Abstract
Chronic GVHD is a heterogenous syndrome whose symptoms and treatment are often associated with decrease in functional status and quality of life among survivors of transplantation. We explored definitions of chronic GVHD-related disability and factors associated with disability in chronic GVHD. We analyzed 371 patients with chronic GVHD requiring a new systemic therapy with enrollment and 18 month assessments through the Chronic GVHD Consortium, evaluating disability as a composite endpoint including any one of five impairments previously defined by Flowers et al1 (score 2 or 3 keratoconjunctivitis sicca, score 2 or 3 scleroderma, any diagnosis of bronchiolitis obliterans, score 2 or 3 joint/fasciae involvement, or score 3 esophageal stricture requiring dilation). We also evaluated disability defined as decline in a human activity profile (HAP) score ≥8 or Karnofsky Performance Status (KPS) decline ≥ 20 from enrollment to 18 months. At enrollment, 47% of patients had at least one of the 5 Flowers disability features, with 50% of this group acquiring additional impairments at 18 months. Of the 197 (53%) patients with no Flowers disability at enrollment, 50% of this group progressed with disability features at 18 months. We found that any progressive Flowers impairment was associated with decline in HAP/KPS as well as increased NIH severity scores at 18 months. Enrollment mouth scores, and patient reported eye and skin scores were significantly associated with progressive impairment at 18 months. Progressive disability at 18 months did not predict subsequent non-relapse mortality. Additional studies to define chronic GVHD related-disability and risk factors are needed to develop this important patient-centered outcome.
Introduction
Chronic graft-versus-host disease (GVHD) remains a major cause of long-term morbidity and late mortality in allogeneic hematopoietic cell transplant (HCT) survivors2, 3. Chronic GVHD is a heterogenous syndrome in which most patients have at least three involved organs (most commonly skin, mouth, liver or eyes, but also gastrointestinal tract, lung, joints, and genital tract), and treatment typically requires prolonged (median 5 years) use of immunosuppressive agents4. Chronic GVHD and its treatment are thus often associated with several adverse effects on long-term quality of life and functional abilities among HCT survivors5–7.
Several different endpoints have been evaluated in chronic GVHD trials, including organ response measures (complete response, partial response, stable disease, progression)8, and composite measures such as failure-free survival (absence of systemic treatment change, non-relapse mortality and recurrent malignancy)9–11, however, the impact of chronic GVHD on patient activity and functionality/disability has not been included in clinical trials, perhaps because little attention has been devoted to measuring disability. For clinical trials and drug approval, the Food and Drug Administration (FDA) has required clearly documented evidence of clinical benefit, defined as “living longer or living better,” not only in regards to improved overall survival, but also with fewer or less severe symptoms, or less disability.
Disability is any physical or mental impairment that limits a person to do certain activities and interact with the world around them. According to the World Health Organization, disability encompasses three dimensions: 1) impairment in a person’s body structure or function, or mental functioning; 2) activity limitation, such as difficulty seeing, hearing, walking or problem solving; and 3) participation restrictions in normal daily activities, such as working, engaging in social activities, and obtaining health care services12. Although disability is often associated with chronic medical conditions which can result in physical/mental impairments, there are limited data on disability in chronic GVHD. Fatobene and Flowers et al. evaluated chronic GVHD manifestations most likely to be associated with disability in 396 patients receiving an alternative donor (cord blood, haploidentical and mismatched unrelated donor) transplant1. In this context, disability related to chronic GVHD was defined as 2014 National Institutes of Health Consensus score 2 or 3 keratoconjunctivitis sicca, score 2 or3 scleroderma, any diagnosis of bronchiolitis obliterans, score 2 or 3 joint/fasciae involvement, or score 3 esophageal stricture requiring dilation. These criteria were chosen given their association with fibrosis and frequent irreversible damage and subsequent disability or impairment13. Cord blood and haploidentical donor transplants were associated with significantly lower chronic GVHD-related disability rates, and recipients were more likely to discontinue immunosuppression and return to work/school within 3 years of onset of chronic GVHD1. The concept of chronic GVHD disability may thus serve as part of an important response measurement in chronic GVHD clinical trials.
Using data from two prospective, multi-center observational studies from the Chronic GVHD Consortium, the aim of this current study was to analyze disability, and to identify factors associated with disability in chronic GVHD.
Materials and Methods
Cohort
Data from 371 patients were derived from two prospective, longitudinal, observation cohorts ( NCT00637689 and NCT01902576). Both studies included patients with prior allogeneic stem cell transplant from any graft source, donor type, and GVHD prophylaxis. Patients were enrolled from 13 institutions in the United States. Patients had to meet diagnostic definitions according to NIH consensus criteria13, 14 and either have started or plan to start a new systemic immunosuppressive agent, called the “index treatment,” within 4 weeks (required for enrollment on one study; a subset selected in the other study). Systemic treatment was defined as any medication or intervention with intended systemic effects, including extracorporeal photopheresis. The study was approved by the Institutional Review Boards of all participating centers, and all participants provided signed informed consent.
Data collection
Data used in this analysis were collected from laboratory testing, clinicians, and patients at enrollment and 18 months later. Charts were reviewed annually for relapse, death, addition of a new immunosuppressive treatment or discontinuation of immunosuppression after a patient completed the primary study.
Clinician assessments
Data collected in these cohorts include provider, patient and laboratory measures recommended for collection by the NIH Chronic GVHD Consensus conferences.13–16 These included the eight provider-reported NIH organ severity scores (skin, eye, mouth, vulvo-vaginal, gastrointestinal, lung, and joint). Lung scores are based on provider assessed clinical scoring of NIH organ severity. Available parameters for pulmonary function testing were considered separately. Vulvo-vaginal scoring was also clinically assessed and provider-reported, and gynecologic exams were not mandated within the observational trials. The NIH response measures variables that differ from the scoring variables (mouth, esophagus, upper and lower GI, joint) were also included as potential explanatory variables.
Patient assessments
Patients reported their chronic GVHD symptoms using the Lee symptom scale (30 items, captured as a five-point Likert scale from “no symptoms” to “extremely bothered”). The summary score was calculated according to the recommendations of the developer.17, 18 The Human Activity Profile is a patient-reported measure of physical activity in adults19. The 94 questions are presented in ascending order according to the metabolic equivalents of oxygen consumption required to perform each activity. The HAP therefore provides a survey of activities that the patient performs independently across a wide range of metabolic demand, beginning with getting out of bed, bathing, dressing, performing a series of progressively more physically demanding household chores, and ending with running or jogging 3 miles in 30 minutes or less. Respondents indicate whether they are “still doing this activity,” have “stopped doing this activity,” or “never did this activity.” Two scores are calculated from the HAP: the maximum activity score, which is the number of the most difficult tasks the patient is “still doing,” and the adjusted activity score calculated by counting how many activities with lower values than the maximum activity score the patient has “stopped doing”, subtracted from the maximum activity score. Higher scores represent higher levels of activity. The HAP has been shown to have strong correlations with physical functioning and disability.20–23 A hematopoietic cell transplant adjusted activity score further accounts for activities typically prohibited in patients receiving immunosuppression. The HAP has been validated in patients after allogeneic HCT and shown to correlate with chronic GVHD severity24.
Biostatistical analysis
The analysis was limited to patients who had both enrollment and 18-month assessments without relapse. Two definitions of disability were explored: disability as a composite endpoint including presence of any one of the 5 progressive/additional impairments defined by Flowers criteria1 (grade 2 or 3 keratoconjunctivitis sicca, grade 2 or 3 scleroderma, any grade of bronchiolitis obliterans, grade 2 or 3 joint/fasciae involvement, or grade 3 esophageal stricture requiring dilation) or by decline In HAP score ≥8 or KPS decline ≥20 compared to enrollment. The endpoint of disability using the Flowers criteria was defined by additional features not present at enrollment. Several enrollment patient and transplant-related factors including prior acute GVHD, NIH severity scores, Lee symptom scores, and socio-demographic variables were evaluated. Logistic regression analysis of disability was used to identify enrollment variables associated with additional disability features in patients who had an 18 month visit. Stepwise regression was used to identify the variables most associated with disability.
Using a subset of patients with available data at 6 months, we furthermore tested whether two indices, developed by the Chronic GVHD Consortium to predict treatment response per the NIH Consensus Criteria and failure-free survival (FFS)25, 26, also predicted disability at 18 months.
Results
Cohort characteristics
Characteristics of the 371 patients evaluated in this cohort are shown in Table 1. Patients with available HAP and KPS at enrollment and 18 months (N = 261) are also detailed (Table 1), demonstrating similar characteristics between the two groups. Table 2 shows chronic GVHD characteristics. Over 60% of patients were enrolled within 3 months of diagnosis (61% entire cohort and 63% with HAP/KPS) representing incident cases, and most presented with moderate (48% and 50% respectively) or severe disease (42% and 39% respectively). Skin, mouth, and eye involvement were the most frequently involved organs, seen in more than half of patients.
Table 1.
Demographic characteristics of patients
| Characteristic | n (%) or median (range) | |
|---|---|---|
| All patients (n=371) | With HAP/KPS (n=261) | |
| Age at initial treatment, years, median (range) | 54 (2 – 78) | 55 (12 – 78) |
| Patient gender, n (%) | ||
| Male | 227 (61) | 159 (61) |
| Female | 144 (39) | 102 (39) |
| Donor-patient gender combination, n (%)* | ||
| Female to male | 94 (25) | 63 (24) |
| Other | 275 (75) | 196 (76) |
| White, n (%) | 331 (89) | 238 (91) |
| Hispanic, n (%) | 18 (5) | 7 (3) |
| Diagnosis, n (%)** | ||
| Myeloid malignancy | 202 (54) | 141 (54) |
| Lymphoid malignancy | 130 (35) | 94 (36) |
| Other/non-malignant | 38 (11) | 26 (10) |
| Conditioning regimen, n (%) | ||
| High dose with or without TBI | 178 (48) | 131 (50) |
| Reduced intensity or nonmyeloablative | 193 (52) | 130 (50) |
| Graft source, n (%) | ||
| Bone marrow | 19 (5) | 13 (5) |
| Mobilized blood cells | 343 (92) | 241 (92) |
| Cord blood | 9 (2) | 7 (3) |
| Donor and HLA type, n (%) | ||
| HLA-matched related | 135 (36) | 99 (38) |
| HLA-matched unrelated | 190 (51) | 130 (50) |
| HLA antigen or allele-mismatched related | 5 (1) | 4 (2) |
| HLA antigen or allele-mismatched unrelated | 41 (11) | 28 (11) |
| Transplant center, n (%) | ||
| Fred Hutchinson | 186 (50) | 117 (45) |
| Vanderbilt | 35 (9) | 30 (11) |
| University of Minnesota | 29 (8) | 20 (8) |
| Dana-Farber | 23 (6) | 12 (5) |
| Stanford | 17 (5) | 16 (6) |
| Cleveland Clinic | 13 (4) | 11 (4) |
| University of British Columbia | 21 (6) | 21 (8) |
| Moffitt Cancer Center | 9 (2) | 3 (1) |
| Roswell Park | 17 (5) | 13 (5) |
| MD Anderson | 8 (2) | 7 (3) |
| Medical College of Wisconsin | 8 (2) | 7 (3) |
| Other*** | 5 (1) | 4 (2) |
Missing data on 2 patients
Missing data on 1 patient
Duke, 4; Northwestern Children’s Hospital, 1
Table 2.
Chronic GVHD characteristics of patients
| Characteristic | n (%) or median (range) | |
|---|---|---|
| All Patients (n=371) | With HAP/KPS (n=261) | |
| Type of case, n (%) | ||
| Incident (enrolled within 3 months of diagnosis) | 227 (61) | 165 (63) |
| Prevalent (enrolled more than 3 months after | 144 (39) | 96 (37) |
| diagnosis) | ||
| Prior grade II-IV acute GVHD, n (%) | 175 (48) | 116 (45) |
| NIH global severity, n (%) | ||
| Mild or less than mild | 38 (10) | 28 (11) |
| Moderate | 178 (48) | 130 (50) |
| Severe | 155 (42) | 103 (39) |
| Organs involved, n (%) | ||
| Skin | 267 (72) | 189 (72) |
| Fascia/Joints | 162 (44) | 108 (41) |
| Mouth | 227 (61) | 157 (60) |
| Eye | 205 (55) | 142 (55) |
| Lung | 91 (25) | 63 (24) |
| Gastrointestinal tract | 133 (36) | 92 (35) |
| Liver | 71 (20) | 48 (19) |
| Genital | 36 (14) | 24 (13) |
| HAP score at enrollment, median (IQR) | 68 (25 – 94) | 68 (25 – 94) |
| HAP score at enrollment, mean (STD) | 65.7 (14.0) | 65.9 (13.8) |
| Self-assessed Karnofsky performance status | ||
| 90 – 100 | 135 (43) | 113 (44) |
| 70 – 80 | 130 (41) | 102 (39) |
| 50 – 60 | 52 (16) | 44 (17) |
174 patients (47%) had at least 1 feature defined by Flowers criteria at enrollment, with 87 patients subsequently progressing by having at least one new feature by 18 months, 45 patients with stable disease, and 42 patients had resolution of Flowers features (Figure 1). Of 197 patients who did not have any features defined by Flowers criteria at enrollment, 98 progressed to one of these chronic GVHD symptoms (Figure 1). The presence of any progressive impairment at 18 months as defined by Flowers criteria was correlated with decreasing HAP or Karnofsky scores (p=0.004), and progression to overall severe cGVHD according to NIH criteria (p<0.0001), the latter as expected given that severe cGVHD is defined by any score 3 organ involvement or score 2–3 lung involvement. Accordingly, progressive disability was also significantly associated with low response rates (28% achieving CR/PR, P<0.0001) and need for additional systemic therapy (66%, P<0.0001).
Figure 1: Disability in Chronic GVHD at Enrollment and 18 months:
schematic of patients enrolled through the Chronic GVHD Consortium with or without disability defined by Flowers criteria at enrollment (inner circle, light gray) and 18 months (outer circle, dark gray).
Association of enrollment factors with disability
Table 3 details enrollment factors associated with being classified as disabled (new or additional progression) at 18 months in univariable analysis. Higher esophagus, oral erythema, eye, mouth and skin scores were associated with Flowers-defined criteria for disability, but not necessarily with decline in HAP/KPS scores. Interestingly, bilirubin elevation was associated with less frequent progression to disability by both Flowers criteria and HAP/KPS decline. Several patient-reported outcomes measured by the Lee symptom scales demonstrated association with progression by Flowers criteria, including the summary symptom score, energy, eye, mouth, and skin subscales (P≤0.002 for all).
Table 3.
Univariate association of baseline factors with disability at 18 months
| Measure (scale range*) | Flowers | HAP/KPS | ||||
|---|---|---|---|---|---|---|
| Number Evaluated | OR (95% CI) | P | Number Evaluated | OR (95% CI) | P | |
| Alkaline phosphatase, U/dL | 356 | 1.00 (0.99–1.02) | 0.55 | 251 | 0.99 (0.97–1.01) | 0.38 |
| Alkaline phosphatase/upper limit of normal ratio | 356 | 0.98 (0.89–1.07) | 0.61 | 251 | 0.83 (0.65–1.06) | 0.05 |
| Alanine aminotransferase, U/dL | 359 | 0.99 (0.98–1.01) | 0.36 | 254 | 0.98 (0.95–1.01) | 0.07 |
| Alanine aminotransferase/ULN ratio | 359 | 0.97 (0.91–1.04) | 0.41 | 254 | 0.89 (0.77–1.03) | 0.06 |
| Total serum bilirubin, mg/dL | 360 | 0.75 (0.56–1.00) | 0.009 | 255 | 0.41 (0.16–1.07) | 0.007 |
| Total serum bilirubin/ULN ratio | 360 | 0.67 (0.46–0.98) | 0.007 | 255 | 0.35 (0.11–1.14) | 0.01 |
| Esophagus score (0–3) | 371 | 1.66 (1.15–1.91) | 0.004 | 261 | 1.19 (0.78–1.80) | 0.43 |
| Upper gastrointestinal score (0–3) | 371 | 1.23 (0.90–1.67) | 0.18 | 261 | 0.76 (0.45–1.28) | 0.28 |
| Lower gastrointestinal score (0–3) | 369 | 0.89 (0.61–1.30) | 0.55 | 259 | 0.79 (0.45–1.38) | 0.38 |
| Oral erythema score (0–3) | 370 | 1.48 (1.15–1.91) | 0.002 | 260 | 0.86 (0.60–1.23) | 0.41 |
| Oral lichenoid score (0–3) | 370 | 1.28 (1.04–1.56) | 0.02 | 260 | 0.86 (0.66–1.14) | 0.29 |
| Oral ulcer score (0–6) | 369 | 1.02 (0.87–1.19) | 0.79 | 259 | 1.00 (0.80–1.25) | 0.97 |
| Oral sum score (0–12) | 371 | 1.08 (1.00–1.17) | 0.04 | 261 | 0.95 (0.85–1.07) | 0.42 |
| Ankle range of motion score (1–4) | 330 | 0.96 (0.65–1.42) | 0.83 | 229 | 0.95 (0.54–1.64) | 0.84 |
| Elbow range of motion score (1–7) | 331 | 0.80 (0.58–1.11) | 0.17 | 228 | 0.71 (0.48–1.04) | 0.08 |
| Shoulder range of motion score (1–7) | 333 | 0.76 (0.56–1.03) | 0.07 | 230 | 0.68 (0.47–0.98) | 0.04 |
| Wrist and finger range of motion score (1–7) | 332 | 0.85 (0.69–1.04) | 0.10 | 230 | 0.97 (0.74–1.29) | 0.85 |
| Joint range of motion sum score (4–25) | 328 | 0.92 (0.83–1.01) | 0.06 | 228 | 0.93 (0.83–1.05) | 0.27 |
| Eye score (0–3) | 370 | 2.87 (1.87–4.38) | <.0001 | 260 | 1.83 (1.02–3.30) | 0.04 |
| Genital score (0–3) | 253 | 3.03 (1.42–6.47) | 0.003 | 178 | 2.29 (0.92–5.70) | 0.08 |
| Gastrointestinal tract score (0–3) | 371 | 1.13 (0.74–1.73) | 0.56 | 261 | 1.04 (0.58–1.88) | 0.89 |
| Joints/fascia score (0–3) | 371 | 1.64 (1.08–2.48) | 0.02 | 261 | 1.24 (0.70–2.19) | 0.46 |
| Lung score (0–3) | 371 | 1.39 (0.86–2.24) | 0.17 | 261 | 1.19 (0.62–2.26) | 0.60 |
| Mouth score (0–3) | 371 | 1.88 (1.23–2.88) | 0.003 | 261 | 1.25 (0.69–2.23) | 0.46 |
| Skin score (0–3) | 371 | 1.90 (1.20–3.02) | 0.006 | 261 | 1.19 (0.63–2.27) | 0.59 |
| Forced expiratory volume in first second, percent of predicted | 187 | 0.80 (0.67–0.95) | 0.01 | 125 | 0.89 (0.70–1.14) | 0.36 |
| LSS Summary symptom score (0–100) | 322 | 1.68 (1.38–2.03) | <.0001 | 261 | 1.33 (1.08–1.63) | 0.007 |
| LSS Energy subscale (0–100) | 322 | 1.18 (1.06–1.31) | 0.002 | 261 | 1.13 (0.99–1.29) | 0.07 |
| LSS Eye subscale (0–100) | 321 | 1.20 (1.11–1.29) | <0.0001 | 260 | 1.10 (1.01–1.20) | 0.04 |
| LSS Lung subscale (0–100) | 322 | 1.24 (0.98–1.56) | 0.07 | 261 | 1.10 (0.84–1.44) | 0.50 |
| LSS Mouth subscale (0–100) | 322 | 1.16 (1.07–1.25) | <0.0001 | 261 | 1.10 (1.01–1.20) | 0.03 |
| LSS Nutrition subscale (0–100) | 322 | 1.18 (0.99–1.39) | 0.05 | 261 | 1.10 (0.89–1.34) | 0.39 |
| LSS Psych subscale (0–100) | 321 | 1.14 (1.02–1.26) | 0.02 | 261 | 1.11 (0.98–1.27) | 0.11 |
| LSS Skin subscale (0–100) | 322 | 1.22 (1.10–1.36) | 0.0001 | 261 | 1.11 (0.98–1.27) | 0.11 |
| Number of Flowers features (0–2) | 371 | 0.97 (0.67–1.41) | 0.89 | 261 | 1.26 (0.76–2.09) | 0.38 |
| HAP score (25–94) | 320 | 0.88 (0.75–1.03) | 0.12 | 261 | 1.49 (1.18–1.88) | 0.0005 |
| Karnofsky performance status (0–100) | 317 | 0.90 (0.76–1.07) | 0.23 | 259 | 1.43 (1.13–1.80) | 0.002 |
ULN = upper limit of normal
LSS – Lee Symptom Scale
Variables with p<0.05 are indicated in bold
In multivariable analysis including the individual subscales (Table 4), higher mouth scores by NIH grading (OR 2.36, 95% CI 1.42–3.93, and higher patient reported Lee symptoms scores for the eye (OR 1.15, 95% CI 1.06–1.24) and skin (OR 1.23, 95% CI 1.09–1.40), (P=0.0009 for all) were associated with progression of additional Flowers disability criteria by 18 months. Elevated bilirubin remained inversely related to progression (OR 0.59, 95% CI 0.40–0.89, P=0.01).
Table 4.
Multivariate model for Progressive Disability by Flowers criteria (n=308)
| Measure | Number Evaluated | OR (95% CI) | P |
|---|---|---|---|
| LSS Eye subscale (0–100) | 308 | 1.15 (1.06–1.24) | 0.0009 |
| Mouth score (0–3) | 2.36 (1.42–3.93) | 0.0009 | |
| LSS Skin subscale (0–100) | 1.23 (1.09–1.40) | 0.0009 | |
| Total serum bilirubin/ULN ratio | 0.59 (0.40–0.89) | 0.01 |
LSS = Lee Symptom Scale
OR for LSS eye and skin: per 10 units
Association of 6-month factors with disability
Using the subset of patients with available data at 6 months (N=351), we analyzed whether intermediate indices, the cGVHD-FFS index26 and cGVHD CR/PR index19, were also correlated with disability at 18 months. In this cohort, 152 patients had developed a new GVHD disability at 6 months compared to enrollment. Among 199 patients who did not develop any new disability by Flowers criteria at 6 months, the cGVHD-FFS index (AUC 0.54, P=0.28) and cGVHD-CR/PR index (AUC 0.54, P=0.18) at 6 months were not associated with new disability at 18 months. Of note, of the 177 patients within this subset identified as having developed disability by 18 months, the majority (N=124, 70%) had already developed progressive impairment by 6 months.
Association of disability with non-relapse mortality
Within our cohort, 317 patients had survival data beyond 18 months, with a median follow up of 23.5 months (range 0.1–103). There were 47 deaths, the majority of which (N=42) were related to non-relapse mortality. There were no statistically significant association of progressive (HR 1.67, 95% CI 0.9–3.1, P=0.10) or any current (HR 1.58, 95% CI 0.8–3.0, P=0.16) disability at 18 months with subsequent non-relapse mortality.
Discussion
Disability is a complex concept encompassing impairment, activity limitation, and participation restriction that has largely been unexplored and undefined in chronic GVHD. While disability has previously primarily been conceptualized to include impairments in body functioning or structure from health conditions, subsequent definitions also include impairments resulting from contextual environmental or personal factors. In 2001, the World Health Organization (WHO) developed a framework for organizing and documenting information on functioning and disability for individuals and general populations, the International Classification of Functioning, Disability and Health (ICF)27. The ICF represents a framework for health and disability, and is considered a “bio-psycho-social” model of functioning and disability, recognizing the “dynamic interaction between a person’s health condition, environmental factors, and personal factors.“12 Measuring disability within this context, thus, requires assessments that incorporate the patient-reported view of disability, activity limitations in core domains of function, and objective clinical impairments or presence of specific, disabling health conditions28. Any single impairment data element alone thus does not capture the overall disability experiences of individuals and their ability to function in their respective environments.
Given the heterogeneity of chronic GVHD, and its varying impact on physical, emotional, and social functioning and activity, disability is an important concept and measure to further define. Comprehensive studies of disability after HCT that assess patient defined disability, functional limitations and objective clinical impairments or health conditions remain limited.
In this study we explored definitions of disability in chronic GVHD. Flowers-defined chronic GVHD disability (grade 2 or 3 keratoconjunctivitis sicca, grade 2 or 3 scleroderma, any grade of bronchiolitis obliterans, grade 2 or joint/fasciae involvement, or grade 3 esophageal stricture requiring dilation) has been shown to be associated with impaired recovery of pretransplant function, poor quality of life, and need for immunosuppression. In our analysis, Flowers-defined chronic GVHD was also associated with decline in HAP and KPS, which are important measures of function and activity, associated with disability. We determined enrollment factors that were associated with progression to 18 month disability as defined by Flowers. Interestingly, only higher NIH mouth scores at enrollment and patient-reported higher eye and skin symptoms were highly associated with progression to disability. Eye, skin, and mouth symptoms have all previously been associated with subsequent failure-free survival10, 29, and represent symptoms associated with high symptom burden and potential irreversibility. These findings also highlight once again the importance of patient-reported symptoms in chronic GVHD outcomes. The significance of the inverse relationship of elevated bilirubin is unclear. Given that only 4% of patients at enrollment had elevated bilirubin >2 mg/dL, it is unclear whether this finding is clinically meaningfully. Intermediate (6 month) indices of cGVHD-FFS and cGVHD-CR/PR were not associated with 18-month disability.
There are several limitations to this analysis. We only included patients with enrollment and 18 month assessments, thus we are unable to assess potential risk factors and predictors of outcomes for patients who did not complete an 18 month assessment. Although most cases in this cohort were “incident” cases (within 3 months of diagnosis), there were also a proportion of patients that had established chronic GVHD (greater than 3 months from diagnosis). Thus, per Flowers criteria, some patients were already “disabled” when enrolled in the study. Due to our interest in developing an endpoint for clinical trials, we primarily analyzed “progressive disability”, defined as the development of additional impairments. Disability, however, whenever present, may impact patients adversely, not just when it is “progressive.” We also did not have data regarding specific time points when patients progressed by Flowers criteria and thus could not perform any disability related time-to-event analysis. Importantly, we were unable to explore all definitions of disability. Our analysis primarily focused on objective clinical impairments available from the NIH Consensus Conference recommended measures, which have been presumed to be associated with disability. We did not have direct patient perspective of “disability,” including activity and participation, or data on the environmental/social contexts of individuals that may further affect the experience of disability. We also did not have data on other objective functional indicators of disability or change in disability at 18 months (e.g. walk test, return to work status, etc.) to further correlate our findings and better understand the concept of disability in chronic GVHD.
Nevertheless, disability is an important concept to measure patients’ functionality and quality of life in chronic GVHD, which may be an important measure to include in response assessments. Our analysis demonstrates that in this cohort of chronic GVHD patients initiating new systemic therapy, over half (62%) of patients will have a clinical impairment or decline in functionality associated with disability by 18 months. As we were not able to fully explore all definitions of disability, this analysis highlights the critical need for further evaluation in defining disability in chronic GVHD, including the patient’s perspective on personal activity, functionality and participation in normal social roles (e.g. patient-reported outcomes, return to work/school status, etc.) together with objective measures of activity and disease status. Data is also needed about predictive risk factors for disability, ultimately to use this information to understand how transplantation results in disability, so that it may be prevented.
Highlights.
Disability as defined by progressive chronic GVHD impairments are associated with decline in human activity profile scores and performance status at 18 months.
Worse oral scores, and patient-reported eye and skin scores are significantly associated with progressive chronic GVHD impairment at 18 months.
Funding:
CA118953
Footnotes
Conflict of Interest: None
References:
- 1.Fatobene G, Storer BE, Salit RB, Lee SJ, Martin PJ, Cheng GS et al. Disability related to chronic graft -versus-host disease after alternative donor hematopoietic cell transplantation. Haematologica 2019; 104(4): 835–843. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Martin PJ, Counts GW Jr., Appelbaum FR, Lee SJ, Sanders JE, Deeg HJ et al. Life expectancy in patients surviving more than 5 years after hematopoietic cell transplantation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2010; 28(6): 1011–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Wingard JR, Majhail NS, Brazauskas R, Wang Z, Sobocinski KA, Jacobsohn D et al. Long-term survival and late deaths after allogeneic hematopoietic cell transplantation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2011; 29(16): 2230–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Lee SJ, Flowers ME. Recognizing and managing chronic graft-versus-host disease. Hematology/the Education Program of the American Society of Hematology. American Society of Hematology. Education Program 2008: 134–41. [DOI] [PubMed] [Google Scholar]
- 5.Pidala J, Kurland B, Chai X, Majhail N, Weisdorf DJ, Pavletic S et al. Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium. Blood 2011; 117(17): 4651–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Khera N, Storer B, Flowers ME, Carpenter PA, Inamoto Y, Sandmaier BM et al. Nonmalignant late effects and compromised functional status in survivors of hematopoietic cell transplantation. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 2012; 30(1): 71–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Syrjala KL, Langer SL, Abrams JR, Storer B, Sanders JE, Flowers ME et al. Recovery and long-term function after hematopoietic cell transplantation for leukemia or lymphoma. JAMA : the journal of the American Medical Association 2004; 291(19): 2335–43. [DOI] [PubMed] [Google Scholar]
- 8.Martin PJ, Lee SJ, Przepiorka D, Horowitz MM, Koreth J, Vogelsang GB et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: VI. The 2014 Clinical Trial Design Working Group Report. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2015; 21(8): 1343–59. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Palmer J, Chai X, Pidala J, Inamoto Y, Martin PJ, Storer B et al. Predictors of survival, nonrelapse mortality, and failure-free survival in patients treated for chronic graft-versus-host disease. Blood 2016; 127(1): 160–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Palmer J, Chai X, Martin PJ, Weisdorf D, Inamoto Y, Pidala J et al. Failure-free survival in a prospective cohort of patients with chronic graft-versus-host disease. Haematologica 2015; 100(5): 690–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Inamoto Y, Flowers ME, Sandmaier BM, Aki SZ, Carpenter PA, Lee SJ et al. Failure-free survival after initial systemic treatment of chronic graft-versus-host disease. Blood 2014; 124(8): 1363–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.World Health Organization. International classification of functioning, disability and health ICF. In. 1.0. ed Geneva: World Health Organization,, 2001. pp 1 CD-ROM. [Google Scholar]
- 13.Jagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant 2015; 21(3): 389–401 e1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005; 11(12): 945–56. [DOI] [PubMed] [Google Scholar]
- 15.Lee SJ, Wolff D, Kitko C, Koreth J, Inamoto Y, Jagasia M et al. Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report. Biol Blood Marrow Transplant 2015; 21(6): 984–99. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Pavletic SZ, Martin P, Lee SJ, Mitchell S, Jacobsohn D, Cowen EW et al. Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria Working Group report. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2006; 12(3): 252–66. [DOI] [PubMed] [Google Scholar]
- 17.Lee S, Cook EF, Soiffer R, Antin JH. Development and validation of a scale to measure symptoms of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2002; 8(8): 444–52. [DOI] [PubMed] [Google Scholar]
- 18.Merkel EC, Mitchell SA, Lee SJ. Content Validity of the Lee Chronic Graft-versus-Host Disease Symptom Scale as Assessed by Cognitive Interviews. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2016; 22(4): 752–758. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Daughton DM, Fix AJ, Kass I, Bell CW, Patil KD. Maximum oxygen consumption and the ADAPT quality-of-life scale. Archives of physical medicine and rehabilitation 1982; 63(12): 620–2. [PubMed] [Google Scholar]
- 20.Farrell MJ, Gibson SJ, Helme RD. Measuring the activity of older people with chronic pain. Clin J Pain 1996; 12(1): 6–12. [DOI] [PubMed] [Google Scholar]
- 21.Tran PV, Schwarz J, Gorman M, Helme RD. Validation of an automated up-timer for measurement of mobility in older adults. The Medical journal of Australia 1997; 167(8): 434–6. [DOI] [PubMed] [Google Scholar]
- 22.Stuifbergen AK. Physical activity and perceived health status in persons with multiple sclerosis. The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses 1997; 29(4): 238–43. [DOI] [PubMed] [Google Scholar]
- 23.Johansen KL, Painter P, Kent-Braun JA, Ng AV, Carey S, Da Silva M et al. Validation of questionnaires to estimate physical activity and functioning in end-stage renal disease. Kidney international 2001; 59(3): 1121–7. [DOI] [PubMed] [Google Scholar]
- 24.Herzberg PY, Heussner P, Mumm FH, Horak M, Hilgendorf I, von Harsdorf S et al. Validation of the human activity profile questionnaire in patients after allogeneic hematopoietic stem cell transplantation. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2010; 16(12): 1707–17. [DOI] [PubMed] [Google Scholar]
- 25.Martin PJ, Storer BE, Palmer J, Jagasia MH, Chen GL, Broady R et al. Organ Changes Associated with Provider-Assessed Responses in Patients with Chronic Graft-versus-Host Disease. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Pidala J, Hamilton BK, Martin PJ, Onstad L, Storer BE, Palmer J, Alousi A, Cutler C, Jagasia MH, Chen GL, Arora M, Flowers ME, Lee SJ. . The chronic graft-versus-host disease failure-free survival (cGVHD-FFS) index. . Biol Blood Marrow Tr 2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Ustun TB, Chatterji S, Bickenbach J, Kostanjsek N, Schneider M. The International Classification of Functioning, Disability and Health: a new tool for understanding disability and health. Disabil Rehabil 2003; 25(11–12): 565–71. [DOI] [PubMed] [Google Scholar]
- 28.Tucker CA, Cieza A, Riley AW, Stucki G, Lai JS, Bedirhan Ustun T et al. Concept analysis of the patient reported outcomes measurement information system (PROMIS((R))) and the international classification of functioning, disability and health (ICF). Quality of life research : an international journal of quality of life aspects of treatment, care and rehabilitation 2014; 23(6): 1677–86. [DOI] [PubMed] [Google Scholar]
- 29.Pidala JA, Hamilton BK, Martin PJ, Onstad L, Storer BE, Palmer J et al. The Chronic Graft-vs.-Host Disease Failure-Free Survival (cGVHD-FFS) index. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation 2019. [DOI] [PMC free article] [PubMed] [Google Scholar]