Ruxolitinib Pharmacokinetics and Pharmacodynamics in Children with Acute and Chronic Graft-versus-Host Disease.

We evaluated the pharmacokinetics (PK) of oral ruxolitinib in children with steroid-refractory acute graft-versus-host disease (aGVHD) (age <12 years) and chronic GVHD (cGVHD) (age ≤18 years) using our published pediatric dosing. PK sampling was performed before and 2 hours after ruxolitinib administration in patients with established cGVHD. More extensive PK analyses were performed in patients with newly diagnosed aGVHD or cGVHD before and .5, 1, 2, 4, and 6 hours after ruxolitinib administration in patients weighing >10 kg and before, 3+, and 6+ hours in children weighing <10 kg. pSTAT1, pSTAT3, and pSTAT5 expression levels were measured on CD4+ and CD8+ T cells before and 2 hours after ruxolitinib administration as a pharmacodynamic marker of JAK/STAT inhibition. Thirteen patients were prospectively enrolled, including 8 with existing cGVHD (age 0 to ≤18 years), 4 with new-onset steroid-refractory aGVHD (age 0 to <12 years) and 1 with newly diagnosed steroid-refractory cGVHD. Great variability in PK was seen. Mean oral clearance (CL/F) was 7.76 ± 4.09 L/h (range, 3.1 to 15.3 L/h). The average elimination half-life was 2.32 ± 1.0 hours. Mean ruxolitinib clearance was higher in children age <2 years versus those age >2 years (12.1 ± 3.0 L/h versus 5.7 ± 2.8 L/h; P = .005) and was reduced with concurrent treatment with azoles and azithromycin. We saw a variable reduction in pSTAT1/3/5 expression on T cells at time of peak ruxolitinib absorption (2 hours after dosing). Children <10 kg had lower ruxolitinib exposure, possibly due to inherent increased drug clearance or variability in dosing methods, leading to decreased drug absorption.

A randomized phase 2 trial of oral vitamin A for graft-versus-host disease in children and young adults.

ABSTRACT: Vitamin A plays a key role in the maintenance of gastrointestinal homeostasis and promotes a tolerogenic phenotype in tissue resident macrophages. We conducted a prospective randomized double-blinded placebo-controlled clinical trial in which 80 recipients of hematopoietic stem cell transplantation (HSCT) were randomized 1:1 to receive pretransplant high-dose vitamin A or placebo. A single oral dose of vitamin A of 4000 IU/kg, maximum 250 000 IU was given before conditioning. The primary end point was incidence of acute graft-versus-host disease (GVHD) at day +100. In an intent-to-treat analysis, incidence of acute GVHD was 12.5% in the vitamin A arm and 20% in the placebo arm (P = .5). Incidence of acute gastrointestinal (GI) GVHD was 2.5% in the vitamin A arm (P = .09) and 12.5% in the placebo arm at day +180. Incidence of chronic GVHD was 5% in the vitamin A arm and 15% in the placebo arm (P = .02) at 1 year. In an "as treated" analysis, cumulative incidence of acute GI GVHD at day +180 was 0% and 12.5% in recipients of vitamin A and placebo, respectively (P = .02), and cumulative incidence of chronic GVHD was 2.7% and 15% in recipients of vitamin A and placebo, respectively (P = .01). The only possibly attributable toxicity was asymptomatic grade 3 hyperbilirubinemia in 1 recipient of vitamin A at day +30, which self-resolved. Absolute CCR9+ CD8+ effector memory T cells, reflecting gut T-cell trafficking, were lower in the vitamin A arm at day +30 after HSCT (P = .01). Levels of serum amyloid A-1, a vitamin A transport protein with proinflammatory effects, were lower in the vitamin A arm. The vitamin A arm had lower interleukin-6 (IL-6), IL-8, and suppressor of tumorigenicity 2 levels and likely a more favorable gut microbiome and short chain fatty acids. Pre-HSCT oral vitamin A is inexpensive, has low toxicity, and reduces GVHD. This trial was registered at www.ClinicalTrials.gov as NCT03202849.

Increased Body Mass Index Augments Endothelial Injury and Clinical Outcomes after Hematopoietic Stem Cell Transplantation.

Higher body mass index (BMI) is characterized as a chronic inflammatory state with endothelial dysfunction. Endothelial injury after allogeneic hematopoietic stem cell transplantation (allo-HSCT) puts patients at risk for such complications as transplantation-associated thrombotic microangiopathy (TA-TMA) and acute graft-versus-host-disease (aGVHD). To evaluate the impact of increased BMI on endothelial injury after allo-HSCT in pediatric and young adult patients, we conducted a retrospective cohort study evaluating 476 consecutive allo-HSCT children and young adult recipients age 0 to 20 years. Our analysis was subdivided based on distinct age categories (<2 years and 2 to 20 years). BMI was considered as a variable but was also expressed in standard deviations from the mean adjusted for age and sex (z-score), based on established criteria from the World Health Organization (age <2 years) and the Centers for Disease Control and Prevention (age 2 to 20 years) to account for differences associated with age. Primary endpoints included the incidences of TA-TMA and aGVHD. Increased BMI z-score was associated with TA-TMA after allo-HSCT in patients age <2 years (median, 18.1; IQR, 17 to 20; P = .006) and in patients age 2 to 20 years (median, 18.7; IQR, 16 to 21.9; P = .02). Higher BMI z-score correlated with TA-TMA risk in both age groups, with a BMI z-score of .9 in the younger cohort and .7 (IQR, -.4 to 1.6; P = .04) in the older cohort. Increased BMI z-score was associated with an increased risk of TA-TMA in a multivariate analysis of the entire cohort (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.05 to 1.37; P = .008). Multivariate analysis also demonstrated that patients with BMI in the 85th percentile or greater had an increased risk of developing TA-TMA compared to those with a lower BMI percentile (OR, 2.66; 95% CI, 1.62 to 4.32; P < .001). Baseline and day +7 ST2 levels were elevated in subjects with TA-TMA compared to those without TA-TMA in both age groups. Baseline sC5b-9 concentration was not correlated with BMI z-score, but sC5b-9 concentration was increased markedly by 7 days post-allo-HSCT in patients age <2 years who later developed TA-TMA compared to those who never developed TA-TMA (P = .001). The median BMI z-score was higher for patients with aGVHD compared to patients without aGVHD (.7 [range, -3.9 to 3.9] versus .2 [range, -7.8 to 5.4]; P = .03). We show that high BMI is associated with augmented risk of endothelial injury after HSCT, specifically TA-TMA. These data identify a high-risk population likely to benefit from early interventions to prevent endothelial injury and prompt treatment of established endothelial injury.

Intestinal permeability in patients undergoing stem cell transplantation correlates with systemic acute phase responses and dysbiosis.

Intestinal permeability may correlate with adverse outcomes during hematopoietic stem cell transplantation (HSCT), but longitudinal quantification with traditional oral mannitol and lactulose is not feasible in HSCT recipients because of mucositis and diarrhea. A modified lactulose:rhamnose (LR) assay is validated in children with environmental enteritis. Our study objective was to quantify peri-HSCT intestinal permeability changes using the modified LR assay. The LR assay was administered before transplant, at day +7 and +30 to 80 pediatric and young adult patients who received allogeneic HSCT. Lactulose and rhamnose were detected using urine mass spectrometry and expressed as an L:R ratio. Metagenomic shotgun sequencing of stool for microbiome analyses and enzyme-linked immunosorbent assay analyses of plasma lipopolysaccharide binding protein (LBP), ST2, REG3α, claudin1, occludin, and intestinal alkaline phosphatase were performed at the same timepoints. L:R ratios were increased at day +7 but returned to baseline at day +30 in most patients (P = .014). Conditioning regimen intensity did not affect the trajectory of L:R (P = .39). Baseline L:R ratios did not vary with diagnosis. L:R correlated with LBP levels (r2 = 0.208; P = .0014). High L:R ratios were associated with lower microbiome diversity (P = .035), loss of anaerobic organisms (P = .020), and higher plasma LBP (P = .0014). No adverse gastrointestinal effects occurred because of LR. Intestinal permeability as measured through L:R ratios after allogeneic HSCT correlates with intestinal dysbiosis and elevated plasma LBP. The LR assay is well-tolerated and may identify transplant recipients who are more likely to experience adverse outcomes.

Transcriptome analysis in acute gastrointestinal graft-versus host disease reveals a unique signature in children and shared biology with pediatric inflammatory bowel disease.

We performed transcriptomic analyses on freshly frozen (n=21) and paraffin-embedded (n=35) gastrointestinal (GI) biopsies from children with and without acute acute GI graft-versus-host disease (GvHD) to study differential gene expressions. We identified 164 significant genes, 141 upregulated and 23 downregulated, in acute GvHD from freshy frozen biopsies. CHI3L1 was the top differentially expressed gene in acute GvHD, involved in macrophage recruitment and bacterial adhesion. Mitochondrial genes were among the top downregulated genes. Immune deconvolution identified a macrophage cellular signature. Weighted gene co-expression network analysis showed enrichment of genes in the ERK1/2 cascade. Transcriptome data from 206 ulcerative colitis (UC) patients were included to uncover genes and pathways shared between GvHD and UC. Comparison with the UC transcriptome showed both shared and distinct pathways. Both UC and GvHD transcriptomes shared an innate antimicrobial signature and FCγ1RA/CD64 was upregulated in both acute GvHD (log-fold increase 1.7, P=0.001) and UC. Upregulation of the ERK1/2 cascade pathway was specific to GvHD. We performed additional experiments to confirm transcriptomics. Firstly, we examined phosphorylation of ERK (pERK) by immunohistochemistry on GI biopsies (acute GvHD n=10, no GvHD n=10). pERK staining was increased in acute GvHD biopsies compared to biopsies without acute GvHD (P=0.001). Secondly, plasma CD64, measured by enzyme-linked immunsorbant assay (n=85) was elevated in acute GI GvHD (P<0.001) compared with those without and was elevated in GVHD compared with inflammatory bowel disease (n=47) (P<0.001), confirming the upregulated expression seen in the transcriptome.

α4ß7 Integrin expression and blockade in pediatric and young adult gastrointestinal graft-versus-host disease.

BACKGROUND: We hypothesized that α4ß7 integrin expression on effector memory T cells (TEMs) would be elevated in pediatric hematopoietic stem cell transplant (HSCT) patients before and at diagnosis of acute gastrointestinal graft-versus-host disease (GI GVHD) symptoms compared to patients without GVHD, and that clinical blockade of α4ß7 integrin with vedolizumab would be effective in pediatric GI GVHD. METHODS: We analyzed surface expression of α4ß7 integrin on T cells from 48 pediatric allogeneic HSCT recipients from our biorepository with known clinical outcomes as follows: acute GI GVHD (n = 22), isolated skin GVHD (n = 12), and no GVHD (n = 14). T-cell analyses were performed 1 week before and at GVHD diagnosis in patients with GVHD, and day +30 after HSCT in patients without GVHD. We describe clinical outcomes of seven additional patients, different from above-described 48 patients, who received vedolizumab (anti-α4ß7 integrin antibody) for the treatment of steroid-refractory acute GI GVHD. RESULTS: Expression of α4ß7 integrin on CD8+ TEMs was upregulated in patients with GI GVHD compared to the no GI GVHD (skin GVHD + no GVHD) group 1 week prior to clinical symptoms (p = .02) and at acute GI GVHD diagnosis (p = .05). Four of seven treated patients with clinical steroid-refractory acute GI GVHD were evaluable for response to vedolizumab. One patient had a complete response at day +28, while two had a partial response, and one had no response. No adverse effects directly attributable to vedolizumab were observed. CONCLUSION: Our data suggest a rationale for the blockade of α4ß7 integrin for acute GI GVHD management in children.

Tryptophan metabolism is dysregulated in individuals with Fanconi anemia.

Fanconi anemia (FA) is a complex genetic disorder associated with progressive marrow failure and a strong predisposition to malignancy. FA is associated with metabolic disturbances such as short stature, insulin resistance, thyroid dysfunction, abnormal body mass index (BMI), and dyslipidemia. We studied tryptophan metabolism in FA by examining tryptophan and its metabolites before and during the stress of hematopoietic stem cell transplant (HSCT). Tryptophan is an essential amino acid that can be converted to serotonin and kynurenine. We report here that serotonin levels are markedly elevated 14 days after HSCT in individuals with FA, in contrast to individuals without FA. Kynurenine levels are significantly reduced in individuals with FA compared with individuals without FA, before and after HSCT. Most peripheral serotonin is made in the bowel. However, serotonin levels in stool decreased in individuals with FA after transplant, similar to individuals without FA. Instead, we detected serotonin production in the skin in individuals with FA, whereas none was seen in individuals without FA. As expected, serotonin and transforming growth factor ß (TGF-ß) levels were closely correlated with platelet count before and after HSCT in persons without FA. In FA, neither baseline serotonin nor TGF-B correlated with baseline platelet count (host-derived platelets), only TGF-B correlated 14 days after transplant (blood bank-derived platelets). BMI was negatively correlated with serotonin in individuals with FA, suggesting that hyperserotonemia may contribute to growth failure in FA. Serotonin is a potential therapeutic target, and currently available drugs might be beneficial in restoring metabolic balance in individuals with FA.

Endothelial injury, F-actin and vitamin-D binding protein after hematopoietic stem cell transplant and association with clinical outcomes.

Endothelial injury after hematopoietic stem cell transplant is an important initiating factor for early transplant toxicities of thrombotic microangiopathy and acute graft versus host disease. We hypothesized that release of the angiopathic molecule filamentous actin from hematopoietic cells lysed during conditioning prior to stem cell transplant would be associated with clinical outcomes. We detected filamentous actin in the blood of 52% of stem cell transplant recipients in the first 14 days after transplant, and children with detectable filamentous actin had significantly elevated risk of thrombotic microangiopathy (p= 0.03) and non-relapse mortality (p= 0.04). Filamentous actin is cleared from the circulation by vitamin D binding protein so we expected that higher levels of vitamin D binding protein would improve outcomes. In a cohort of 190 children receiving allogeneic transplant, risk of thrombotic microangiopathy was reduced in those with serum concentrations of vitamin D binding protein above the median at day 30 (10% vs 31%, p=0.01), and graft versus host disease and non-relapse mortality were reduced in those with levels above the median at day 100 (3% vs 18%, p=0.04 and 0% vs 15%, p=0.002). Western blot analyses demonstrated actin-vitamin D binding protein complexes in the blood, which cleared by day 21-28. Our data support modulation of cytokine secretion and macrophage phenotype by vitamin D binding protein later after transplant. Taken together, our data identify an association between filamentous-actin, a mediator of endothelial damage, and vitamin D binding protein, an actin scavenger, as modifiers of risk of clinical consequences of endothelial injury.

Chromosome fragility in the buccal epithelium in patients with Fanconi anemia.

Fanconi anemia (FA) is a rare genome instability syndrome characterized by progressive bone marrow failure and predisposition to cancer, especially head and neck squamous cell carcinoma. Surgical resection is the standard of care for solid tumors, as patients with FA do not tolerate genotoxic chemotherapies or radiation, leading to poor prognosis. It is therefore imperative to develop chemoprevention strategies such as the identification of novel biomarkers to detect the formation of the tumor before its emergence and to use them in clinical trials aimed to counteract genome instability of patients with FA in tissues at risk. Micronuclei (MN) are chromosome fragments that are left behind in anaphase and appear in daughter cells as small additional nuclei. In this work, we analyzed MN frequencies in exfoliated buccal cells from 40 patients with FA and 24 controls. We found that MN frequency was significantly increased in the FA cohort indicating that we can detect chromosome fragility in patients with FA in basal conditions and in a tissue that is divided in vivo. Consequently, the MN assay in exfoliated buccal cells of patients with FA could be used in cancer risk studies and clinical trials aimed to identify cancer chemopreventive drugs.

The Natural History of BK Polyomavirus and the Host Immune Response After Stem Cell Transplantation.

BACKGROUND: BK polyomavirus (BKPyV) is associated with symptomatic hemorrhagic cystitis after hematopoietic cell transplantation (HCT). Little is known about the host immune response, effectiveness of antiviral treatment, or impact of asymptomatic replication on long-term kidney function. METHODS: In children and young adults undergoing allogeneic HCT, we quantified BKPyV viruria and viremia (pre-HCT and at Months 1-4, 8, 12, and 24 post-HCT) and tested associations of peak viremia ≥10 000 or viruria ≥109 copies/mL with estimated kidney function (glomerular filtration rate, eGFR) and overall survival at 2 years posttransplant. We examined the factors associated with viral clearance by Month 4, including BKPyV-specific T cells by enzyme-linked immune absorbent spot at Month 3 and cidofovir use. RESULTS: We prospectively enrolled 193 participants (median age 10 years) and found that 18% had viremia ≥10 000 copies/mL and 45% had viruria ≥109 copies/mL in the first 3 months post-HCT. Among the 147 participants without cystitis (asymptomatic), 58 (40%) had any viremia. In the entire cohort and asymptomatic subset, having viremia ≥10 000 copies/mL was associated with a lower creatinine/cystatin C eGFR at 2 years post-HCT. Viremia ≥10 000 copies/mL was associated with a higher risk of death (adjusted hazard ratio, 2.2; 95% confidence interval, 1.1-4.2). Clearing viremia was associated with detectable BKPyV-specific T cells and having viremia <10 000 copies/mL, but not cidofovir exposure. CONCLUSIONS: Screening for BKPyV viremia after HCT identifies asymptomatic patients at risk for kidney disease and reduced survival. These data suggest potential changes to clinical practice, including prospective monitoring for BKPyV viremia to test virus-specific T cells to prevent or treat BKPyV replication.

A Pilot Study of Human Milk to Reduce Intestinal Inflammation After Bone Marrow Transplant.

OBJECTIVE: Human milk administration in the early peritransplant period would lower intestinal inflammation after bone marrow transplant (BMT). MATERIALS AND METHODS: Children 0-5 years undergoing BMT received either a ready-to-feed human milk preparation designed for these children (Prolacta Bioscience, Duarte, CA) or standard formula. Babies breastfeeding at the time of BMT were also enrolled on the human milk arm. Human milk was administered from day -3 until day +14 after BMT. Metagenomic shotgun sequencing and metabolomics of stool, plasma cytokines, and regenerating islet-derived 3α (REG3α) levels were measured at enrollment and day +14. Human leukocyte antigen-DR isotype (HLA-DR), CD38, and CD69 expression on T cells were evaluated at day +21. RESULTS: Forty-six children were enrolled, 32 received human milk (donor milk n = 23, breastfeeding babies n = 9), and 14 were controls who received standard feeds supervised by a BMT dietician. Twenty-four patients received at least 60% of goal human milk and were evaluable. Plasma interleukin (IL)-8 (p = 0.04), IL-10 (p = 0.02), and REG3α (p = 0.03) were decreased in the human milk cohort. Peripheral blood CD69+ CD8+ T cells were higher in controls (p = 0.01). Species abundance of Adenovirus (p = 0.00034), Escherichia coli (p = 0.0017), Cryptosporidium parvum (p = 0.0006), Dialister invisus (p = 0.01), and Pseudomonas aeruginosa (p = 0.05) from stool was higher in controls. Stool alanine, tyrosine, methionine, and the ratio of fecal alanine to choline and phosphocholine were higher in controls (p < 0.05). No difference was observed in stool propionate and butyrate levels as measures of short-chain fatty acids between the two cohorts. CONCLUSIONS: Administration of human milk resulted in decreased markers of intestinal inflammation and could be a valuable adjunct for patients after BMT.

A novel strategy for identifying early acute kidney injury in pediatric hematopoietic stem cell transplantation.

Acute kidney injury (AKI) is a common complication in pediatric hematopoietic stem cell transplantation (HSCT). Serum creatinine is an imprecise biomarker of AKI. We hypothesized that combining creatinine with serum cystatin C (cysC) and urinary neutrophil gelatinase-associated lipocalin (NGAL) more effectively characterizes AKI during the first 28 days of HSCT and better identifies patients at risk of adverse outcomes than creatinine alone. We prospectively assessed the type and severity of AKI in 80 consecutive allogeneic HSCT patients using weekly creatinine, cysC, and NGAL. We combined the biomarkers to define 7 Composite Types of AKI, including All Positive AKI (simultaneously detected creatinine, cysC, and NGAL AKI). Outcomes included renal replacement therapy and transplant-related mortality. In all, 75% of patients had AKI by at least one measure; 33% developed >1 type of AKI. Mild AKI often preceded Severe AKI. Patients with creatinine or NGAL AKI that were Severe or Repeated tended to have worse outcomes. The five patients with All Positive AKI had the highest rates of morbidity and mortality. AKI evaluation with creatinine, cysC, and NGAL provides a comprehensive profile of early AKI and narrowly identifies patients at highest risk of adverse outcomes, providing opportunities for early, impactful intervention.

Antibiotic Exposure and Reduced Short Chain Fatty Acid Production after Hematopoietic Stem Cell Transplant.

Human studies have shown loss of diversity of the gut microbiome following hematopoietic stem cell transplantation (HSCT) in association with significant gut injury caused by the preparative regimen. Prolonged antibiotic use worsens loss of microbiome diversity and increases risk of complications such as graft-versus-host disease (GVHD). Our data support the hypothesis that loss of intestinal commensals that produce short-chain fatty acids (SCFAs) may increase dysbiosis. Here, we report an extensive longitudinal examination of changes in the luminal SCFAs in children undergoing allogeneic HSCT, and the relationship of those changes to the microbiota and antibiotic exposure. We found significant and progressive alterations in butyrate, and in additional SCFAs in stool in the first 14 days after transplant, a finding not observed in published mouse studies. SCFA levels were lower in children receiving antibiotics with activity against anaerobic organisms. Moreover, day 14 post-HSCT butyrate and propionate levels are lower in children who went on to develop GVHD, although our disease population was small. These data provide insight into the mechanism of prior observations that loss of diversity and increased antibiotic use are associated with GVHD following HSCT. Our findings offer potential modifiable targets to reduce risk of GVHD and improve survival after HSCT.

Circulating dsDNA, endothelial injury, and complement activation in thrombotic microangiopathy and GVHD.

Transplant-associated thrombotic microangiopathy (TA-TMA) is a common and poorly recognized complication of hematopoietic stem cell transplantation (HSCT) associated with excessive complement activation, likely triggered by endothelial injury. An important missing piece is the link between endothelial injury and complement activation. We hypothesized that neutrophil extracellular traps (NETs) mechanistically link endothelial damage with complement activation and subsequent TA-TMA. Neutrophil activation releases granule proteins together with double-stranded DNA (dsDNA) to form extracellular fibers known as NETs. NETs have been shown to activate complement and can be assessed in humans by quantification of dsDNA in serum. We measured levels of dsDNA, as a surrogate for NETs in 103 consecutive pediatric allogeneic transplant recipients at day 0, +14, +30, +60, and +100. A spike in dsDNA production around day +14 during engraftment was associated with subsequent TA-TMA development. Peak dsDNA production around day +14 was associated with interleukin-8-driven neutrophil recovery. Increased dsDNA levels at days +30, +60, and +100 were also associated with increased mortality and gastrointestinal graft-versus-host disease (GVHD). NETs may serve as a mechanistic link between endothelial injury and complement activation. NET formation may be one mechanism contributing to the clinical overlap between GVHD and TA-TMA.

Lower levels of vitamin A are associated with increased gastrointestinal graft-versus-host disease in children.

Vitamin A promotes development of mucosal tolerance and enhances differentiation of regulatory T cells. Vitamin A deficiency impairs epithelial integrity, increasing intestinal permeability. We hypothesized that higher vitamin A levels would reduce the risk of graft-versus-host disease (GVHD) through reduced gastrointestinal (GI) permeability, reduced mucosal injury, and reduced lymphocyte homing to the gut. We tested this hypothesis in a cohort study of 114 consecutive patients undergoing allogeneic stem cell transplant. Free vitamin A levels were measured in plasma at day 30 posttransplant. GI GVHD was increased in patients with vitamin A levels below the median (38% vs 12.4% at 100 days, P = .0008), as was treatment-related mortality (17.7% vs 7.4% at 1 year, P = .03). Bloodstream infections were increased in patients with vitamin A levels below the median (24% vs 8% at 1 year, P = .03), supporting our hypothesis of increased intestinal permeability. The GI mucosal intestinal fatty acid-binding protein was decreased after transplant, confirming mucosal injury, but was not correlated with vitamin A levels, indicating that vitamin A did not protect against mucosal injury. Expression of the gut homing receptor CCR9 on T-effector memory cells 30 days after transplant was increased in children with vitamin A levels below the median (r = -0.34, P = .03). Taken together, these data support our hypothesis that low levels of vitamin A actively promote GI GVHD and are not simply a marker of poor nutritional status or a sicker patient. Vitamin A supplementation might improve transplant outcomes.

A Genetic Modifier of the Gut Microbiome Influences the Risk of Graft-versus-Host Disease and Bacteremia After Hematopoietic Stem Cell Transplantation.

The human gut microbiome is involved in vital biological functions, such as maintenance of immune homeostasis and modulation of intestinal development and enhanced metabolic capabilities. Disturbances of the intestinal microbiota have been associated with development and progression of inflammatory conditions, including graft-versus-host disease (GVHD). The fucosyltransferase 2 (FUT2) gene produces an enzyme that is responsible for the synthesis of the H antigen in body fluids and on the intestinal mucosa. FUT2 genotype has been shown to modify the gut microbiome. We hypothesized that FUT2 genotype influences risk of GVHD and bacterial translocation after allogeneic hematopoietic stem cell transplantation (HSCT). FUT2 genotype was determined in 150 consecutive patients receiving allogeneic HSCT at our center. We abstracted clinical characteristics and outcomes from the transplantation database. Cumulative risk of any acute GVHD varied by FUT2 genotype, with decreased risk in those with A/A genotype and increased risk in those with G/G genotype. In contrast, the cumulative incidence of bacteremia was increased in those with A/A genotype. We conclude that the FUT2 genotype influences risk of acute GVHD and bacteremia after HSCT. We hypothesize that the mechanisms involve altered intestinal surface glycosylation and microbial composition but this requires additional study.