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.
Age range 0 - 18 years.
Life expectancy > 12 weeks.
Diagnosis of malignant or non-malignant disorder.
Pre-HSCT Lansky / Karnofsky score ≥ 40%.
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).
70 pediatric patients (aged 0 to 18 years) affected by malignant or non-malignant disorders and with an indication for HSCT will be enrolled at 13 transplantation sites
Cohort
Prospective
Not listed
percentage of patients in therapeutic range after the first dose of TREO during the pre-transplant conditioning regimen
proposed cumulative therapeutic target AUC 4800 mg x h /L; range 3840 -6000 mg x h /L
correlation between TREO exposure and early toxicity using the NCI Common Toxicity Criteria (Toxicity score 1- 5 for each organ/system) at 100 days post HSCT
treo exposure is calculated by plasma concentration AUC measurement; correlation of out-of-range AUC(0-∞) and NCI grade will be analysed using the chi-square test. Intra and inter-individual variability will be estimated with a coefficient of variation (CV%).
To evaluate the inter-individual and intra-individual variability of PK profile
a PK profile will be performed by collecting plasma samples for treo plasma concentration AUC measure
To study the cumulative incidence of non-relapse mortality at 100 days post HSCT
correlation between TREO exposure (measured by AUC) and efficacy
measured as time to engraftment and donor chimerism percentage post-HSCT
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