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. 2016 Nov 10;128(19):2350-2358.
doi: 10.1182/blood-2015-09-669846. Epub 2016 Sep 13.

Late acute graft-versus-host disease: a prospective analysis of clinical outcomes and circulating angiogenic factors

Shernan G Holtan  1 , Nandita Khera  2 , John E Levine  3 , Xiaoyu Chai  4 , Barry Storer  4 , Hien D Liu  5 , Yoshihiro Inamoto  6 , George L Chen  7 , Sebastian Mayer  8 , Mukta Arora  1 , Jeanne Palmer  2 , Mary E D Flowers  4 , Corey S Cutler  9 , Alexander Lukez  9 , Sally Arai  10 , Aleksandr Lazaryan  1 , Laura F Newell  11 , Christa Krupski  12 , Madan H Jagasia  12 , Iskra Pusic  13 , William Wood  14 , Anne S Renteria  3 , Gregory Yanik  15 , William J Hogan  16 , Elizabeth Hexner  17 , Francis Ayuk  18 , Ernst Holler  19 , Phandee Watanaboonyongcharoen  20 , Yvonne A Efebera  21 , James L M Ferrara  3 , Angela Panoskaltsis-Mortari  1 , Daniel Weisdorf  1 , Stephanie J Lee  4 , Joseph Pidala  22
Affiliations

Late acute graft-versus-host disease: a prospective analysis of clinical outcomes and circulating angiogenic factors

Shernan G Holtan et al. Blood. .

Abstract

Late acute (LA) graft-versus-host disease (GVHD) is persistent, recurrent, or new-onset acute GVHD symptoms occurring >100 days after allogeneic hematopoietic cell transplantation (HCT). The aim of this analysis is to describe the onset, course, morbidity, and mortality of 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, 128-204) days after HCT. Although 51 out of 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 2 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 an AREG/EGF ratio at or above the median was associated with inferior OS and increased nonrelapse mortality 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.

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Figures

Figure 1
Figure 1
Overall grade at LA GVHD onset. Comparison of recurrent vs de novo disease.
Figure 2
Figure 2
LA GVHD treatment response at 28, 56, and 180 days.
Figure 3
Figure 3
Clinical outcomes of LA GVHD. (A) Cumulative incidence of treatment failure after initial systemic treatment. (B) Failure-free survival after onset of LA GVHD.
Figure 4
Figure 4
Plasma levels of angiogenic factors in patients with LA GVHD and their respective controls. Data are presented as mean ± standard error of the mean. Asterisk indicates statistically significant difference in amphiregulin between LA GVHD cases and controls.
Figure 5
Figure 5
AREG, AREG/EGF ratio, OS, and NRM after LA GVHD. Boxplot of (A) AREG and (B) AREG/EGF ratio in LA GVHD cases vs controls. (C) OS and (D) NRM (d) by AREG/EGF ratio. *Cohort 1, LA GVHD vs matched control comparison from national Chronic GVHD Consortium; cohort 2, validation cohort of patients with LA GVHD at onset from the Mount Sinai Acute GVHD International Consortium (MAGIC).
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References

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