The influence of gut-decontamination prophylactic antibiotics on acute graft-versus-host disease and survival following allogeneic hematopoietic stem cell transplantation

Abstract

The intestinal microbiota plays a key role in the pathogenesis of acute graft-versus-host disease (aGVHD). High-dose conditioning regimens given prior to allogeneic hematopoietic stem cell transplantation (aHSCT) modulate the composition of gut microbiota and damage the gut epithelial barrier, resulting in increased systemic inflammation. We assessed whether gut decontamination with antibiotics (ATB) prior to aHSCT influenced the frequency of aGVHD and mortality in 500 patients from two Canadian centers between 2005 and 2012. The rate of grade II-IV aGVHD was higher in the ATB arm compared with the arm without ATB (42% vs 28%; p < 0.001). This difference was mainly driven by a 2-fold higher rate of grade II-IV gastrointestinal aGVHD (GI-GVHD) in the ATB arm compared with the arm without ATB (20.7% vs 10.8%; p = 0.003). Multivariate analyses adjusted for known aGVHD risk factors revealed that more patients in the ATB group developed clinically significant GI-GVHD and liver aGVHD; adjusted odds ratio (aOR) = 1.83; p = 0.023 and aOR = 3.56; p = 0.047, respectively. Importantly, median overall survival (OS) was significantly lower in the group receiving ATB and the OS at 10 y remained decreased in the ATB group; adjusted hazard ratio (aHR) = 1.61 (p < 0.001). Without undermining the role of ATB prophylaxis to prevent infection in aHSCT, we have shown that the use of ATB that targets intestinal bacteria is associated with a more severe aGVHD that involves the GI organs and impacts OS. Prospective studies that evaluate the contribution of bacterial decontamination to aGVHD are warranted.

Keywords: Acute graft-versus-host disease; allogeneic hematopoietic stem cell transplantation; antibiotics; gut decontamination; microbiota.

Figure 1.

Incidence of aGVHD and sub-types in patients in the ATB and no ATB groups. (A) Percentage of patients that developed Stage 0–I vs II–IV aGVHD in the ATB and no ATB groups. (B) Percentage of patients that developped each stage of aGVHD in both groups. (C–E) Percentage of aGVHD sub-types in patients receiving or no ATB for gastrointestinal-aGVHD, liver-aGVHD, and skin-aGVHD, respectively. Raw p values are shown based on comparaison of aGVHD incidence using a ordinal regression based on the aGVHD stage. aGVHD: acute graft-versus-host disease, ATB: antibiotics; *p < 0.05, **p < 0.01,***p < 0.001, ns = not significant.

Figure 2.

Forest plots demontrating the impact of antibiotics in aGVHD after multivariable analysis. (A) Association of incidence of GI-GVHD with demographic and clinical parameters. Measurement of the odds ratio of patients developing GI-aGVHD comparing patients that received ATB or not ATB. After adjusting for the clinical parameters, patients on ATB develop more severe GI-aGVHD compared with the no ATB group. (B) Forest plot for liver-aGVHD, aOR was higher in the ATB group and they experienced more liver-aGVHD. Odds ratios are presented adjusting for all relevant clinical parameters, than the one tested. Confidence intervals is censored at 1/10 and 10. Raw p values are provided. aGVHD: acute graft-versus-host disease, GI: gastrointestinal, ATB: antibiotics, CI: confidence interbal, OR:odds ratio, aOR: adjusted odds ratio, Flu-CY: fludarabine–cyclophosphamide, Bu-Cy: busulfan–cyclophosphamide, Cy-TBI: cyclophosphamide–total body irradiation, Flu-Bu: fludarabine–busulfan, Flu-Mel: fludarabine– melphalan, Cat-Bu: cyclophosphamide–cytarabine–topotecan–busulfan; *p < 0.05, **p < 0.01,***p < 0.001, ns = not significant.

Figure 3.

Antibiotics given to patients pre-aHSCT worsen overall survival. (A) Survival analysis by Kaplan–Meier curves of all aHSCT patients either in the ATB or no ATB group. Day 0 was the day of stem cell infusion. The OS was reduced in patient receiving ATB before their transplant at 1 y, 2 y, and 10 y. (B) Survival analysis by Kaplan–Meier cruves of patients that undergone a myeloablative aHSCT and either received or not ATB before the transplant. OS was reduced in the ATB group at 1 y and 2 y. Log-rank (Mantel–Cox); *p < 0.05, **p < 0.01,***p < 0.001, ns = not significant.

Figure 4.

Decrease overall survival in patients on ATB after multvariable analysis. (A) Forest plot analysis on overall survival assessing the role of each clinical parameters and the influence of ATB on HR and aHR. ATB pre-aHSCT lead to a higher aHR compared with the no ATB group. For each comparison, HR were adjusted for all other clinical parameters, confidence intervals were censored at 1/3 and 5. aGVHD: acute graft-versus-host disease, ATB: antibiotics, CI: confidence interbal, HR: hazard ratio, aHR: adjusted hazard ratio, Flu-CY: fludarabine–cyclophosphamide, Bu-Cy: busulfan–cyclophosphamide, Cy-TBI: cyclophosphamide–total body irradiation, Flu-Bu: fludarabine–busulfan, Flu-Mel: fludarabine–melphalan, Cat-Bu: cyclophosphamide–cytarabine–topotecan–busulfan; *p < 0.05, **p < 0.01,***p < 0.001, ns = not significant.