Cost-Effectiveness Of Arsenic Trioxide + All-Trans Retinoic Acid Compared With All-Trans Retinoic Acid + Idarubicin In The Treatment Of Newly Diagnosed Acute Promyelocytic Leukemia In Canada
Authors: Lachaine Jean , Mathurin Karine , Barakat Stephane 
Published: October 2019

Abstract
Acute promyelocytic leukemia (APL) is a distinct and rare morphological, clinical and pathological subtype of acute myeloid leukemia (AML). It represents approximately 10% to 15% of AML patients. APL is characterized by a high incidence of coagulopathy caused by disseminated intravascular coagulation and/or excessive fibrinolysis and is associated with a high early mortality. Treatment can exacerbate the coagulopathy. Untreated, APL is rapidly fatal, but if promptly diagnosed and treated, it is frequently curable. Although current treatments (all-trans retinoic acid (ATRA), anthracyclines and conventional chemotherapy) are associated with high remission rates, cytotoxic effects of chemotherapy remain a concern in the management of newly diagnosed APL.
Trisenox® is a sterile injectable solution of arsenic trioxide (ATO). Trisenox® has been approved in several countries, including Canada, for the induction of remission and consolidation in patients with APL who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy. Since the first approval of ATO is for the indication of relapsed/refractory APL, the safety and efficacy of ATO during induction and consolidation of newly diagnosed APL patients have been demonstrated. Specifically, Lo-Coco et al. compared the combination of ATO+ATRA to ATRA + idarubicin (IDA) and confirmed that the combination of ATO+ATRA is at least as effective as standard treatment in the first-line setting.
The objective of this study was to assess, from a Canadian perspective, the economic impact of the combination of ATO+ATRA in the treatment of newly diagnosed APL.
A time-dependent Markov model was constructed to assess the cost-effectiveness of ATO+ATRA compared to ATRA+IDA in the treatment of newly diagnosed APL. The Markov model comprises four health states: event-free survival (EFS), treatment failure/relapse (TF), post-failure (PF) and death. The length of each Markov cycle was one month for the 48-month period of the Lo-Coco et al. study and then of one year. The model continued to run until all patients reached the absorbing state, defined as death. All patients started in the EFS state and could then move to other health states. In the case of treatment relapse/failure, patients were subsequently treated with a salvage induction therapy composed of ATRA and conventional chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) as consolidation treatment. The model also takes into account the incidence of treatment-induced adverse events that were significantly different between both treatment arms in the Lo-Coco et al. study(neutropenia, thrombocytopenia, fever episodes, and QTc interval prolongation). The model also allows comparison with the combination of ATRA+IDA+cytarabine, which is also used in Canada. Analyses were conducted from both a Canadian Ministry of Health (MoH) and a societal perspective over a lifetime horizon.
In the treatment of newly diagnosed APL, ATRA+ATO is associated with incremental cost-effectiveness ratios (ICERs) of $50,193 per QALY and $46,367 per QALY, from a MoH and societal perspective respectively when compared with ATRA+IDA.
According to the deterministic analysis Results, the ICER of ATO+ATRA compared to ATRA+IDA varied from $23,045 / QALY and $60,759 / QALY from a MoH perspective and between $21,294 / QALY and $56,933 / QALY from a societal perspective. Results of the probabilistic sensitivity analysis indicated that the ICER remains below $50,000 in 48.33% and 74.21% of the Monte Carlo simulations from a MoH and a societal perspective respectively. However, ICER remains below $100,000 in 100% of the simulations from both perspectives.
The use of Trisenox in the first line therapy of patients with APL provides significant additional clinical benefits and is associated with an ICUR below the ICUR of many other oncology treatments currently in use.

Disclosures:
Lachaine: Lundbeck Canada: Research Funding. Off Label Use: Arsenic trioxide is not yet approved in Canada for the First-line treatment of acute promyelocytic leukemia. Barakat:Lundbeck Canada: Employment.