COMPLETE REMISSION AFTER TREATMENT OF ACUTE PROMYELOCYTIC LEUKEMIA WITH ARSENIC TRIOXIDE

Background Two reports from China have suggested that arsenic trioxide can induce complete remissions in patients with acute promyelocytic l eukemia (APL). We evaluated this drug in patients with APL in an attem pt to elucidate its mechanism of action. Methods Twelve patients with APL who had relapsed after extensive prior therapy were treated with a rsenic trioxide at doses ranging from 0.06 to 0.2 mg per kilogram of b ody weight per day until visible leukemic cells were eliminated from t he bone marrow. Bone marrow mononuclear cells were serially monitored by flow cytometry for immunophenotype, fluorescence in situ hybridizat ion, reverse-transcription-polymerase-chain-reaction (RT-PCR) assay fo r PML-RAR-alpha: fusion transcripts, and Western blot analysis for exp ression of the apoptosis-associated proteins caspases 1, 2, and 3. Res ults Of the 12 patients studied, 11 had a complete remission after tre atment that lasted from 12 to 39 days (range of cumulative doses, 160 to 515 mg). Adverse effects were relatively mild and included rash, li ghtheadedness, fatigue, and musculoskeletal pain. Cells that expressed both CD11b and CD33 (antigens characteristic of mature and immature c ells, respectively), and which were found by fluorescence in situ hybr idization to carry the t(15;17) translocation, increased progressively in number during treatment and persisted in the early phase of comple te remission. Eight of 11 patients who initially tested positive for t he PML-RAR-alpha fusion transcript by the RT-PCR assay later tested ne gative; 3 other patients, who persistently tested positive, relapsed e arly. Arsenic trioxide induced the expression of the proenzymes of cas pase 2 and caspase 3 and activation of both caspase 1 and caspase 3. C onclusions Low doses of arsenic trioxide can induce complete remission s in patients with APL who have relapsed. The clinical response is ass ociated with incomplete cytodifferentiation and the induction of apopt osis with caspase activation in leukemic cells. (C) 1998, Massachusett s Medical Society.