Burden of Illness in Chronic Graft vs. Host Disease - A Prospective Cohort Study.
Authors: Pusic Iskra , Dickinson John , Steinberg Seth , Odom Jeanne , Atlam Niveen , Mitchell Sandra , Avila Daniele , Krumlauf Michael , Baird Kristin , Pavletic Steven 
Published: April 2020

Abstract
BACKGROUND: Chronic Graft vs. Host Disease (cGVHD) is a complex and prevalent complication in long term survivors after allogeneic stem cell transplant. The scope and severity of abnormalities in cGVHD have never been systematically described and are essential for health care delivery planning or testing new therapies.
METHODS: Patients with cGVHD were studied in a cross-sectional prospective natural history protocol. They were systematically assessed by a multidisciplinary team specialized in cGVHD clinical research. A detailed history, organ-specific evaluations, functional performance and laboratory parameters were obtained using standardized measures. Questionnaires administered in strictly controlled conditions included clinician-administered NIH scoring (Filipovich et al, BMT11:945, 2005) and measures of quality of life (FACT-BMT, SF-36, Lee cGVHD symptom scale). An exploratory statistical analysis was performed by grouping parameters into “predictors” (patient and transplant characteristics, laboratory data) and “outcomes” (cGVHD severity, functional performance, QOL) using descriptive statistics and correlation analysis (p&lt;0.01 or correlation coefficient &gt;0.70 as indicators of strong association).
RESULTS: Cohort included 52 patients (29 male, median age 48) with cGVHD. Median time post-transplant was 27 mo and time from diagnosis of cGVHD 14 mo, 42 patients had a sibling donor, 47 received peripheral blood stem cells, 26 had progressive onset of cGVHD, 51 had extensive disease, 38 were on systemic immunosuppression (31 on two or more drugs). Median number of organ systems involved was 5, range from 2 to 9 (max possible 9 for women, 8 for men); median total NIH score was 7.5, range from 2 to 15 (max 27 for women, 24 for men); 22 patients had at least one organ with NIH score of 3 indicating seriously disabling manifestations. Unrelated donor transplant recipients had more organ systems involved (p=0.009) and higher total score (p=0.036). Male recipients with female donors had higher NIH scores (p&lt;0.043). Myeloablative regimens were associated with higher scores for eye (p=0.004). Patients with longstanding cGVHD had higher scores for skin sclerosis (p&lt;0.003), eye (p&lt;0.005) and joint (p&lt;0.0001) while those with early onset of cGVHD had higher mouth scores (p=0.005). Total white count and absolute lymphocyte count were associated with eye involvement (p=0.01 and 0.007 respectively), total cholesterol and LDL with mouth involvement (p=0.0004 and 0.003 respectively), complement C3 and IL-6 with skin sclerosis (p= 0.003 and 0.006 respectively). 26 patients had at least one auto-antibody present and 9 had two or more. Presence of anti-cardiolipin antibodies IgG type was associated with higher skin score (p=0.0008) and IgM with lower eye score (p=0.009). B-cell activating factor (BAFF) was higher in patients who were 9 mo or less from their transplant (p=0.024). BAFF was negatively associated with eye disease (p&lt;0.05) and positively with beta-2-microglobulin (p=0.0001). There were no significant correlations between any predictor and QOL outcomes.
CONCLUSION: Patients with cGVHD manifest wide range of clinical and laboratory abnormalities. Some abnormalities occur together and are time related suggesting heterogeneous and dynamic disease biology. Patient reported QOL measures may not be good correlates of cGVHD pathophysiology. A substantial number of associations are worthy of further exploration to better understand the mechanisms which generate the diverse clinical spectrum of cGVHD.