Liver toxicity is frequently seen in relation to allogeneic hematopoietic stem cell transplantation (HSCT), but pathogenesis and the risk factors are poorly understood. The purpose of this study was to investigate associations between liver toxicity, gastrointestinal toxicity, and levels of immune-regulating cytokines during the early post-transplantation period. We prospectively included 81 children and adults undergoing HSCT after myeloablative conditioning. Alanine aminotransferase (ALT), total bilirubin levels, and international normalized ratio were measured longitudinally until 3 months after the transplantation and related to levels of inflammatory markers (C-reactive protein [CRP], IL-6, and IL-10) and to plasma citrulline as a marker of intestinal toxicity during the first 3 weeks after HSCT. The majority of patients experienced ALT levels above the normal range (45 U/L) with significant increases at 3 months after HSCT. Increased levels of total bilirubin were observed in 26% during the 3-month period. Citrulline levels decreased significantly to a nadir at day 7 (B = .23; 95% confidence interval [CI], .12 to .35; P < .0001), but citrulline levels at nadir were not associated with parameters of liver toxicity. However, a faster reconstitution of mucosa with higher citrulline levels at day +21 correlated with lower bilirubin levels 3 months after HSCT (r = -.26, P = .034) and increased overall survival (hazard ratio, .88; 95% CI, .79 to .97; P = .008) . Increased levels of CRP and IL-6 at day 7 after HSCT correlated positively with ALT and bilirubin, and in the multivariate analysis, IL-6 at day 7 appeared to be the only predicting risk factor for increased mean bilirubin during the early post-transplantation phase (B = .01; 95% CI, .01 to .02; P = .001) as well as maximum levels of bilirubin (B = .3; 95% CI, .12 to .48; P= .001) and occurrence of sinusoidal obstruction syndrome during the first 3 months after HSCT (odds ratio,  1.003; 95% CI, 1.001 to 1.005; P = .002). The results of this study indicate that liver toxicity after HSCT is associated with an increased inflammatory response mounted during the phase of maximal gastrointestinal toxicity in the early phase after transplantation.

Allogeneic myeloablative haematopoietic stem cell transplantation (HSCT) is challenged by severe adverse events, as cytotoxic effects of the conditioning may result in systemic inflammation, leaky epithelial barriers and organ toxicities, contributing to treatment-related morbidity and mortality. We hypothesised that insulin-like growth factor-1 (IGF-1), a mediator of growth and proliferation of various tissues, may attenuate chemotherapy-induced tissue damage after HSCT. We prospectively measured plasma levels of IGF-1 and its binding protein 3 (IGFBP-3) in 41 patients undergoing myeloablative HSCT. IGF-1 and IGFBP-3 levels were inversely correlated with C-reactive protein and interleukin-6 levels post HSCT. In multivariate analyses, low levels of IGF-1 and IGFBP-3 before conditioning were associated with increased risk of developing sinusoidal obstruction syndrome (SOS; OR=5.00 per 1 SDS decrease in IGF-1 (95% CI: 1.45-16.67), P=0.011 and OR=5.00 (1.37-20.00), P=0.015, respectively). Furthermore, low pre-transplant levels of IGF-1 and IGFBP-3 were associated with increased fluid retention during the first 21 days post transplant (OR=7.69 (95% CI: 1.59-33.33), P=0.012, and OR=2.94 (1.03-8.33), P=0.045). These data suggest that high levels of IGF-1 and IGFBP-3 may have a protective effect against fluid retention and SOS, possibly by attenuating systemic inflammation, and may prove useful as predictive biomarkers of SOS.

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Chemotherapy‐induced mucositis increases the risk of blood stream infections (BSI) due to translocation of bacteria across the intestinal epithelium. Our study investigated if quantitative measures of intestinal mucositis severity, including plasma citrulline (a marker of functional enterocytes) and CCL20 (an intestinal immune homeostatic chemokine), could identify patients at risk of BSI. A total of 106 children with ALL undergoing induction treatment (NOPHO ALL 2008) were included and information regarding BSI episodes was collected from the patients' medical records. Twenty‐seven patients (25%) developed BSI during induction. Patients with BSI had a larger decrease in citrulline after chemotherapy than patients without BSI, and nearly all BSI episodes (25/27) occurred in the group of patients exhibiting a drop in citrulline (OR = 6.4 [95% CI: 1.4‐29.3], P = .008). Patients who developed BSI had higher plasma CCL20 levels on days 8, 15 and 22 than patients without BSI (all P < .05), and elevated CCL20 levels on day 8 increased the risk of subsequent BSI (OR = 1.57 [1.11‐2.22] per doubling of CCL20 level, P = .01) in a multivariable logistic regression analysis. These findings suggest that children with ALL who develop BSI during chemotherapy are characterised by more severe intestinal mucositis, as measured by plasma citrulline and CCL20. These markers may be useful in early risk stratification to guide treatment decisions.