Fecal Microbiota Transplantation Can Cure Steroid-Refractory Intestinal Graft-Versus-Host Disease

Abstract

Introduction: Severe acute graft-versus-host disease (aGVHD) is characterized by an imbalance of circulating tissue repair factors, with elevated amphiregulin (AREG) and very low (<10 pg/ml) plasma epidermal growth factor (EGF). We hypothesized that giving supplemental EGF, contained in an inexpensive, commercially available drug (urinary-derived human chorionic gonadotropin [hCG], Pregnyl Ò) in addition to standard aGVHD therapy would improve outcomes. Patients and Methods: Twenty-six patients received hCG/EGF in addition to standard aGVHD therapy (13 with Minnesota high risk aGVHD and 13 receiving 2 nd line therapy). 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. Initial hCG dosing was at 500 units hCG/m 2 SQ, escalating to 2,000 units hCG/m 2 in cohorts of 2, with dose assignment by the continual reassessment method. We analyzed GVHD-associated plasma biomarkers during therapy. Results: HCG/EGF was well tolerated, with no dose-limiting toxicities. 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 2 nd 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). In initial therapy patients, plasma EGF rose from baseline 3 pg/ml to 25.4 pg/ml at 6 hours post-hCG/EGF dose (p=0.02), while in 2 nd line patients, plasma EGF never rose from baseline 5 pg/ml. Patients with a day 28 CR/PR had a 4.6-fold reduction in plasma AREG over time (Figure 1B). Conclusions: HCG/EGF is a novel adjunct therapy in lifethreatening aGVHD. The mechanisms of benefit may include 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 results. Decreasing plasma AREG may reflect successful treatment of severe aGVHD.

The gut microbiome in pediatric patients undergoing allogeneic hematopoietic stem cell transplantation

“…In adult patients, it has been used to treat refractory Clostridium difficile infections and steroid-resistant gut aGvHD, and to eradicate drug-resistant microorganisms. [70][71][72] Bluestone et al reported FMT administration to treat refractory C. difficile infection in three children, using related and unrelated donors via a gastric tube or colonoscopy. No adverse events were reported, but only one achieved remission.…”

The clinical role of the gut microbiome and fecal microbiota transplantation in allogeneic stem cell transplantation

“…Response to treatment was seen within a median of 14 days (range: 3-28), with a median of two FMT (range: 1-7), and a median of 7 days between treatments (range: 2-60). 46,[98][99][100][101][102][103][104][105][106] Infectious complications occurred in 11 patients. Two had sepsis with bacteria not originating from FMT, 102 and one patient developed diarrhea due to Norovirus that was traced to FMT.…”

“…In general, in order to consider FMT as an efficacious therapeutic approach for SR GI aGvHD management, an overall response rate of around 60-70%, with a complete response rate of 30-50% should be a desired target, as these rates are achieved with the use of the approved ruxolitinib treatment and in non-randomized FMT studies. 46,[98][99][100][101][102][103][104][105][106]110 As for the antibiotic treatment peri-FMT, if feasible, 24-48 hours prior to FMT, systemic antibiotics should be stopped or replaced by one with less anti-anaerobic activity such as rifaximin for prophylaxis or cefepime for febrile neutropenic treatment. 46,98,99 Microbiome sequencing of donor and patient samples could help interpreting clinical outcomes.…”

Insights into the role of intestinal microbiota in hematopoietic stem-cell transplantation

“…One week after FMT, the fecal microbial composition of patients with complete response, defined as resolution of all GvHD symptoms 4 weeks after FMT without other interventions to alleviate symptoms, resembled that of the donors. 116 Two more case reports deserve mention: Kaito and colleagues reported a case of refractory gut GvHD treated effectively and safely using FMT with oral capsules, representing the only case to date in the literature. 117 Zhang and colleagues treated a case of post-HSCT diarrhoea in an adult patient with repeated FMTs from two unrelated infants, one with mixed feeding (formula and complementary food) and one exclusively breastfed, leading to an improvement in symptoms.…”