Treosulfan Therapeutic Drug Monitoring in Pediatric Hematopoietic Stem Cell Transplant Recipients

One of the major challenges to improve the outcome of hematopoietic stem cell transplantation (HSCT) is the reduction of toxicity and non-relapse mortality caused by the pre-transplant conditioning regimen, while maintaining efficacy. Treosulfan (TREO) (L-treitol-1,4-bis-methanesulfonate) is a busulfan analogue with a distinct site of alkylation that results in a more favourable toxicity profile in comparison with busulfan and total body irradiation. TREO is the prodrug of L-epoxybutane, a water-soluble bifunctional alkylating agent with remarkable myeloablative and immunosuppressive properties. The use of TREO, in combination with other chemotherapy agents, as part of the conditioning regimen for hematopoietic stem cell transplantation (HSCT) in children has progressively increased during the last decade for both malignant and non-malignant disorders. Data on TREO pharmacokinetics in the pediatric population are still scarce. To date, only a few studies, including small numbers of pediatric patients, have investigated the PK profile of TREO. These studies reported high variability of TREO pharmacokinetics, and the relationship between TREO exposure, toxicity and clinical outcome is still unresolved. Therefore, therapeutic drug monitoring with a personalized approach may be an important tool to optimize outcomes in the pediatric population. The aim of the investigators' study is to characterize TREO PK/PD profiles in children undergoing HSCT and to evaluate the relationship between TREO exposure and early toxicity and clinical outcome.

Inclusion Criteria: * Age range 0 - 18 years. * Life expectancy \> 12 weeks. * Diagnosis of malignant or non-malignant disorder. * Pre-HSCT Lansky / Karnofsky score ≥ 40%. * Indication to allogeneic or autologous HSCT with TREO as part of the pre-transplant conditioning regimen. * Negativity of pregnancy test for female patients. * Written informed consent signed by the parents or guardians. Exclusion Criteria: * Absence of written informed consent signed by the parents or guardians. * Current clinically active infectious disease (including positive HIV serology or viral RNA). * Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or left ventricular ejection fraction \<40%). * Liver dysfunction (AST/ALT ≥ 3 times institutional upper limit normal value -ULN- or bilirubin \> 3 times ULN). * Renal dysfunction: serum creatinine \> 1.5 times ULN or calculated creatinine clearance \< 60 ml/min/1.73 m2 * End stage irreversible multi-system organ failure. * Pregnant or breast feeding female patient.