Glucagon-Like Peptide-1 Is Associated With Systemic Inflammation in Pediatric Patients Treated With Hematopoietic Stem Cell Transplantation.

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are challenged with severe side effects, which are propagated by mucosal barrier disruption, and the related microbial translocation and systemic inflammation. Glucagon-like peptide-1 (GLP-1), a well-known incretin hormone, possesses anti-inflammatory properties and promotes regeneration of damaged intestinal epithelium in animal studies. We hypothesized that the immense inter-individual variation in the degree of mucosal damage and systemic inflammation, seen after HSCT is influenced by endogenous GLP-1 and could be related to acute post-transplant complications. In this prospective study we measured serial weekly fasting plasma GLP-1, along with C-reactive protein (CRP), and citrulline in 82 pediatric patients during allogeneic HSCT together with a fasting plasma GLP-1 in sex- and age-matched healthy controls. Overall, GLP-1 levels were increased in the patients during the course of HSCT compared with the controls, but tended to decrease post-transplant, most pronounced in patients receiving high-intensity conditioning regimen. The increase in CRP seen in the early post-transplant phase was significantly lower from day +8 to +13 in patients with GLP-1 above the upper quartile (>10 pmol/L) at day 0 (all P ≤ 0.03). Similar findings were seen for peak CRP levels after adjusting for type of conditioning (-47.0%; 95% CI, -8.1 - -69.4%, P = 0.02). Citrulline declined significantly following the transplantation illustrating a decrease in viable enterocytes, most evident in patients receiving high-intensity conditioning regimen. GLP-1 levels at day 0 associated with the recovery rate of citrulline from day 0 to +21 (34 percentage points (pp)/GLP-1 doubling; 95% CI, 10 - 58pp; P = 0. 008) and day 0 to day +90 (48 pp/GLP-1 doubling; 95% CI, 17 - 79pp; P = 0. 004), also after adjustment for type of conditioning. This translated into a reduced risk of acute graft-versus-host disease (aGvHD) in patients with highest day 0 GLP-1 levels (>10 pmol/L) (cause-specific HR: 0.3; 95% CI, 0.2 - 0.9, P = 0.02). In conclusion, this study strongly suggests that GLP-1 influences regeneration of injured epithelial barriers and ameliorates inflammatory responses in the early post-transplant phase.

Insulin-like growth factor-I predicts sinusoidal obstruction syndrome following pediatric hematopoietic stem cell transplantation.

Sinusoidal obstruction syndrome (SOS) is a potentially fatal complication of hematopoietic stem cell transplantation (HSCT) initiated through damage of sinusoidal endothelium and inflammation. Insulin-like growth factor-l (IGF-l) maintains and repairs endothelium and intestinal mucosa. We hypothesized that low IGF-l levels may increase the risk of inflammatory complications, such as SOS, in HSCT-patients. We prospectively measured IGF-l concentrations in 121 pediatric patients before, during, and after allogeneic HSCT. Overall, IGF-l levels were significantly reduced compared with healthy sex- and age-matched children. IGF-I levels pre-HSCT and at day 0 were inversely associated with C-reactive protein levels, hyperbilirubinemia, and number of platelet transfusions within the first 21 days post-transplant. Low levels of IGF-I before conditioning and at day of transplant were associated with increased risk of SOS diagnosed by the modified Seattle criteria (pre-HSCT: OR = 1.7 (95% CI: 1.2-2.6, p = 0.01), and the pediatric EBMT criteria (pre-HSCT: 1.7 (1.2-2.5, p = 0.009) and day 0: 1.7 (1.3-2.5, p = 0.001)/SDS decrease in IGF-1). These data suggest that IGF-I is protective against cytotoxic damage and SOS, most likely through trophic effects on endothelial cells and anti-inflammatory properties, and may prove useful as a predictive biomarker of SOS.

Insulin-Like Growth Factor Gene Polymorphisms Predict Clinical Course in Allogeneic Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) is challenged by significant toxicities that are propagated by systemic inflammation caused by cytotoxic damage. Insulin-like growth factor-1 (IGF-1) is key in repair of most tissues and is to a large extent genetically determined. We investigated eight single nucleotide polymorphisms (SNPs) in the genes encoding IGF-1 and its binding protein (IGFBP3) in 543 patients undergoing HSCT to access their impact on systemic inflammation and clinical outcomes. Overall, median serum levels of both IGF-1 and IGFBP3 were found reduced from the referral until 2 years post-HSCT compared with healthy sex- and age-matched individuals, but, for individuals homozygous of the known high-producer minor allele of rs1520220 (IGF1), rs978458 (IGF1), or rs2854744 (IGFBP3) serum levels remained normal during the whole period. In accordance, maximum C-reactive protein levels were lower for these genotypes of IGF1 (rs1520220: median 66 vs. 102 mg/L, P = 0.005 and rs978458: 53 vs. 104 mg/L, P < 0.001), translating into borderline significant superior survival (P = 0.060 for rs1520220) and reduced treatment-related mortality (P = 0.050 for rs978458). In conclusion, we found that three SNPs in the IGF-1 axis with known functional impact were associated with circulating IGF-1 or IGFBP-3 levels also in the setting of HSCT, and predictive of the severity of the toxic-inflammatory response during the treatment.

Glucagon-Like Peptide-1 Is a Marker of Systemic Inflammation in Patients Treated with High-Dose Chemotherapy and Autologous Stem Cell Transplantation.

Autologous stem cell transplantation (ASCT) is challenged by side effects that may be propagated by chemotherapy-induced mucositis, resulting in bacterial translocation and systemic inflammation. Because gastrointestinal damage appears as an early event in this cascade of reactions, we hypothesized that markers reflecting damage to the intestinal barrier could serve as early predictive markers of toxicity. Glucagon-like peptide-1 (GLP-1), a well-known regulator of blood glucose, has been found to promote intestinal growth and repair in animal studies. We investigated fasting GLP-1 plasma levels in 66 adults undergoing ASCT for lymphoma and multiple myeloma. GLP-1 increased significantly after chemotherapy, reaching peak levels at day +7 post-transplant (median, 8 pmol/L [interquartile range, 4 to 12] before conditioning versus 10 pmol/L [interquartile range, 6 to 17] at day +7; P = .007). The magnitude of the GLP-1 increase was related to the intensity of conditioning. GLP-1 at the day of transplantation (day 0) was positively associated with peak C-reactive protein (CRP) levels (46 mg/L per GLP-1 doubling, P < .001) and increase in days with fever (32% per GLP-1 doubling, P = .0058). Patients with GLP-1 above the median at day 0 had higher CRP levels from days +3 to +10 post-transplant than patients with lower GLP-1 (P ≤ .041) with peak values of 238 versus 129 mg/L, respectively. This study, which represents the first clinical investigation of fasting GLP-1 in relation to high-dose chemotherapy, provides evidence that GLP-1 plays a role in regulation of mucosal defenses. Fasting GLP-1 levels may serve as an early predictor of systemic inflammation and fever in patients receiving high-dose chemotherapy.

Role of TPMT and ITPA variants in mercaptopurine disposition.

PURPOSE: To explore the levels of thioguanine incorporated into DNA (DNA-TG), and erythrocyte levels of 6-thioguanine nucleotides (Ery-TGN) and methylated metabolites (Ery-MeMP) during 6-mercaptopurine (6MP)/Methotrexate (MTX) therapy of childhood acute lymphoblastic leukemia (ALL) and the relation to inosine triphosphatase (ITPA) and thiopurine methyltransferase (TPMT) gene variants. METHODS: Blood samples were drawn during 6MP/MTX maintenance therapy from 132 children treated for ALL at Rigshospitalet, Copenhagen. The samples were analysed for thiopurine metabolites and compared to TPMT (rs1800460 and rs1142345) and ITPA (rs1127354) genotypes. RESULTS: Median DNA-TG (mDNA-TG) levels were higher in TPMT and ITPA low-activity patients as compared to wildtype patients (TPMTLA 549 vs. 364 fmol/µg DNA, p = 0.007, ITPALA 465 vs. 387 fmol/µg DNA, p = 0.04). mDNA-TG levels were positively correlated to median Ery-TGN (mEry-TGN)(rs = 0.37, p = 0.001), but plateaued at higher mEry-TGN levels. DNA-TG indices (mDNA-TG/mEry-TGN) were 42% higher in TPMTWT patients as compared to TPMTLA patients but no difference in DNA-TG indices was observed between ITPAWT and ITPALA patients (median 1.7 vs. 1.6 fmol/µg DNA/ nmol/mmol Hb, p = 0.81). DNA-TG indices increased with median Ery-MeMP (mEry-MeMP) levels (rs = 0.25, p = 0.001). CONCLUSIONS: TPMT and ITPA genotypes significantly influence the metabolism of 6MP. DNA-TG may prove to be a more relevant pharmacokinetic parameter for monitoring 6MP treatment intensity than cytosolic metabolites. Prospective trials are needed to evaluate the usefulness of DNA-TGN for individual dose adjustments in childhood ALL maintenance therapy.

Hepatotoxicity During Maintenance Therapy and Prognosis in Children With Acute Lymphoblastic Leukemia.

Hepatotoxicity is a known toxicity to treatment of childhood acute lymphoblastic leukemia. Hepatotoxicity occurs during maintenance therapy and is caused by metabolites of 6-Mercaptopurine (6 MP) and Methotrexate (MTX). Our objective was to investigate the association between alanine aminotransferases (ALAT) levels and relapse rate. We included 385 patients enrolled in the NOPHO ALL-92 protocol. Data on ALAT levels, 6 MP and MTX doses, cytotoxic MTX/6 MP metabolites, and thiopurine methyltransferase (TPMT) activity were prospectively registered. In total, 91% of the patients had a mean ALAT (mALAT) level above upper normal limit (40 IU/L) and ALAT levels were positively correlated to 6 MP doses (rs=0.31; P<0.001). In total, 47 patients suffered a relapse, no difference in mALAT levels were found in these compared with nonrelapse patients (median, 107 vs. 98 IU/L; P=0.39). mALAT levels in patients classified as TPMT high activity (TPMT) were higher than in TPMT low-activity patients (median, 103 vs. 82 IU/L; P=0.03). In a Cox regression model risk of relapse was not associated with ALAT levels (P=0.56). ALAT levels increased 2.7%/month during the last year of maintenance therapy (P<0.001). In conclusion, elevated ALAT levels are associated with TPMT and may indicate treatment adherence in these patients. If liver function is normal, elevated ALAT levels should not indicate treatment adaptation.