Malignant Disorders, Non-malignant Disorders, Pediatric Hematopoietic Stem Cell Transplantation
Conditions
Brief summary
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.
Interventions
None listed
Sponsors
Fondazione IRCCS Policlinico San Matteo di Pavia
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
No minimum to 18 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| percentage of patients in therapeutic range after the first dose of TREO during the pre-transplant conditioning regimen | within 24 hours from the first dose | proposed cumulative therapeutic target AUC 4800 mg x h /L; range 3840 -6000 mg x h /L |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 | day 0-3 | 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 | 100 days post HSCT | — |
| correlation between TREO exposure (measured by AUC) and efficacy | 1 year post HSCT | measured as time to engraftment and donor chimerism percentage post-HSCT |
Countries
Italy
Contacts
CONTACTMarco Zecca, MD
Outcome results
None listed