Arsenic trioxide therapy for relapsed acute promyelocytic leukemia: an useful salvage therapy

Arsenic trioxide (As203) was recently identified as a very potent agent against acute promyelocytic leukemia (APL). Intravenous infusion of 10 mg As203 daily for one to two months can induce significant complete remission (CR) of APL, and there is no cross drug-resistance between As203 and other antileukemic agents, including all-trans retinoic acid (ATRA). The CR rate of relapsed and/or refractory APL patients who received As203 treatment ranged from 52.3% to 93.3%. The median duration to CR ranged from 38 to 51 days, with accumulative As203 dosage of 340 similar to 430 mg. Although most adverse reactions of As203 treatment were tolerable, certain infrequent but severe toxicities related to As203 were observed, including renal failure, hepatic damage, cardiac arrhythmia and chronic neuromuscular degeneration, which should be monitored carefully. As203 can induce partial differentiation and subsequent apoptosis of APL cells through degradation of wild type PML and PML/RAR alpha chimeric proteins and possible anti-mitochondrial effects. Like the treatment of ATRA in APL, early relapses from As203 treatment within a few months were not infrequently seen, indicating that rapid emerging resistance to As203 can occur. Nevertheless, the PML/RAR alpha fusion protein was reported to disappear in some APL patients who received As203, and who might earn long-survival. However, the follow-up is still too short to draw the conclusion. Intriguingly, it has been shown that As203 can also induce apoptosis of other non-APL tumor cells with clinical achievable concentrations. However, the detailed molecular mechanisms are not yet fully understood. Further studies regarding to the pharmacological characters, clinical efficacies, toxicities, apoptogenic mechanisms, and spectrum of anti-tumor activity of As203 are warranted.