
Clinical information retrieved from the institutional database included patient’s age, sex, diagnosis, disease stage, conditioning regimen, donor type, graft source, GvHD prophylaxis, diagnosis of chronic GvHD, post-transplant relapse and vital status.
Statistical analysis
Patient, transplant and chronic GvHD characteristics and known characteristics of responders and non-responders were compared using chi-square or Fisher exact tests and t-tests for cat- egorical and continuous variables, respectively. Only patients who answered the chronic GvHD question on the survey were includ- ed in this analysis because this question was used to classify whether chronic GvHD was currently active and its severity. This information is not captured in the transplant database; only the onset date and maximum severity are routinely recorded.
Patient-reported surveys were scored according to the directions of the developers, including methods for handling missing data. Multivariate linear regression models were used to examine the associations between the SF-36, PROMIS and LSS scores and potential explanatory variables including those from the medical record: patient’s age and sex, conditioning intensity, donor type and graft source, diagnosis of chronic GvHD, post-transplant relapse,
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haematologica | 2018; 103(9)