Arsenic trioxide: safety issues and their management

Arsenic trioxide (As2O2) has been used medicinally for thousands of years. Its therapeutic use in leukaemia was described a century ago. Recent rekindling in the interest of As2O3 is due to its high efficacy in acute promyelocytic leukaemia (APL). As2O3 has also been tested clinically in other blood and solid cancers. Most studies have used intravenous As2O3, although an oral As2O3 is equally efficacious. Side effects of As2O3 are usually minor, including skin reactions, gastrointestinal upset, and hepatitis. These respond to symptomatic treatment or temporary drug cessation, and do not compromise subsequent treatment with As2O3. During induction therapy in APL, a leucocytosis may occasionally occur, which can be associated with fluid accumulation and pulmonary infiltration. The condition is similar to the APL differentiation syndrome during treatment with all-trans retinoic acid, and responds to cytoreductive treatment and corticosteroids. Intravenous As2O3 treatment leads to QT prolongation. In the presence of underlying cardiopulmonary diseases or electrolyte disturbances, particularly hypokalaemia and hypomagnesaemia, serious arrhythmias may develop, with torsades du pointes reported in 1% of cases. This may be related to a dose-dependent arsenic-mediated inhibition of potassium ion channels that compromises cardiac repolarization. Because of slow intestinal absorption, oral-As2O3 gives a lower plasma arsenic concentration, which is associated with lesser QT prolongation and hence a more favorable cardiac safety profile. As2O3 does not appear to enter the central nervous system. However, if the blood brain barrier is breached, elemental arsenic may enter the cerebrospinal fluid. As2O3 is predominantly excreted in the kidneys, and dose adjustment is required when renal function is impaired.