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.