High-dose cyclophosphamide treatment of acute myelocytic leukemia. Studies in the BNML rat model

Abstract

In view of its application in patients with acute leukemia prior to bone marrow transplantation, the toxicity and efficacy of high-dose cyclophosphamide treatment were evaluated in a rat model for human acute myelocytic leukemia (BNML). The ld 50 in leukemic rats proved to be lower than that in normal rats (100 vs 164 mg/kg respectively). With dosages above 120 mg/kg, bone marrow transplantation was required to overcome irreversible aplasia. Additional causes of death were lung-, bladder- and intestinal tract hemorrhages (160–200 mg/kg) or acute cardiopulmonary failure (250–300 mg/kg). In leukemic rats, excessive leukemic cell kill leading to tumor cell embolism was another contributing factor. In this respect, treatment of late-stage leukemia proved invariably fatal. In leukemic rats, the highest therapeutic index was achieved with 100 mg/kg. Depending on the stage of disease, a 5–8.5 log leukemic cell kill was achieved. An increased proliferation rate of residual leukemic cells after cyclophosphamide treatment appeared likely. Finally, the present data are extrapolated to the current treatment of human acute myelocytic leukemia in complete remission with high-dose cyclophosphamide in combination with supralethal total-body irradiation.