The effect of high-dose thiotepa, alone or in combination with other chemotherapeutic agents, on a murine B-cell leukemia model simulating autologous stem cell transplantation

Abstract

The use of thiotepa (TH) is increasing, especially in stem cell transplantation, mainly due to its safety and blood–brain barrier penetration. We evaluated the use of TH in a murine model simulating autologous stem cell transplantation, with or without additional agents. Between 1 and 11 days following inoculation of BALB/c mice with 10⁵–10⁸ B-cell leukemia (BCL1) cells (simulating pre-transplant leukemia loads), each group received an ‘induction-like’ irradiation and/or cytotoxic regimen. Animals were either followed without treatment, or an adoptive transfer (AT) was performed to untreated BALB/c mice. Administered alone without AT, high-dose TH did not change the time to appearance of leukemia. Nevertheless, in the AT experiments, TH as a single agent showed better antileukemic activity than busulfan (BU). Cyclophosphamide (CY)-containing regimens were the most effective, and the TH–CY combination was as effective as the commonly used BU–CY combination, and more effective than the BU–TH combination. Moreover, a synergistic effect was seen in the TH–CY combination (none of the animals developed leukemia, whereas 4/10 animals in the CY–TBI group developed leukemia (P=0.029)). In conclusion, although TH produced only a moderate effect against BCL1 leukemia when used alone, its combination with CY is promising and should be tested further in allogeneic murine models and clinical studies.