) Recent reports from China suggested that arsenic trioxide induced complete remission in a high proportion of patients with acute promyelocytic leukemia (APL). We have recently confirmed these results using a U.S. formulation developed at this Center. Our early results showed that 11 of 12 heavily pretreated APL patients achieved CR. Moreover, 7 of 10 evaluable patients converted their RT-PCR assays for PML/RAR-alpha to negative, a finding which suggests that this compound is more potent than all-trans retinoic acid in this disease. We have also shown that clinical treatment with this drug is associated with appearance of an intermediate leukemic cell immunophenotype (i.e. """"""""non-terminal"""""""" differentiation), followed by activation of caspases and apoptosis. However, we do not confirm reports by others that arsenic specifically targets the aberrant gene products expressed in APL, but rather that the drug has greater breadth of anticancer activity, particularly in hematologic cancers. Having secured adequate clinical supplies of the drug, this application requests support for a clinical study that will examine escalating doses of this agent in patients with a variety of hematologic cancers, with the following specific aims: (1) To evaluate the safety and potential clinical activity of arsenic trioxide in patients with advanced hematologic cancers. (2) To evaluate the pharmacokinetics and speciation of arsenic trioxide at doses in excess of those used in acute promyelocytic leukemia. (3) To evaluate whether arsenic trioxide therapy is associated with induced cytodifferentiation and/or apoptosis in selected malignant hematologic disorders. Results from this application will define a tolerable dose schedule, will yield important information with respect to clinical pharmacology and mechanism of action, and will be used to guide future disease-specific clinical investigations with the drug.
| Novick, S C; Warrell Jr, R P (2000) Arsenicals in hematologic cancers. Semin Oncol 27:495-501 |
