Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Phenasen (Phebra)
10 mL vials containing 10 mg/10 mL
Approved indication: acute promyelocytic leukaemia
Australian Medicines Handbook Appendix A

Acute promyelocytic leukaemia is a subtype of acute myeloid leukaemia. There is a translocation of chromosomes 15 and 17 resulting in the expression of abnormal proteins. It is currently treated with regimens containing all-trans-retinoic acid. The persistence of an abnormal transcript, promyelocytic leukaemia-retinoic acid receptor-alfa (PML-RARα), after chemotherapy predicts relapse. Relapses can be managed with chemotherapy, but the toxicity is high so alternatives are needed.

The active ingredient in a traditional Chinese medicine used to treat leukaemia was found to be arsenic trioxide. Chinese researchers therefore tried a purified solution of arsenic trioxide in the treatment of relapsed acute promyelocytic leukaemia. The percentage of blast cells in the bone marrow was reduced to less than 5% in 14 of 15 patients. These complete responses were obtained after a median of 38 days treatment with arsenic trioxide.1

An American study then tried arsenic trioxide in 12 patients with relapsed disease. Although one patient died the others all had a complete response after a median of 33 days. In eight patients PML-RARα was no longer present after two courses of treatment.2

A multi centre study enrolled 40 patients during their first or second relapse. There was a complete response, confirmed by bone marrow examination in 34 patients. In 25 patients the PML-RARα transcript was no longer present after treatment. Overall survival at 18 months was estimated to be 66%.3

The recommended regimen of arsenic trioxide for relapsed disease is a daily intravenous infusion until there is bone marrow remission. Three to six weeks after induction therapy is completed, 25 doses of arsenic trioxide are given in a consolidation regimen which can last for up to five weeks.

The infusion is given over 1-2 hours. Pharmacokinetic information is limited, but arsenic trioxide is thought to be metabolised in the liver and excreted in the urine.

As the clinical trials only involved small numbers of patients, safety data are limited. All patients will experience some drug-related adverse events. Common complaints are oedema, fever, fatigue, nausea, vomiting, diarrhoea and abdominal pain. Hypokalaemia, hyperglycaemia and hypocalcaemia are also frequent. In the multi centre study of arsenic trioxide, 25% of the patients developed symptoms suggestive of acute promyelocytic leukaemia differentiation syndrome. This presents with fever, weight gain, dyspnoea, pulmonary infiltration and pleural or pericardial effusions. It requires urgent treatment with high doses of intravenous steroids. Arsenic prolongs the QTc interval on the ECG so patients have an increased risk of arrhythmia. It is therefore important to monitor the patients for electrolyte abnormalities which may contribute to potentially fatal arrhythmias.

Arsenic is a carcinogen. It also suppresses the production of normal blood cells so blood counts and coagulation should be checked twice a week.

Patients with relapsed promyelocytic leukaemia are likely to respond to arsenic trioxide. If remission has not occurred within 60 days the patient is unlikely to respond. The published clinical trials have not compared arsenic trioxide with other approaches to treating relapsed disease. The optimum use of arsenic trioxide with other treatments needs further study to see if the high response rates translate into improved long-term survival.

manufacturer provided the product information

The Transparency Score ( ) is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.