Late acute graft-versus-host disease: A prospective analysis of clinical outcomes and circulating angiogenic factors
Angiogenesis Inducing Agents
Graft vs Host Disease
Late acute (LA) graft vs. host disease (GVHD) is persistent, recurrent, or new onset acute GVHD symptoms occurring after 100 days post-allogeneic hematopoietic cell transplantation (HCT). The aim of this analysis is to describe the onset, course, morbidity, mortality, and examine angiogenic factors associated with LA GVHD. A prospective cohort of patients (n=909) was enrolled as part of an observational study within the Chronic GVHD Consortium. Eighty-three patients (11%) developed LA GVHD at a median of 160 (interquartile range, IQR 128-204) days after HCT. While 51/83 (61%) achieved complete or partial response to initial therapy by 28 days, median failure free survival was only 7.1 months (95% confidence interval 3.4-19.1 months), and estimated overall survival (OS) at two years was 56%. Given recently described alterations of circulating angiogenic factors in classic acute GVHD, we examined whether alterations in such factors could be identified in LA GVHD. We first tested cases (n-55) and controls (n=50) from the Chronic GVHD Consortium and then validated the findings in 37 cases from Mount Sinai Acute GVHD International Consortium. Plasma amphiregulin (AREG, an epidermal growth factor [EGF] receptor ligand) was elevated, and the AREG/EGF ratio ≥ median was associated with inferior OS and increased NRM in both cohorts. Elevation of AREG was detected in classic acute GVHD, but not chronic GVHD. These prospective data characterize the clinical course of LA GVHD, and demonstrate alterations in angiogenic factors that make LA GVHD biologically distinct from chronic GVHD.