TY - JOUR
T1 - Facilitating resolution of life-threatening acute GVHD with human chorionic gonadotropin and epidermal growth factor
AU - Holtan, Shernan G.
AU - Hoeschen, Andrea L.
AU - Cao, Qing
AU - Arora, Mukta
AU - Bachanova, Veronika
AU - Brunstein, Claudio G.
AU - Miller, Jeffrey S.
AU - Rashidi, Armin
AU - Slungaard, Arne
AU - Ustun, Celalettin
AU - Vercellotti, Gregory M.
AU - Warlick, Erica D.
AU - Betts, Brian C.
AU - El Jurdi, Najla
AU - He, Fiona
AU - Chen, Chi
AU - Gandhi, Isha
AU - Wagner, John E.
AU - Blazar, Bruce R.
AU - Jacobson, Pamala Ann
AU - Shabaneh, Ashraf
AU - Wang, Jinhua
AU - Panoskaltsis-Mortari, Angela
AU - MacMillan, Margaret L.
AU - Weisdorf, Daniel J.
N1 - Publisher Copyright:
© 2020 by The American Society of Hematology
PY - 2020/4/14
Y1 - 2020/4/14
N2 - Acute graft-versus-host disease (aGVHD) is a potentially fatal complication of allogeneic hematopoietic cell transplantation that fails to improve with intense immunosuppression in some patients. We hypothesized that urinary-derived human chorionic gonadotropin (uhCG) could help facilitate resolution of life-threatening aGVHD when added as supportive care via 2 potential mechanisms: immunomodulation (akin to its role in pregnancy) and supplementation of epidermal growth factor (EGF; to aid in epithelial repair). In a phase 1 study, 26 participants received subcutaneous injections of uhCG in addition to standard immunosuppression (13 receiving initial therapy for high-risk aGVHD [according to the Minnesota criteria] and 13 receiving second-line therapy). Participants underwent serial blood testing for biomarkers of hormone response, immune modulation, and aGVHD activity on study. uhCG was well tolerated, with no dose-limiting toxicities. Sixty-two percent of patients in the high-risk cohort and 54% of patients in the second-line cohort had a complete response at study day 28. Plasma EGF was elevated sixfold (from 4 to 24 pg/mL; P 5 .02) at 6 hours postdose in the high-risk cohort, in contrast to no peak in plasma EGF in the more severe second-line cohort. After 1 week of uhCG, patients reported a twofold increase in the regulatory T cell to conventional T-cell ratio, suggesting immune modulation despite high-dose steroids. Responding patients reported significantly lower plasma amphiregulin and higher plasma butyrate levels at study completion, suggesting improvement in mucosal damage over time. uhCG is a novel, safe, supportive therapy, proceeding to phase 2 testing at 2000 units/m2 in high-risk aGVHD. This study was registered at www.clinicaltrials.gov as #NCT02525029.
AB - Acute graft-versus-host disease (aGVHD) is a potentially fatal complication of allogeneic hematopoietic cell transplantation that fails to improve with intense immunosuppression in some patients. We hypothesized that urinary-derived human chorionic gonadotropin (uhCG) could help facilitate resolution of life-threatening aGVHD when added as supportive care via 2 potential mechanisms: immunomodulation (akin to its role in pregnancy) and supplementation of epidermal growth factor (EGF; to aid in epithelial repair). In a phase 1 study, 26 participants received subcutaneous injections of uhCG in addition to standard immunosuppression (13 receiving initial therapy for high-risk aGVHD [according to the Minnesota criteria] and 13 receiving second-line therapy). Participants underwent serial blood testing for biomarkers of hormone response, immune modulation, and aGVHD activity on study. uhCG was well tolerated, with no dose-limiting toxicities. Sixty-two percent of patients in the high-risk cohort and 54% of patients in the second-line cohort had a complete response at study day 28. Plasma EGF was elevated sixfold (from 4 to 24 pg/mL; P 5 .02) at 6 hours postdose in the high-risk cohort, in contrast to no peak in plasma EGF in the more severe second-line cohort. After 1 week of uhCG, patients reported a twofold increase in the regulatory T cell to conventional T-cell ratio, suggesting immune modulation despite high-dose steroids. Responding patients reported significantly lower plasma amphiregulin and higher plasma butyrate levels at study completion, suggesting improvement in mucosal damage over time. uhCG is a novel, safe, supportive therapy, proceeding to phase 2 testing at 2000 units/m2 in high-risk aGVHD. This study was registered at www.clinicaltrials.gov as #NCT02525029.
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U2 - 10.1182/bloodadvances.2019001259
DO - 10.1182/bloodadvances.2019001259
M3 - Article
C2 - 32236525
AN - SCOPUS:85083795813
SN - 2473-9529
VL - 4
SP - 1284
EP - 1295
JO - Blood Advances
JF - Blood Advances
IS - 7
ER -