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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 China1 and multicentre phase 3 trials in the USA.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 antileukemic activity in APL by inducing apoptosis in the leukemic 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 given also.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, terfenadine 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.
Document references
- Sun HD, Ma L, Hu X-C et al. Ai-Lin 1 treated 32 cases of acute promyelocytic leukemia. Chin J Integrat Chin Western Med 1992;12:170-172.
- Soignet SL, Frankel SR, Douer D, et al; United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia.; J Clin Oncol. 2001 Sep 15;19(18):3852-60. [abstract]
- Lengfelder E, Gnad U, Buchner T, et al; Treatment of relapsed acute promyelocytic leukemia.; Onkologie. 2003 Aug;26(4):373-9. [abstract]
- Leoni F, Gianfaldoni G, Annunziata M, et al; Arsenic trioxide therapy for relapsed acute promyelocytic leukemia: a bridge to transplantation.; Haematologica. 2002 May;87(5):485-9. [abstract]
- Bachleitner-Hofmann T, Kees M, Gisslinger H; Arsenic trioxide: acute promyelocytic leukemia and beyond.; Leuk Lymphoma. 2002 Aug;43(8):1535-40. [abstract]
- Lin LM, Li BX, Xiao JB, et al; Synergistic effect of all-trans-retinoic acid and arsenic trioxide on growth inhibition and apoptosis in human hepatoma, breast cancer, and lung cancer cells in vitro.; World J Gastroenterol. 2005 Sep 28;11(36):5633-7. [abstract]
- Luo L, Qiao H, Meng F, et al; Arsenic trioxide synergizes with B7H3-mediated immunotherapy to eradicate hepatocellular carcinomas.; Int J Cancer. 2006 Apr 1;118(7):1823-30. [abstract]
- Kong B, Huang S, Wang W, et al; Arsenic trioxide induces apoptosis in cisplatin-sensitive and -resistant ovarian cancer cell lines.; Int J Gynecol Cancer. 2005 Sep-Oct;15(5):872-7. [abstract]
- Ryu KH, Woo SY, Lee MY, et al; Morphological and biochemical changes induced by arsenic trioxide in neuroblastoma cell lines.; Pediatr Hematol Oncol. 2005 Oct-Nov;22(7):609-21. [abstract]
- BCSH Guidelines on the management of acute myeloid leukaemia in adults.
- Naito K, Kobayashi M, Sahara N, et al; Two cases of acute promyelocytic leukemia complicated by torsade de pointes during arsenic trioxide therapy.; Int J Hematol. 2006 May;83(4):318-23. [abstract]
- Sanz MA, Fenaux P, Lo Coco F; Arsenic trioxide in the treatment of acute promyelocytic leukemia. A review of current evidence.; Haematologica. 2005 Sep;90(9):1231-5. [abstract]
- Summary of Product Characteristics - Trisenox® (Arsenic trioxide), Cephalon Limited, Updated Feb 2007, Electronic Medicines Compendium
Internet and further reading
- NICE Clinical Guidance; Improving outcomes in haemato-oncology cancer. October 2003.
DocID: 278
Document Version: 3
DocRef: bgp25246
Last Updated: 7 Oct 2007
Review Date: 6 Oct 2008
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