Randomized Double-Blind Phase II Trial of Fecal Microbiota Transplantation Versus Placebo in Allogeneic Hematopoietic Cell Transplantation and AML

Abstract

PURPOSE Gut microbiota injury in allogeneic hematopoietic cell transplantation (HCT) recipients and patients with AML has been associated with adverse clinical outcomes. Previous studies in these patients have shown improvements in various microbiome indices after fecal microbiota transplantation (FMT). However, whether microbiome improvements translate into improved clinical outcomes remains unclear. We examined this question in a randomized, double-blind, placebo-controlled phase II trial. METHODS Two independent cohorts of allogeneic HCT recipients and patients with AML receiving induction chemotherapy were randomly assigned in a 2:1 ratio to receive standardized oral encapsulated FMT versus placebo upon neutrophil recovery. After each course of antibacterial antibiotics, patients received a study treatment. Up to three treatments were administered within 3 months. The primary end point was 4-month all-cause infection rate. Patients were followed for 9 months. RESULTS In the HCT cohort (74 patients), 4-month infection density was 0.74 and 0.91 events per 100 patient-days in FMT and placebo arms, respectively (infection rate ratio, 0.83; 95% CI, 0.48 to 1.42; P = .49). In the AML cohort (26 patients), 4-month infection density was 0.93 in the FMT arm and 1.25 in the placebo arm, with an infection rate ratio of 0.74 (95% CI, 0.32 to 1.71; P = .48). Unique donor bacterial sequences comprised 25%-30% of the fecal microbiota after FMT. FMT improved postantibiotic recovery of microbiota diversity, restored several depleted obligate anaerobic commensals, and reduced the abundance of expanded genera Enterococcus, Streptococcus, Veillonella, and Dialister. CONCLUSION In allogeneic HCT recipients and patients with AML, third-party FMT was safe and ameliorated intestinal dysbiosis, but did not decrease infections. Novel findings from this trial will inform future development of FMT trials.

Role of mucositis in predicting gut microbiota composition in people with cancer

“…Varying conditioning regimens induce varying levels of MBI, and thus microbial phenotypes and their associated clinical implications. Of interest, the recent trial conducted by Rahsidi et al investigating FMT for BSI prevention in HSCT recipients did not reach its primary endpoint, that is, FMT did not significantly reduce the incidence of BSI [36]. This may reflect the fact that although microbes were successfully delivered to recipients, their ability to durably colonize the gut may be impacted by persistent mucosal damage.…”

Ecological insights into hematopoiesis regulation: unraveling the influence of gut microbiota

“…While statistical differences were not observed in this clinical trial, it still acknowledges the positive value of FMT in the context of HSCT. 118 , 119 Van den Brink’s lab explored the value of the intestinal microbiota in recipient hematopoietic system reconstruction after bone marrow transplantation. They found that in mice lacking intestinal microbiota, there is impaired hematopoietic system reconstruction after bone marrow transplantation.…”

Long- and short-term effects of fecal microbiota transplantation on antibiotic resistance genes: results from a randomized placebo-controlled trial

“…FMT was safe and ameliorated intestinal dysbiosis. 10 The large number of ARGs analyzed (47 ARGs), access to longitudinal stool samples collected over 9 months, and the randomized design of the trial allowed us to address the three knowledge gaps of interest.…”