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 bloodbrain 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 10 5 -10 8 B-cell leukemia (BCL1) cells (simulating pre-transplant leukemia loads), each group received an 'inductionlike' 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 ¼ 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.

Fludarabine‐based reduced toxicity yet myeloablative conditioning is effective and safe particularly in patients with high‐risk thalassemia undergoing allogeneic transplantation

“…In this new protocol, we substituted fludarabine for Cy, to minimize complications of Cy with busulfan, without compromising engraftment . We also added thiotepa, in myeloablative doses (5 mg/kg for 2 days), to augment conventional myeloablation to prevent rejection rates and improve on engraftment, especially in high‐risk patients . We have presented here the long‐term update of our previously published analysis, using fludarabine‐based reduced toxicity protocol to improve outcomes, especially in patients with high‐risk thalassemia.…”

Primary central nervous system lymphoma: implication of high-dose chemotherapy followed by auto-SCT

“…Thiotepa has better brain penetration and carries theoretical advantage over other conditioning regimens by effective local blood–brain tissue penetration, 31 and needs to be considered in selected patients as it also carries excess toxicities in combination with BU-containing conditioning regimens. 32,33 …”