Facilitating Resolution of Life-Threatening Acute Graft-Versus-Host Disease By Supplementation of Human Chorionic Gonadotropin and Epidermal Growth Factor (Pregnyl): A Phase I Study

Abstract INTRODUCTION Patients with severe acute graft-versus-host disease (aGVHD) are at high risk of death due to damaged organs and tissues. We have previously shown that severe aGVHD is characterized by an imbalance of circulating tissue repair factors, with elevated amphiregulin (AREG) and very low ( PATIENTS AND METHODS Twenty-six patients received hCG/EGF in addition to standard aGVHD therapy. We treated 13 patients with onset Minnesota High Risk aGVHD with high-dose steroids (methylprednisolone 48 mg/m2) plus subcutaneous (SQ) injections of hCG/EGF every other day for 7 days. In the 2nd line therapy cohort, we treated 13 patients with hCG/EGF SQ every other day for 14 days, recognizing the time to response may be longer in this cohort relative to those with onset aGVHD, along with increased steroids (steroid dependent, N=5) and intensified immune suppression (steroid refractory, N=8). We then assessed response after 7 days in High Risk aGVHD and after 14 days in steroid dependent/refractory aGVHD. In both cohorts, patients with a complete or partial response (CR/PR) at the end of the initial dosing period were eligible to receive maintenance hCG/EGF SQ twice weekly for up to 5 weeks, whereas patients with no response (NR) received no further study drug doses and received best available therapy from their treating physicians. Initial hCG dosing was at 500 units hCG/m2 SQ, escalating to 2,000 units hCG/m2 in cohorts of 2, with dose assignment by the continual reassessment method. We analyzed GVHD-associated plasma biomarkers and enumerated circulating CD4+FoxP3+CD127- Tregs and CD8+ T lymphocytes during therapy. RESULTS HCG/EGF was well tolerated, with no dose-limiting toxicities. The median EGF dose was 50,833 pg/ml. The most common treatment emergent side effect was edema (N=16, 62%). At day 28 of study, responses for initial therapy were 8/13 CR (62%), 0/13 PR (0%), and 5/13 NR (38%), higher than institutional historical (n=269) 26% CR, 16% PR, 57% NR (Figure 1A). Responses for 2nd line therapy were 7/13 CR (54%), 1/13 PR (8%), 5/13 NR (38%), 4 of which were deaths (31%), improved relative to historical outcomes (n=85) of 18% CR, 19% PR, 63% NR (including 16% deaths, Figure 1A). Cytopenias were not worse during hCG/EGF; responders had a slight leukocytosis (day 7 median white blood cells [WBC] 9.7 x 109/L), returning to baseline (WBC 5.8 x 109/L, p=0.015) by day 56. Patients had increases in serum hCG (median 1.5 vs 138 IU/L, p CONCLUSIONS HCG/EGF is a novel and well-tolerated adjunct therapy in high-risk and steroid-dependent/refractory aGVHD, associated with minimal toxicity and encouraging response rates. The mechanisms of benefit may include immunomodulation via Treg expansion despite high-dose steroids and facilitation of tissue repair with detectable increases in circulating EGF. The optimal dose and duration of hCG/EGF are under investigation, with ongoing dose escalation in patients with steroid-refractory aGVHD based upon these initial results. Decreasing plasma AREG over time may reflect successful treatment of life-threatening aGVHD. Disclosures Holtan: Incyte: Consultancy. Bachanova: Gamida Cell: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; GT Biopharma: Research Funding. Brunstein: Gamidacell: Research Funding. Ustun: novartis: Speakers Bureau. Wagner: Novartis: Research Funding; Magenta Therapeutics: Consultancy, Research Funding. Blazar: Kadmon Corporation, LLC: Consultancy, Research Funding. MacMillan: Angiocrine: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Equillium: Consultancy. Weisdorf: SL Behring: Consultancy; FATE: Consultancy; Equillium: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy.