ABSTRACT
Treosulfan-based conditioning is increasingly employed in paediatric haematopoietic stem cell transplantation (HSCT). Data on treosulfan pharmacokinetics in children are scarce, and the relationship between treosulfan exposure, toxicity and clinical outcome is unresolved. In this multicentre prospective observational study, we studied treosulfan pharmacokinetics and the drug's relationship with regimen-related toxicity and early clinical outcome in 77 paediatric patients. Treosulfan dose was 30 g/m2 , administered over 3 consecutive days in infants <1 year old (n = 12) and 42 g/m2 in children ≥1 year old (n = 65). Mean day 1 treosulfan exposure was 1744 ± 795 mg*h/l (10 g/m2 ) and 1561 ± 511 mg*h/l (14 g/m2 ), with an inter-individual variability of 56 and 33% in the respective groups. High treosulfan exposure (>1650 mg*h/l) was associated with an increased risk of mucosal [Odds ratio (OR) 4·40; 95% confidence interval (CI) 1·19-16·28, P = 0·026] and skin toxicity (OR 4·51; 95% CI 1·07-18·93, P = 0·040). No correlation was found between treosulfan exposure and the early clinical outcome parameters: engraftment, acute graft-versus-host disease and donor chimerism. Our study provides the first evidence in a large cohort of paediatric patients of high variability in treosulfan pharmacokinetics and an association between treosulfan exposure and early toxicity. Ongoing studies will reveal whether treosulfan exposure is related to long-term disease-specific outcome and late treatment-related toxicity.
Subject(s)
Antineoplastic Agents, Alkylating/adverse effects , Busulfan/analogs & derivatives , Hematologic Diseases/therapy , Hematopoietic Stem Cell Transplantation/adverse effects , Transplantation Conditioning/adverse effects , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Agents, Alkylating/blood , Busulfan/administration & dosage , Busulfan/adverse effects , Busulfan/blood , Chemical and Drug Induced Liver Injury/etiology , Child , Child, Preschool , Drug Eruptions/etiology , Female , Graft Survival , Graft vs Host Disease/etiology , Hematologic Diseases/blood , Hematopoietic Stem Cell Transplantation/methods , Humans , Infant , Male , Mucositis/chemically induced , Prospective Studies , Transplantation Chimera , Transplantation Conditioning/methodsABSTRACT
BACKGROUND & AIMS: In cardiac surgical patients, undernutrition increases the risk of adverse clinical outcome. We investigated whether the bioelectrical impedance phase angle is an indicator of undernutrition and clinical outcome in cardiac surgery. METHODS: In 325 cardiac surgical patients, we prospectively analyzed the associations between a preoperative low phase angle, measured by bioelectrical impedance spectroscopy, and well-established indicators of undernutrition such as body mass index (kg/m(2)), unintended weight loss, and fat free mass index (kg/m(2)), and muscle strength (handgrip strength (kg)), immune function (C-reactive protein and albumin), and adverse clinical outcomes. RESULTS: A low phase angle (<5.38°) was present in 29.8% (n = 96) of the patients, and was associated with low body mass index (p < 0.001), low fat free mass index (p < 0.001), and less handgrip strength (p = 0.063), but not with unintended weight loss or immune function. Furthermore, a preoperative low phase angle was associated with a prolonged intensive care unit and hospital stay (adj. hazard ratio: 0.68; 95%CI: 0.49-0.94; p = 0.020 and adj. hazard ratio: 0.74; 95%CI: 0.55-0.99; p = 0.048, respectively). CONCLUSIONS: A preoperative low bioelectrical impedance phase angle is associated with undernutrition, and increases the risk of adverse clinical outcome after cardiac surgery. The phase angle might help to identify undernourished cardiac surgical patients.
