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.

Study Overview

• Status: Recruiting
• Conditions: Non-malignant Disorders; Pediatric Hematopoietic Stem Cell Transplantation; Malignant Disorders

• Study Type: Observational
• Enrollment (Estimated): 70

Contacts and Locations

• Study Contact: Name: Marco Zecca, MD; Phone Number: +390382502848; Email: m.zecca@smatteo.pv.it

Study Locations

• Italy
  • Brescia
    • Brescia, Brescia, Italy, 25123
      • Recruiting
      • Ospedali Civili, Presidio Ospedale Dei Bambini, Oncoematologia Pediatrica e TMO
      • Contact: Fulvio Porta
  • Genova
    • Genova, Genova, Italy, 16147
      • Recruiting
      • IRCCS Istituto Giannina Gaslini, U.O.S.D. Centro Trapianto di Midollo Osseo
      • Contact: Maura Faraci; Phone Number: +3901056362405
  • Milano
    • Milan, Milano, Italy, 20132
      • Recruiting
      • Ospedale San Raffaele, U.O. Immunoematologia Pediatrica
      • Contact: Maria Ester Bernardo; Phone Number: +390226434875
  • Monza-brianza
    • Monza, Monza-brianza, Italy, 20900
      • Recruiting
      • Fondazione IRCCS San Gerardo dei Tintori - Clinica Pediatrica
      • Contact: Sonia Bonanomi; Phone Number: +392332442
  • Padova
    • Padova, Padova, Italy, 35128
      • Recruiting
      • Azienda Ospedaliera di Padova, Oncoematologia Pediatrica
      • Contact: Elisabetta Calore; Phone Number: +390498218030
  • Pavia
    • Pavia, Pavia, Italy, 27100
      • Recruiting
      • Fondazione IRCCS Policlinico San Matteo, S.C. Ematologia 2 - Oncoematologia Pediatrica
      • Contact: Marco Zecca; Email: m.zecca@smatteo.pv.it
  • Torino
    • Torino, Torino, Italy, 10126
      • Recruiting
      • AOU Città della Salute e della Scienza Di Torino, SC Oncoematologia Pediatrica e Centro Trapianti
      • Contact: Franca Fagioli; Phone Number: +390113135230
  • Trieste
    • Trieste, Trieste, Italy, 34137
      • Recruiting
      • IRCCS Materno Infantile "Burlo Garofolo", SC Oncoematologia Pediatrica e SS Trapianto Di Midollo
      • Contact: Natalia Maximova; Phone Number: +390403785565
  • VR
    • Verona, VR, Italy, 37126
      • Recruiting
      • Ospedale Donna Bambino Azienda Ospedaliera Universitaria Integrata, U.O.C. Oncoematologia Pediatrica
      • Contact: Simone cesaro; Phone Number: +390458127874
  • bOLOGNA
    • Bologna, bOLOGNA, Italy, 40138
      • Recruiting
      • Policlinico Sant'Orsola Malpighi, Clinica Pediatrica Oncologia Ed Ematologia Pediatrica "Lalla Seràgnoli"
      • Contact: Arcangelo Prete; Phone Number: +39051346044

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

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

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Pediatric patients with a indication for HSCT and who will will receive TREO; Pediatric patients (aged 0 to 18 years) affected by malignant or non-malignant disorders and with an indication for HSCT and who will will receive TREO as part of the pre-transplant conditioning regimen, in combination with other chemotherapy agents.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	within 24 hours from the first dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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%).	100 days post HSCT
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	day 0-3
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	measured as time to engraftment and donor chimerism percentage post-HSCT	1 year post HSCT

Collaborators and Investigators

• Sponsor: Fondazione IRCCS Policlinico San Matteo di Pavia

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2021
• Primary Completion (Estimated): July 31, 2027
• Study Completion (Estimated): July 31, 2027

Study Registration Dates

• First Submitted: February 24, 2025
• First Submitted That Met QC Criteria: February 28, 2025
• First Posted (Actual): March 6, 2025

Study Record Updates

• Last Update Posted (Actual): April 24, 2026
• Last Update Submitted That Met QC Criteria: April 23, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Other Study ID Numbers: TREO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No