Investigating the Relationship between Graft-Versus-Host Disease Incidence and Increased Risk of Death within Three Years after Allogeneic Hematopoietic Stem Cell Transplantation in Patients Receiving Antibiotics Containing Activity Against Obligate Anaerobes

Background: There is evidence that suggests a relationship may exist between altering the intestinal microbiome and development of Graft-Versus-Host Disease (GVHD) in allogeneic hematopoietic stem cell transplantation (AHSCT) recipients. Though this relationship is not well understood, it is an important topic to further investigate as many patients undergoing AHSCT are exposed to broad-spectrum antibiotics that have an effect on the commensal bacteria that play a role in intestinal health. Of the commensal bacteria, it has been suggested that obligate anaerobes may be beneficial in mediating intestinal homeostasis and inflammation, thus antibiotics against these organisms may increase the incidence of GVHD and GVHD-related mortality. Neutropenic fever is a common occurrence in patients undergoing AHSCT, thus patients are frequently exposed to antibiotics that may be negatively affecting the intestinal flora, leading to worse outcomes.

Methods: We retrospectively analyzed adult patients (age ≥ 21) who received AHSCT from January 2011 to June 2016 and specifically identified those that were exposed to antibiotics against obligate anaerobes within 30 days post-AHSCT and those who developed both acute and chronic GVHD. Of those that received antibiotics against obligate anaerobes, GVHD-related mortality was also assessed. The most common indication for antibiotic administration was neutropenic fever and the most common antibiotics used were cefepime, meropenem, imipenem-cilastatin, vancomycin, and metronidazole. 3 patients that were under suspicion for developing GVHD (acute or chronic) but were not definitively diagnosed per chart review were excluded.

Results: A total of 137 adult AHSCT recipients were reviewed and 3 patients with an unclear diagnosis of GVHD were excluded. Of the patients evaluated, approximately 46% (n= 61) were female 54% were male (n= 73). The age range was between 21-74 (mean = 45, median = 47) and the most common underlying hematologic disorders included AML (43.2%), ALL (28.3%), myelofibrosis (8.2%), and CML (6.7%). The types of AHSCT were also evaluated with the majority of patients receiving allogeneic-related HLA matched transplantation (47%) followed by allogeneic-unrelated HLA matched transplantation (32%), and haploidentical transplantation (20%). Of the 134 AHSCT recipients, 52.2% of patients (n = 70) were noted to have developed GVHD that received antibiotics against obligate anaerobes within 30 days of AHSCT. 62% of patients in this group developed acute GVHD while 37% developed chronic GVHD, with the most common affected site being skin followed by liver and the gastrointestinal tract. The primary end-point was the incidence of GVHD in those that had been exposed to antibiotics against obligate anaerobes and a second end-point evaluated was the incidence of GVHD-related mortality. Though no statistically significant association was observed between the incidence of GVHD and antibiotic exposure, we found an increased incidence of GVHD-related mortality within 3 years of AHSCT in those who received antibiotics with significant activity against obligate anaerobes within 30 days of receiving AHSCT (35.4% in patients who received antibiotics with significant activity against obligate anaerobes vs. 7.69% in patients who received antibiotics with reduced activity against obligate anaerobes.) The relative risk of death in AHSCT patients who developed GVHD and received antibiotics against obligate anaerobes was found to be 4.61 (p =0.005) as compared with those who received antibiotics with reduced activity. Of note, 75% of the GVHD cases were acute.

Conclusions: Our results suggest that there might be a significant association between administration of antibiotics with increased activity against obligate anaerobes and GVHD-related mortality. Further research is warranted in order to better understand the relationship and to prevent GVHD-related deaths in AHSCT recipients.