Amphiregulin modifies the Minnesota Acute Graft-versus-Host Disease Risk Score: results from BMT CTN 0302/0802

Shernan G. Holtan, Todd E. DeFor, Angela Panoskaltsis-Mortari, Nandita Khera, John E. Levine, Mary E.D. Flowers, Stephanie J. Lee, Yoshihiro Inamoto, George L. Chen, Sebastian Mayer, Mukta Arora, Jeanne Palmer, Corey S. Cutler, Sally Arai, Aleksandr Lazaryan, Laura Newell, Madan H. Jagasia, Iskra Pusic, William A. Wood, Anne S. RenteriaGregory Yanik, William J. Hogan, Elizabeth Hexner, Francis Ayuk, Ernst Holler, Udomsak Bunworasate, Yvonne A. Efebera, James L.M. Ferrara, Joseph Pidala, Alan Howard, Juan Wu, Javier Bolaños-Meade, Vincent Ho, Amin Alousi, Bruce R. Blazar, Daniel J. Weisdorf, Margaret L. MacMillan

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Abstract

Amphiregulin (AREG) is an epidermal growth factor receptor ligand that can restore integrity to damaged intestinal mucosa in murine models of acute graft-versus-host disease (aGVHD). We previously reported that circulating AREG is elevated in late-onset aGVHD (occurring after 100 days posttransplant), but its clinical relevance in the context of aGVHD risk is unknown. We measured AREG in 251 aGVHD onset blood samples from Blood and Marrow Clinical Trials Network (BMT CTN) primary treatment trials and determined their association with GVHD severity, day 28 complete or partial response (CR/PR) to first-line therapy, overall survival (OS), and nonrelapse mortality (NRM). Every doubling of plasma AREG was associated with a 33% decrease in the odds of day 28 CR/PR (odds ratio [OR], 0.67; P < .01). An AREG threshold of 33 pg/mL or greater divided patients with Minnesota standard-risk (SR) aGVHD into a distinct group with a significantly lower likelihood of: day 28 CR/PR (72% vs 85%; P = .02); greater 2-year NRM (42% vs 15%; P < .01); and inferior OS (40% vs 66%; P < .01). High AREG ≥ 33 pg/mL also stratified patients with Minnesota high-risk (HR) aGVHD: day 28 CR/PR (54% vs 83%; P = .03) and 2-year NRM (53% vs 11%; P < .01), with a trend toward inferior 2-year OS (37% vs 60%; P = .09). High-circulating AREG (≥33 pg/mL) reclassifies patients into HR subgroups and thereby further refines the Minnesota aGVHD clinical risk score.

Original languageEnglish (US)
Pages (from-to)1882-1888
Number of pages7
JournalBlood advances
Volume2
Issue number15
DOIs
StatePublished - Aug 14 2018

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Holtan, S. G., DeFor, T. E., Panoskaltsis-Mortari, A., Khera, N., Levine, J. E., Flowers, M. E. D., Lee, S. J., Inamoto, Y., Chen, G. L., Mayer, S., Arora, M., Palmer, J., Cutler, C. S., Arai, S., Lazaryan, A., Newell, L., Jagasia, M. H., Pusic, I., Wood, W. A., ... MacMillan, M. L. (2018). Amphiregulin modifies the Minnesota Acute Graft-versus-Host Disease Risk Score: results from BMT CTN 0302/0802. Blood advances, 2(15), 1882-1888. https://doi.org/10.1182/bloodadvances.2018017343