AS1-KL-1 DEVELOPMENT OF HIGH-DOSE CHEMOTHERAPY INCLUDING THIOTEPA COMBINED WITH AUTOLOGOUS PERIPHERAL BLOOD STEM CELL RESCUE

Thiotepa is a classic alkylating agent that was launched in 1958 in Japan. We have consistently developed thiotepa-containing HDC since 1992, inspired by the fact that thiotepa was used as an alternative to melphalan as a high-dose chemotherapy (HDC) drug for neuroblastoma in the United States. Thiotepa is considered to be a drug suitable for brain tumor treatment because of its good BBB permeability, equal concentration in cerebrospinal fluid and blood, and the characteristics of alkylating agents that enhance the effect by log ratio of dose. Melphalan, which is also an alkylating agent as a central agent of HDC, has a strong antitumor effect, so we planned to use both at the maximum tolerated dose for each. Therefore, in order to reduce toxicity, it was decided to divide it into two doses at weekly intervals and to administer thiotepa for 24 hours in order to prevent hepatic sinus obstruction syndrome (SOS). Since 1993, a dose determination study was conducted, and the doses of thiotepa and melphalan were determined to be 800 mg/m2 and 280 mg/m2, respectively. Autologous peripheral blood stem cell transplantation using this regimen was performed as a consolidation therapy for metastatic pediatric medulloblastoma in 28 and 15 patients, respectively, in 2 series. Five-year progression-free survival rates of 82.1 ± 7.2% and 92.9 ± 6.9% were obtained. After that, the supply was stopped in 2009. This time, a domestic study was conducted with the dose of melphalan reduced to 210 mg/m2, and this year, a new indication (pretreatment for autologous hematopoietic stem cell transplantation in childhood malignant solid tumors) was acquired and launched. By this dose reduction, reduced gastrointestinal toxicity such as mucosal damage is expected. The JCCG clinical trials incorporating HDC will be conducted in medulloblastoma, ATRT, and refractory germ cell tumors.