High-Dose Thiotepa and Melphalan with Autologous HSCT in Pediatric Solid Tumors

Overview

This expanded access study evaluated the safety and efficacy of high-dose thiotepa combined with melphalan followed by autologous hematopoietic stem cell transplantation (HSCT) in pediatric patients with solid tumors, including brain tumors. The regimen was well tolerated and showed promising survival outcomes in this population.

Background

Cancer remains a leading cause of mortality in children worldwide, with solid tumors, particularly those in the central nervous system, being the second most common pediatric cancers after leukemia. High-dose chemotherapy (HDT) combined with hematopoietic stem cell transplantation (HSCT) enables escalation of cytotoxic therapy beyond marrow tolerance. Thiotepa, an alkylating agent capable of crossing the blood-brain barrier, has been used as HDT prior to HSCT but was unavailable in Japan until recently due to manufacturing discontinuation. This study addresses the clinical need by evaluating thiotepa plus melphalan as HDT before autologous HSCT in Japanese pediatric patients with solid tumors.

Data Highlights

The study enrolled pediatric patients aged ≥2 years with solid or brain tumors who had completed hematopoietic cell collection for autologous HSCT. Thiotepa was administered intravenously at 200 mg/m2/day over 24 hours on days −12, −11, −5, and −4 before HSCT. Melphalan was given intravenously at 70 mg/m2/day over 1 hour on days −11, −5, and −4. Dose adjustments were permitted based on renal function and investigator judgment. The study was conducted at eight sites in Japan between 2017 and 2020.

Key Findings

• Thiotepa crosses the blood-brain barrier effectively, achieving cerebrospinal fluid concentrations >90% of serum levels, making it suitable for CNS tumors.
• The combination of thiotepa and melphalan as HDT prior to autologous HSCT was well tolerated in pediatric patients with solid tumors, including brain tumors.
• Survival rates in the phase I study were high, with 77.8% survival in pediatric solid tumors and 100% in malignant lymphoma patients.
• The regimen allowed dose escalation beyond marrow tolerance, potentially improving treatment efficacy for refractory or high-risk tumors.
• Strict inclusion criteria ensured patients had adequate organ function and performance status to tolerate intensive therapy.
• The study protocol included provisions for dose reduction or discontinuation based on renal function to enhance safety.

Clinical Implications

This combination regimen offers a viable HDT option for pediatric patients with solid and brain tumors undergoing autologous HSCT, particularly in settings where CNS penetration is critical. Careful patient selection and monitoring of renal function are essential to optimize safety and treatment outcomes. The availability of thiotepa in Japan now expands therapeutic options for this vulnerable population.

Conclusion

High-dose thiotepa combined with melphalan followed by autologous HSCT is a feasible and effective treatment strategy for pediatric solid tumors, including brain tumors, demonstrating favorable tolerability and promising survival outcomes in Japanese patients.

References

1. Japanese Society of Pediatric Hematology/Oncology Database 2015 -- Pediatric Solid Tumors
2. Phase I Study of Thiotepa HDT with Autologous HSCT in Japan 2019
3. Thiotepa Approval and Expanded Access Program in Japan 2017-2020