Pentostatin increases the acute toxicity of high dose cyclophosphamide

Abstract

One dose of pentostatin was added to a standard cyclophosphamide (CY) based transplant regimen in two patients in an attempt to decrease the rate of non-engraftment in haploidentical allogeneic BMT. Despite a normal cardiac history and evaluation prior to transplant, both patients suffered fatal cardiac toxicity within 48 h of receiving the chemotherapy. This phenomenon was further investigated in an animal model. Laboratory rats were treated with progressive doses of CY in a range that produces acute cardiac toxicity. Successive groups of rats were treated with either pentostatin or fludarabine and CY at 400 mg/kg. Neither pentostatin nor fludarabine alone produced early mortality. However, a marked increase in early mortality was noted in those animals treated with pentostatin and high-dose CY. The addition of fludarabine did not increase the early toxicity of CY. Autopsy revealed no gross or microscopic abnormalities in the animals. The implications of adding agents that interfere with adenosine metabolism to CY based transplant regimens is discussed.