Efficacy of high-dose cyclophosphamide in combination with total-body irradiation in the treatment of acute myelocytic leukemia: studies in a relevant rat model.
The efficacy of current clinical leukemia treatment with high-dose cyclophosphamide, supralethal total-body irradiation (TBI), and bone marrow transplantation was evaluated in a rat model for human acute myelocytic leukemia. In rats, both at an early stage of disease and in an advanced stage after remission-induction with 1-beta-D-arabinofuranosylcytosine, treatment with cyclophosphamide (100 mg/kg i.p.) followed by either acute, unfractionated TBI (900 centigrays) or fractionated TBI (200 centigrays for seven doses; 450 centigrays for three doses) achieved cure in 90 to 100% and 75% of the animals, respectively. The remaining rats died from treatment-related toxicity despite isologous bone marrow transplantation. Applying the cyclophosphamide-TBI treatment regimens in advanced stage leukemia (tumor load, 5 X 10(9) cells) resulted in death from leukemia relapse in the majority of rats (71%). From the increase in life span after treatment, it was deduced that a 9-log leukemic cell kill was achieved at the most. There was no significant difference between the regimens using fractionated or unfractionated TBI. Toxicity-related deaths occurred mainly in the TBI group receiving 450 centigrays for three doses (38%). In another approach, (repeated) low-dose cyclophosphamide was given subsequent to high-dose cyclophosphamide-TBI treatment applied in advanced stage leukemia. This proved to be effective in eradicating residual leukemia in 80 to 90% of the rats without destroying the bone marrow graft. In general, the outcome of the various treatment regimens was predictable through accurate information on the tumor load at various stages of disease. The major obstacle in extrapolating the present experimental results to clinical practice is the lack of similar quantitative data in human leukemia.
D000818:Animals; D003520:Cyclophosphamide / Q000008:administration & dosage* / Q000627:therapeutic use; D004195:Disease Models, Animal; D015470:Leukemia, Myeloid, Acute / Q000628:therapy*; D008297:Male; D051381:Rats; D011914:Rats, Inbred BN; D014916:Whole-Body Irradiation
D003520:Cyclophosphamide