Arsenic Trioxide

Arsenic trioxide (ATO), the active ingredient in Fowler's solution, has been used to lower white blood cell counts since 1878. It remained in use until the advent of radiation therapy and the use of modern chemotherapeutic drugs. The drug re-emerged as an antileukemia agent in the 1990s, with the report from Chinese investigators that remissions of up to 90% were seen in patients with acute promyelocytic leukemia (APL).33 The FDA approved ATO for use in relapsed/refractory APL in September 2001.

ATO has a wide spectrum of biologic activity, which makes it an ideal drug to use in the treatment of MDS. ATO binds to proteins with available sulfhydryl groups, causing disruption of the membrane potential of the mitochondria, releasing cytochrome c with subsequent activation of caspase effectors, and initiation of apoptosis. ATO has antiangiogenic properties, resulting in suppression of VEGF synthesis from myeloid cells, as well as significant antiproliferative activity, in part related to modulating cytokine release and interfering with cell-cycle progression. In addition, ATO can promote histone acetylation through activation of the mitogen-activated protein kinase (MAPK) signaling pathway, and can promote differentiation by modulating gene expression. It is also known to inhibit DNA methyltransferase, an important epigenetic target, as discussed above.

List et al. conducted a phase II study in which 53 MDS patients (median age 69) with both low/int-1 and int-2/high-risk groups received ATO 0.25 mg/kg, Monday to Friday for two consecutive weeks every 28 days. Response was evaluated every 8 weeks.34 Hematologic responses were observed in 7 of 28 evaluable patients (25%). Responses were maintained for 2 months and often noted after 8-22 weeks after starting treatment. Immunosuppression was the primary adverse effect, although a small number of patients suffered from cardiac and pulmonary toxicities.

Similar results were reported by another group, who treated MDS patients on a slightly different regimen.35 Here, ATO was given as a 1-h i.v. infusion, with a loading dose of 0.30 mg/kg/day for 5 days, and maintenance with 0.25 mg/kg/day twice weekly for 15 weeks or more. Patients were evaluated at 8 weeks. Eighty-one patients were enrolled with a median age of 67 years, of all IPSS groups. Hematologic responses, mostly erythroid, were achieved in 13 of 50 evaluable patients. There was a 5/19 (26%) response in low-risk and 8/31 (26%) response in high-risk patients. Once again, responses were seen after 6-22 weeks. Forty-four patients had stable disease for up to 6 months while on study.

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