Polymorphisms of genes involved in innate and adaptive immunity have become an object of major interest in regard to hematopoietic stem cell transplantation (HSCT) complications. Regimen-related gastrointestinal toxicity (RR-GIT) is the dominant complication during the pre-engraftment period and has been linked to increased risk of graft-versus-host disease (GVHD) development. According to our hypothesis, functional variants of genes participating in DNA damage response (DDR) may have an impact on the extent of tissue damage caused by the conditioning regimen. In our single-center study, we analyzed 62 patients who underwent HSCT from HLA-identical donors after reduced conditioning. The patients were genotyped for 5 single nucleotide polymorphisms (SNPs, rs4585 T/G, rs189037 A/G, rs227092 T/G, rs228590 C/T, and rs664677 T/C) of the ATM gene-the essential member of the DDR pathways, using allele-specific matrix-assisted laser desorption/ionization, time-of-flight (MALDI-TOF) mass spectrometry assay. Because of almost absolute linkage disequilibrium observed among all 5 SNPs, association of 2 major ATM haplotypes (ATM1/ATM2) with RR-GIT and acute GVHD (aGVHD) was analyzed. Importantly, the univariate and multivariate analysis showed that patients homozygous for ATM2 haplotype (rs4585*T, rs189037*A, rs227092*T, rs228590*C, and rs664677*T) are more likely to suffer from high-grade RR-GIT than ATM1 homozygous patients. The association with aGVHD was not significant. To our knowledge, this is the first report showing the ATM gene variability in relation to RR-GIT in the allogeneic HSCT setting.

• Klíčová slova
• ATM gene, Acute graft-versus-host disease, Allogeneic hematopoietic stem cell transplantation, Gastrointestinal toxicity, Single-nucleotide polymorphism,
• MeSH
• akutní nemoc MeSH
• alely MeSH
• analýza přežití MeSH
• ATM protein genetika   imunologie   MeSH
• dárci tkání MeSH
• dospělí MeSH
• exprese genu MeSH
• frekvence genu MeSH
• gastrointestinální trakt účinky léků   imunologie   patologie   MeSH
• haplotypy MeSH
• hematologické nádory genetika   imunologie   mortalita   terapie   MeSH
• homologní transplantace MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• myeloablativní agonisté aplikace a dávkování   škodlivé účinky   MeSH
• nemoc štěpu proti hostiteli genetika   imunologie   mortalita   MeSH
• příprava pacienta k transplantaci metody   MeSH
• prognóza MeSH
• prospektivní studie MeSH
• protein - isoformy genetika   imunologie   MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ATM protein, human MeSH Prohlížeč
• ATM protein MeSH
• myeloablativní agonisté MeSH
• protein - isoformy MeSH

BACKGROUND: Series of observations indicate PK/PD variability challenging the accuracy of the body-weight based busulfan (Bu) dosing schedule for (HSCT) conditioning therapy. The purpose of this communication is to describe the frequency of dose changes in initially body-weight-based fixed IV Bu dose and to emphasize the importance of TDM. MATERIAL AND METHODS: Sixty-two children (ages 2 months-18 years) were treated with IV busulfan doses based on body weight for myeloablation. TDM utilizing a limited sample strategy (trough concentration immediately before the 5th dose, followed by samples immediately after the end of the 2-h infusion peak, 4 h, and 6 h from initiation of the infusion) was performed in 46 of 62 subjects. Busulfan concentrations were determined by high-performance liquid chromatography (HPLC). AUC was calculated according to the trapezoidal rule. RESULTS: We observed trough levels of 25-1244 µg/L, peak levels of 849-4586 µg/L, and AUC of 2225-12818 µg/L·h following body weight-based high-dose busulfan. The doses were changed in 54% of cases. AUC in 5 of 9 patients with VOD were within target, in 3 patients AUS was higher, and in 1 patient AUC was lower. One of the 2 patients with neurotoxicity had higher AUC. Engraftment was 100%, but relapse occurred in 25% of cases. CONCLUSIONS: Our results demonstrate that even with IV busulfan, intra-individual PK/PD variability is challenging. Although AUC does not necessarily correspond with outcomes (due to the role of other factors the fact that doses were changed in 54% of cases underlines the importance of TDM.

• MeSH
• adjuvancia imunologická aplikace a dávkování   MeSH
• busulfan aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• dítě MeSH
• dithiokarb aplikace a dávkování   MeSH
• intravenózní infuze MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• monitorování léčiv metody   MeSH
• myeloablativní agonisté aplikace a dávkování   škodlivé účinky   farmakokinetika   MeSH
• předškolní dítě MeSH
• příprava pacienta k transplantaci škodlivé účinky   metody   MeSH
• tělesná hmotnost MeSH
• transplantace hematopoetických kmenových buněk metody   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• předškolní dítě MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adjuvancia imunologická MeSH
• busulfan MeSH
• dithiokarb MeSH
• myeloablativní agonisté MeSH

AIMS: This study compares the outcomes of patients with high-risk acute myeloid leukemia (AML) who underwent allogeneic stem cell transplantation (SCT) after conditioning combining busulfan (16 mg/kg orally) and cyclophosphamide (120 mg/kg intravenously) (BU-CY) with those allografted after administration of fludarabine (150 mg/m(2) intravenously), busulfan (12 mg/kg orally) and thymoglobulin (6 mg/kg intravenously) (FLU-BU12-TG). MATERIAL AND METHODS: SCT after BU-CY and FLU-BU12-TG was performed in 21 and 10 AML patients. There were no significant differences between groups in number of patients treated in complete disease remission, gender, age, donors, CD34+, mononuclear cell (MNC) count in the graft and follow-up period. However, significantly more SCTs from unrelated (90% vs. 19%; p=0.00018) and HLA-mismatched donors (50% vs. 0%; p=0.0004) were performed in the FLU-BU12-TG group. The Cox proportional hazards model was used to assess the risk of post-transplant AML relapse and non-relapse mortality (NRM). The probability of post-transplant 2-year event-free survival (EFS) and overall survival (OS) were calculated using the Kaplan-Meier method. RESULTS: No significant differences were found between the FLU-BU12-TG and BU-CY groups in risk of AML relapse (HR=1.036; 95% CI [0.102 - 10.47]; p=0.9), post-transplant NRM (HR=0.25; 95% CI [0.031 - 1.96]; p=0.18), 2-year EFS (89% vs. 43%; p=0.19) or OS (79% vs. 57%; p=0.23). CONCLUSION: These pilot results demonstrate the efficacy of the new FLU-BU12-TG conditioning regimen in patients allografted for high-risk AML. This conditioning might become an alternative approach in patients at high risk of severe post-transplant complications after the standard BU-CY myeloablative regimen.

• MeSH
• akutní myeloidní leukemie mortalita   terapie   MeSH
• antilymfocytární sérum aplikace a dávkování   škodlivé účinky   MeSH
• busulfan aplikace a dávkování   škodlivé účinky   MeSH
• cyklofosfamid aplikace a dávkování   škodlivé účinky   MeSH
• dospělí MeSH
• homologní transplantace MeSH
• imunosupresiva aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• mladý dospělý MeSH
• myeloablativní agonisté aplikace a dávkování   škodlivé účinky   MeSH
• nemoc štěpu proti hostiteli etiologie   MeSH
• přežití bez známek nemoci MeSH
• příprava pacienta k transplantaci * MeSH
• recidiva MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• vidarabin aplikace a dávkování   škodlivé účinky   analogy a deriváty   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• antilymfocytární sérum MeSH
• busulfan MeSH
• cyklofosfamid MeSH
• fludarabine MeSH Prohlížeč
• imunosupresiva MeSH
• myeloablativní agonisté MeSH
• thymoglobulin MeSH Prohlížeč
• vidarabin MeSH

Cardiac toxicity of preparative regimen (PR) containing high-dose Cyclophosphamide (120 mg/kg) followed by hematopoietic cell transplantation (HCT) was evaluated with 6 biomarkers of cardiac injury: N-terminal pro brain natriuretic peptide (NT-proBNP), creatine kinase MB (CK-MB mass), cardiac troponins (cTnT, cTnI), heart-type fatty acid binding protein (H-FABP), glycogen phosphorylase BB (GPBB). Twenty-three patients (mean age 44.5+/-10.6 years, 15 males) with acute leukemia were studied. All biomarkers were measured the day before PR, the day after PR, the day after HCT and 14 days after HCT. We found NT-proBNP elevations above 500 ng/L in 6 (26.1 %) patients after PR, in 9 (39.1 %) after HCT and in 7 (30.4 %) 14 days after HCT. GPBB became elevated (above 7.30 microg/L) in 5 (21.7 %) patients after PR, remained elevated in 5 (21.7 %) after HCT and in 2 (8.7 %) 14 days after HCT. A significant correlation between elevation in NT-proBNP and GPBB was found. Other markers remained within the reference range early after PR and HCT. Our findings show that administration of PR and HCT for acute leukemia is associated with acute neurohumoral activation of cardiac dysfunction (significant rise in NT-proBNP) and may lead to GPBB elevation. These changes could indicate acute cardiac toxicity due to treatment and require further follow-up. The predictive value for development of cardiomyopathy in the future is unclear. Further studies will be needed to define the potential role of new biomarkers in this context.

• MeSH
• akutní nemoc MeSH
• biologické markery analýza   MeSH
• cyklofosfamid škodlivé účinky   MeSH
• dospělí MeSH
• leukemie terapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• myeloablativní agonisté škodlivé účinky   MeSH
• nemoci srdce chemicky indukované   diagnóza   terapie   MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• biologické markery MeSH
• cyklofosfamid MeSH
• myeloablativní agonisté MeSH

INTRODUCTION: Cardiotoxicity is a relatively frequent and potentially serious complication of antitumor treatment. Anthracyclines and other high-dose chemotherapy represent the greatest risk. The aim of the study was to assess cardiotoxicity during preparative regimen (PR) and hematopoietic cell transplantation (HCT) in acute leukemia (AL) with biochemical markers - "N-terminal pro brain natriuretic peptide" (NT-proBNP), cardiac troponin T (cTnT) and creatine kinase MB (CK-MB mass). METHODS: Nineteen adult AL patients previously treated with anthracyclines--idarubicine, daunorubicine, mitoxantrone with standard doses for a cycle as 3 x 12 mg/m(2), 3 x 50 mg/m(2), 3 x 10 mg/m(2) accordingly were studied. PR consisted of high-dose cyclophosphamide (HD-C) in combination with busulphan or total body irradiation (TBI). Plasma NT-proBNP, cTnT and CK-MB mass concentrations were measured the day before PR, the day after PR, the day after HCT and 14 days after HCT. RESULTS: Before PR, mean plasma NT-proBNP value was 106.3+/-55.7 ng/l. After PR, it increased to 426.1+/-391.5 ng/l. After HCT, a further increase to 847.6+/-780.6 ng/l was observed. Fourteen days after HCT, the mean NT-proBNP was 330.8+/-236.8 ng/l. The differences were statistically significant in comparison with the baseline values (p<0.01). The NT-proBNP elevations were more pronounced in patients with cumulative doses (CD) of anthracyclines above 450 mg/m(2) (p<0.05), in patients with PR containing HD-C and TBI (p<0.05). In all patients, plasma cTnT and CK-MB mass concentrations remained unchangable during PR and HCT. CONCLUSION: Our results suggest that administration of PR and HCT is in most AL patients associated with acute neurohumoral activation (significant rise in NT-proBNP). Persistent NT-proBNP elevations, in our study in 12 (63.2%) patients, indicate subclinical cardiotoxicity (risk for development of heart failure) and require further follow-up. More pronounced NT-proBNP elevations in patients with higher CD of anthracyclines and in patients with PR containing combination of HD-C and TBI confirm that these therapeutic procedures seem to be more cardiotoxic and not very appropriate for patients with cumulation of risk factors for cardiotoxicity. Negative plasma cTnT and CK-MB mass concentrations show no detectable damage of cardiomyocyte structure during PR and HCT.

• MeSH
• akutní nemoc MeSH
• antracykliny škodlivé účinky   MeSH
• biologické markery krev   MeSH
• dospělí MeSH
• echokardiografie MeSH
• kreatinkinasa, forma MB krev   MeSH
• leukemie terapie   MeSH
• lidé MeSH
• myeloablativní agonisté škodlivé účinky   MeSH
• natriuretický peptid typu B krev   MeSH
• nemoci srdce chemicky indukované   MeSH
• peptidové fragmenty krev   MeSH
• transplantace hematopoetických kmenových buněk škodlivé účinky   MeSH
• troponin T krev   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antracykliny MeSH
• biologické markery MeSH
• kreatinkinasa, forma MB MeSH
• myeloablativní agonisté MeSH
• natriuretický peptid typu B MeSH
• peptidové fragmenty MeSH
• pro-brain natriuretic peptide (1-76) MeSH Prohlížeč
• troponin T MeSH