Amifostine (WR2721) for dose escalation in marrow-ablative treatment of leukaemia

The in vivo effect of the radiochemoprotectant Amifostine on the therapeutic efficacy of marrow ablative treatment with cyclophosphamide (CP) and total body irradiation (TBI) followed by bone marrow transplantation (BMT) was studied in normal rats as well as in the Brown Norway rat acute myelocytic leukaemia (BNML) model. In normal rats, when the dose of TBI was escalated and the CP dose was kept constant, pretreatment with Amifostine yielded a positive dose modification factor of 1.26. No significant improvement was found after Amifostine pretreatment when the TBI dose was kept constant and CP dose escalated. When leukaemic rats received CP as the only antileukaemia treatment, Amifostine pretreatment did not lead to a reduction in the antileukaemic efficacy of CP, although protection against treatment-related mortality was observed. In the CP only groups, 9 out of 40 animals died of treatment-related toxicity, compared with none of the 40 animals in the Amifostine pretreatment groups. When applying the maximum tolerated treatment of CP and TBI in various combinations to leukaemic rats, 25 out of 36 rats died from treatment-related toxicity, whilst pretreatment with Amifostine reduced this to 11 out of 36, (P = 0.002). Of those animals which survived the CP + TBI conditioning treatment, 10 out of 25 in the Amifostine pretreatment group were cured, versus 8/11 in the CP + TBI only control group (P = 0.146). In conclusion, incorporation of Amifostine as a radiochemoprotectant in a marrow-ablative conditioning regimen allows the use of escalated doses of chemoradiotherapy without reducing the antileukaemic efficacy.