Arsenic Trioxide

Arsenic has been used medicinally for over 2,400 years:

• Arsenic trioxide (ATO), was Madame Bovary's poison and is a constituent in many traditional Chinese remedies.
• It was licensed after initial use in China and multicentre phase 3 trials in the USA.^1,2
• It is used in acute promyelocytic leukaemia (APL), in patients who have relapsed or failed to respond to previous treatment with a retinoid and chemotherapy.

About 6,600 cases of all types of leukaemia are diagnosed in the UK each year. 1 in 10 of these cases is APL.

• Arsenic trioxide is indicated for the induction of remission (and consolidation) in adult patients with relapsed/refractory APL.
• This is characterised by the presence of the t(15;17) translocation and/or the presence of the Pro-Myelocytic Leukaemia/Retinoic-Acid-Receptor-alpha (PML/RAR-alpha) gene.
• Other treatments should have been previously used and these should include a retinoid and chemotherapy.

ATO has given very promising results; complete haematological remission rates of 80-92% have been achieved.³
Remissions induced by ATO tend not to be sustained and it has been called "the bridge to transplantation".⁴

Arsenic trioxide exerts its antileukaemic activity in APL by inducing apoptosis in the leukaemic cell population.⁵ It has become evident that the apoptotic effects of ATO are not restricted to APL cells but may also be observed in malignant cells of non-APL origin.
Recent research has shown ATO may inhibit growth and induce apoptosis in the following:

• There may be a synergistic effect when ATO is given with retinoid therapy in hepatocellular carcinoma, breast and lung carcinomas.⁶ Similar increase in efficacy is seen when immunotherapeutic agents are also given.⁷
• Similarly, it is effective in ovarian carcinomas resistant to cisplatin.⁸
• ATO has also been shown to be effective in the treatment of neuroblastomas.⁹

• Induction: ATO is given intravenously over 1-2 hours daily until the bone marrow remission is achieved. This is when there are <5% blasts present in cellular bone marrow and no evidence of leukaemic cells.
  If remission has not occurred by day 50 dosing must be discontinued.
• Consolidation: this begins 3 to 4 weeks after induction therapy. ATO is given intravenously for 5 days per week, followed by 2 days interruption, repeated for 5 weeks.

• ATO may cause birth defects if it is taken at time of conception or particularly during the first trimester. It should be avoided if possible.
• In the second and third trimesters there is an increased risk of miscarriage, premature delivery and small for gestational age fetuses.¹⁰

Cardiac toxicity

There is a prolongation of the QT interval and this may be associated with fatal cardiac arrhythmias; tachycardia and torsades des pointes.¹¹

• A pre-treatment 12 lead ECG should be obtained, then twice weekly if there are no other risk factors for prolongation of QT interval¹² e.g. class Ia and III antiarrythmics, antipsychotics, tricyclic antidepressants, erythromycin, and cisapride.
• Other factors may include a history of torsade de pointes, pre-existing QT interval prolongation, congestive heart failure, administration of potassium-wasting diuretics, or other conditions that result in hypokalaemia or hypomagnesaemia.
• It may be necessary to initiate treatment with continuous monitoring.

Electrolyte disturbances

Hypokalaemia is seen frequently. Serum magnesium and potassium levels should be kept in the high normal range.

APL differentiation syndrome

25-30% of patients with APL treated with ATO have experienced symptoms similar to a syndrome called the retinoic-acid-acute promyelocytic leukaemia (RA-APL) or APL differentiation syndrome. The symptoms include:

• Fever
• Shortness of breath
• Weight gain
• Pulmonary infiltrates and pleural or pericardial effusions on CXR

This can be fatal. Treatment should be halted. High-dose steroid (intravenous dexamethasone for 3 days) has been used and appears to alleviate signs and symptoms.¹³

Others

• Hyperleucocytosis - not requiring modification of treatment
• Hyperglycaemia
• GI haemorrhage

Twice weekly:

• FBC
• U&E
• Glucose
• LFT and coagulation studies

More frequently during induction. Weekly during consolidation.