Hematological Oncology Hematol Oncol 2015; 33: 229–238 Published online 25 November 2014 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/hon.2176
Original Research Article
Economic evaluation of arsenic trioxide for treatment of newly diagnosed acute promyelocytic leukaemia in Canada Jean Lachaine1*, Karine Mathurin1, Stéphane Barakat2 and Andre C. Schuh3 1 2 3
Faculty of Pharmacy, University of Montreal, Montreal, QC, Canada Market Access and Health Outcomes, Lundbeck Canada Inc., Montreal, QC, Canada Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
*Correspondence to: Jean Lachaine, PhD, Faculty of Pharmacy, University of Montreal, P.O. Box 6128, Station CentreVille, Montreal, QC, Canada H3C 3 J7. E-mail: [email protected]
Received 10 September 2014 Accepted 30 September 2014
Abstract To assess, from a Canadian perspective, the economic impact of arsenic trioxide (ATO) + all-trans retinoic acid (ATRA) for treating newly diagnosed acute promyelocytic leukaemia (APL), the cost-effectiveness of ATO + ATRA compared to ATRA + idarubicin (IDA) was assessed over a lifetime horizon using a time-dependent Markov model. The model considers four health states: complete remission, treatment failure or relapse, post-failure, and death. Markov cycle length was 1 month for the first 48 months and 1 year thereafter. Efficacy outcomes in terms of event-free survival and overall survival were taken from a head-to-head clinical trial. Costs were associated with drug and administration, adverse events (AEs), treatment of relapses, follow-up visits, and productivity losses. Utilities and disutilities associated with health states and AEs were derived from the literature. Compared to ATRA + IDA, ATRA + ATO is associated with incremental costeffectiveness ratios (ICERs) of $CAD50,193/quality-adjusted life years (QALY) and $CAD50,338/QALY from a Canadian Ministry of Health (MoH) and societal perspectives, respectively. Results of the one-way sensitivity analysis show that ICER varied from $CAD23,045 to $CAD60,759/QALY (MoH perspective) and from $CAD23,120 to $CAD60,905/QALY (societal perspective). ATO in the first-line therapy for patients with APL can be considered a more cost-effective strategy than standard treatment from a Canadian perspective. Copyright © 2014 John Wiley & Sons, Ltd. Keywords: arsenic trioxide; all-trans retinoic acid; acute promyelocytic leukaemia; Canada; cost-effectiveness; cost-utility
Introduction Acute promyelocytic leukaemia (APL) is a rare and distinct subtype of acute myeloid leukaemia (AML) characterized by acute coagulopathy and/or excessive fibrinolysis, resulting in death at early treatment stages. If left untreated, APL is the most fatal leukaemia, but if promptly diagnosed and treated, it is the most frequently curable AML subtype.[1] Although the Canadian incidence and prevalence of APL remain unknown, it has been estimated to account for approximately 10% to 15% of all AMLs, which amounts to from 0.2 to 0.3 cases per 100,000 Canadians per year [2]. Newly diagnosed APL in adults is usually treated in three successive steps: remission induction, consolidation, and maintenance therapy, all accompanied by supportive care as needed.[3–5] In the absence of Canadian guidelines, APL treatment has not been standardized across provinces. However, all-trans retinoic acid (ATRA) plus anthracycline is available for APL treatment in several Copyright © 2014 John Wiley & Sons, Ltd.
provinces and is recognized by most Canadian experts as the standard of care for patients with newly diagnosed APL, in line with international guidelines. Arsenic trioxide (ATO) has been approved in Canada for remission induction and consolidation in patients with APL who are refractory to or have relapsed from retinoid and anthracycline chemotherapy. The indication of ATO is the same as for other countries. More recently, the efficacy and safety of ATO plus ATRA has been assessed as first-line treatment in phase III randomized clinical trials, [6–8] in which ATO administration during induction and/or consolidation cycles showed clinical benefits in terms of survival and toxicity profile for patients with newly diagnosed APL. Given that the cytotoxic effects of chemotherapy treatments are a concern for these patients, ATO plus ATRA is a valuable option for first-line APL treatment. Indeed, conventional chemotherapy is associated with a myelosuppressive effect and other toxicities, increasing the risk of mortality not only during induction, but in complete remission as well. Moreover, according
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to a panel of Canadian experts and clinical research, the need to use less or no conventional chemotherapy is particularly important in APL, in which coagulopathy (which can be exacerbated by chemotherapy) and consequently the risk of early death are concerns. Furthermore, several studies have found associations between conventional chemotherapies and risks for developing secondary malignancies.[9–11] ATO provides an alternative treatment with significant benefits and a unique toxicity profile that is transient and manageable. To date, no economic study has been performed in APL. The aim of this study was therefore to assess, from a Canadian perspective, the economic impact of ATO + ATRA in treating newly diagnosed APL.
Methods A cost-utility analysis was conducted according to the most recent Canadian Agency for Drugs and Technologies in Health (CADTH) [12] guidelines for the economic evaluation of health technologies.
Model structure A Markov model simulating the course of newly diagnosed APL patients receiving induction therapy followed by consolidation therapy in case of a complete response (CR) was developed. It considered the following health states: event-free survival (EFS), treatment failure (TF), post-treatment failure (PF), and death (D). According to the survival data, the length of each Markov cycle was 1 month during the 48 month study period and 1 year thereafter.[6] In the first treatment month, patients could experience treatment-induced adverse events (AEs) according to the incidence reported in a pivotal clinical trial (Figure 1).[6]
Interventions The model compared the ATO + ATRA combination to the ATRA + chemotherapy combination. Both treatment regimens were taken from standard induction and consolidation treatments.[3] Dosages were taken from a pivotal clinical trial by Lo-Coco et al., which was used as the main data source for the clinical outcomes modelled here.[6] Patients in the ATO + ATRA group received ATO 0.15 mg/kg plus ATRA 45 mg/m2 daily until CR, followed by ATO 5 days/week, 4 weeks on and 4 weeks off, for a total of four courses, followed by ATRA 2 weeks on and 2 weeks off, for a total of seven courses.[13,14] Patients in the ATRA + idarubicin (IDA) group received the standard induction followed by three cycles of anthracyclinebased chemotherapy plus ATRA for consolidation, as Copyright © 2014 John Wiley & Sons, Ltd.
Figure 1. Model structure. *Treatment failure includes relapse or incomplete treatment response
described previously.[15] According to clinical experts and the research, the need for maintenance therapy remains controversial.[16] As a conservative assumption, it was considered to be the same in both treatment groups, and therefore was not included in the model, as validated by Canadian experts. However, in Lo-Coco et al.’s trial, the ATRA + IDA group received maintenance treatment, unlike the ATRA + ATO group.[6] This scenario was considered in a complementary analysis.
Clinical data Clinical data for both regimens were taken from a study conducted in 162 adult patients with newly diagnosed, genetically confirmed, low/intermediate risk (white blood cells ≤ 10x109/L) APL.[6] Of 156 patients evaluable for induction response, CR was achieved in 97.4%: 100% in the ATRA + ATO arm versus 95% in the ATRA + IDA arm (P.12). After a median follow-up of 34.4 months, the 2 year EFS was 97% and 86% (P < .001 for noninferiority) in the ATRA + ATO and ATRA + IDA arm, respectively. Post-remission events included one all-cause death in CR and two relapses in the ATRA + ATO arm, with seven deaths (four in induction, three in CR) and five relapses in the ATRA + IDA arm. The secondary endpoint rates, including overall survival (OS), disease-free survival, and cumulative incidence of relapse rates, were 99% versus 91% (P.02), 97% versus 90% (P.11), and 1% versus 6% (P.24) in the ATRA + ATO and ATRA + IDA arm, respectively. Hematol Oncol 2015; 33: 229–238 DOI: 10.1002/hon
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Transition probabilities The transition probabilities between health states were taken from Kaplan–Meier curves for EFS and OS in LoCoco et al.’s study.[6] After the 48 month study period, the mortality risk for newly diagnosed APL patients in EFS (in CR) was considered to be similar to that observed in the general population.[17] Because the TF state is transient, patients in this state automatically moved from TF to PF state during the cycle following relapse or TF. Patients who did not respond to their first-line therapy or who relapsed after a response received a subsequent therapy. ATO is recognized by Canadian experts as the standard of care for this condition. Before the use of ATO in relapsed/refractory APL, salvage therapy usually consisted of re-administration of induction ATRA and chemotherapy, generally containing high-dose cytarabine and an anthracycline, followed by further chemotherapy and/or haematopoietic stem cell transplantation (HSCT). [18] Thomas et al. assessed the safety and efficacy of HSCT (mainly autologous) as consolidation therapy in APL patients who relapsed and achieved a second complete remission (CR2).[19] These patients had been previously treated with ATRA as first-line treatment and achieved CR2 with ATRA followed by timed sequential chemotherapy (combining etoposide, mitoxantrone, and cytarabine).[20] Data from Thomas et al.’s study were used to estimate the transition probabilities between PF and D (Table 1). After the 48 month study period, the mortality risk for survivors in PF state was considered to be similar to that observed in the general population.[17]
Adverse events Incidences of AEs were based on incidences reported in Lo-Coco et al.’s trial.[6] Only severe AEs (grade ≥ 3) with significantly different incidence between the two groups were taken into account (Table 1), including fever, thrombocytopenia, neutropenia, hepatotoxicities, and QTc interval prolongation. As the AEs included in the model were punctual, they were considered for the first model month only. Moreover, as fewer AEs were reported in consolidation than in induction,[21] it was assumed that AEs occurred during the induction phase only.
Utilities Few publications have reported quality of life data specifically for APL patients.[22,23] However, these data are insufficient to estimate the utilities associated with the model’s health states. Therefore, the utilities for the present economic evaluation were derived from a study conducted in adult AML patients who achieved a first remission on allo-HSCT or chemotherapy (Table 1).[24] Because APL is Copyright © 2014 John Wiley & Sons, Ltd.
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an AML subtype, these values were assumed to best represent the target population, as validated by a Canadian expert. Utilities associated with AEs were assigned after conducting a literature review of published utility scores associated with cancer treatment-related AEs.[25–30] The weighted average of disutilities reported for a same AE was thereafter calculated to estimate the disutility associated with each AE considered in the model (Table 1). No utility loss was considered for patients who experienced a QTc interval prolongation or hepatotoxicities, as management associated with these events was not likely to be associated with utility loss.
Cost data Analyses were conducted from a Canadian Ministry of Health (MoH) and a societal perspective. Table 2 presents the different costs included in the model. Treatment regimens for both therapeutic arms were taken from Lo-Coco et al.’s trial.[6] The median time to CR for each treatment arm was used to determine the number of ATO and ATRA induction doses.[6] Drug wastage was not taken into account in the base-case analysis but was considered in the sensitivity analyses. According to Canadian clinical experts, induction treatments are administered to inpatients and consolidation treatments are administered to outpatients. Therefore, drug administration costs during induction corresponded to inpatient costs. Consolidation drug administration costs were estimated based on nursing and pharmacy workloads as well as physician care and chair time for chemotherapy treatment. Treatment and administration costs were imputed based on Markov cycles according to calendar time. The cost of autologous HSCT was taken from Couban et al. and included all costs incurred during and 100 days after transplantation. These costs included clinic and daycare visits, professional haematologist fees, laboratory and diagnostic tests, medications, hospital readmission costs, and intensive care unit visits.[31] Follow-up costs were added after the treatment period, based on clinical experts’ opinions and follow-up directives in the Canadian AML management guidelines.[3] Costs associated with AEs were assumed to be included in the hospitalization fees incurred during the induction phase. For the societal perspective, the costs of productivity loss associated with APL were added. According to clinical experts, APL patients are off work for about 6 months following their diagnosis, due to the disease itself and the APL treatments. Therefore, a 6 month period of productivity loss was applied for all patients in both treatment arms, based on the mean national hourly wage in April 2013 ($CAD24.28).[32] In the case of relapse or treatment failure, another 6 month period of productivity loss was added. In addition, 1 hour of work loss was added for each Hematol Oncol 2015; 33: 229–238 DOI: 10.1002/hon
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Table 1. Model inputs—clinical parameters Description
Target population Age at onset, years Proportion of males, % Incidence of AEs, %a Neutropenia ATO + ATRA ATRA + IDA Thrombocytopenia ATO + ATRA ATRA + IDA Fever episodes ATO + ATRA ATRA + IDA Hepatotoxicity ATO + ATRA ATRA + IDA QTc prolongation ATO + ATRA ATRA + IDA Mortality risk with subsequent treatment (after relapse), % Parameters associated with drug administration, min ATO Nursing workload Pharmacy workload Chair time ATRA Nursing workload Pharmacy workload Chair time IDA Nursing workload Pharmacy workload Chair time MTZ Nursing workload Pharmacy workload Chair time Utilities/Disutilitiesb Health state EFS Relapse CR2 Death AEs Neutropenia Thrombocytopenia Fever episodes Hepatotoxicity QTc prolongation Discount rate Costs and effects, %
Base case
Lower bound
Upper bound
– –
– –
46.0 79.0
34.5 59.3
57.5 98.8
59.0 88.0
44.3 66.0
73.8 100.0
33.8 74.7
25.3 56.0
42.2 93.4
63.0 6.0
47.3 4.5
78.8 7.5
16.0 0.0 53.0
12.0 – 0.0
20.0 – 100.0
37 10 120
– – –
– – –
0 0 0
– – –
– – –
37 10 10
– – –
– – –
37 10 30
– – –
– – –
0.900 0.500 0.800 0
0.800 0.200 0.400 –
1.00 0.800 0.950 –
0.135 0.095 0.088 0 0
0.300 0.108 0.195 0.136 0.136
0.090 0.081 0 0 0
5
0
3
46 49
Reference
Lo-Coco et al. [6]
Lo-Coco et al. [6]
Thomas et al. [19]
Cancer Care Ontario, Product monographs [40–44]
Kurosawa et al. [24] Literature review [25–30]
CADTH [12]
AE, adverse events; ATO, arsenic trioxide; ATRA, all-trans retinoic acid; CADTH, Canadian Agency for Drugs and Technologies in Health; CR2, second complete remission; EFS, event-free survival; IDA, idarubicin; MTZ, mitoxantrone. a A ±25% variation in the base-case parameter was applied to the incidence of AEs to determine the lower and upper bounds used for sensitivity analyses. b The lower and upper bounds of the confidence interval (95% CI) were included in the sensitivity analyses of the health state utilities and disutilities.
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Table 2. Model inputs—costs Cost parameter
Treatment Costs ATO ATRA IDA MTZ
Base case (2013$CAD)
Lower bound
Upper bound
Reference
$530.00/10 mg ampule $13.11/10 mg capsule $423.03/10 mg per 10 mL Vial $548.15/20 mg per 10 mL Vial
– – – –
– – – –
Lundbeck Canada Inc Wholesale price, Ontario Wholesale price, Ontario Wholesale price, Ontario
Cost parameters associated with drug administrationa Registered nurse Pharmacist Specialist visit Inpatient cost Overhead cost Follow-up costsa 0–4 years
$34.13/hour $46.57/hour $31.00/control visit $1,343/inpatient day $11.06/hour
$25.60 $34.93 $23.25 $1,007 $8.30
$42.66 $58.21 $38.75 $1,678 $13.83
Working in Canada[45] Working in Canada[46] OHIP[47] OCCI[48] Coyte et al. [49]
$34.25/month
$25.69
$42.81
OHIP[47], Guidelines for AML management[3]
5–9 years 10 years and +
$137.00/year $34.25/year
$102.7 5 $25.60
$171.2 5 $292.65
$9,005
–
–
$58,432 $71,159
$73,03 9 $88,94 9 $6,908 $8,350 $3,401 $12,90 5 $4,488
Couban et al. [31] OCCI[48]
Statistics Canada[32] Expert opinion Statistics Canada[32] Expert opinion
Costs associated with relapsea Reinduction therapy (ATRA + CT) HSCT Hospitalization (during reinduction) Costs associated with AEsb Neutropenia Thrombocytopenia Fever episodes Hepatotoxicity QTc prolongation Costs associated with productivity lossesa Productivity losses due to APL treatment (6 months) Productivity losses due to follow-up
$0 $0 $0 $0 $0
$43,82 3 $53,36 9 – – – – –
$3,399
$2,549
$4,249
$24.28/month
$18.21
$30.35
0–4 years 5–9 years 10 years and +
$97.12/year $24.28/year
$72.84 $18.21
$121.4 0 $30.35
Wholesale price, Ontario
Expert opinion OCCI[48]
AE, adverse events; AML, acute myeloid leukaemia; APL, acute promyelocytic leukaemia; ATO, arsenic trioxide; ATRA, all-trans retinoic acid; CT, chemotherapy; HSCT, haematopoietic stem cell transplantation; IDA, idarubicin; MTZ, mitoxantrone; OCCI, Ontario Case Costing Initiative; OHIP, Ontario Health Insurance Plan. a When applicable, a ±25% variation in the base-case parameter was applied to costs to determine the lower and upper bounds used for sensitivity analyses. b Specific costs according to the diagnosis of interest were obtained from the OCCI and were used as lower bounds for the costs associated with AEs in sensitivity analyses.
follow-up visit after the treatment period. Informal care was not included because patients are hospitalized during the induction phase and unlikely to require additional assistance, as validated by clinical experts. All costs estimated before 2013 were adjusted to April 2013 levels based on the health component of the Canadian Consumer Price Index.[33] Copyright © 2014 John Wiley & Sons, Ltd.
Incremental cost-effectiveness ratio The incremental cost-effectiveness ratios (ICERs) were calculated by dividing the difference in total costs for the ATO + ATRA and ATRA + IDA treatment arms by the difference in quality-adjusted survival between the two treatment arms. Hematol Oncol 2015; 33: 229–238 DOI: 10.1002/hon
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Complementary analysis In Lo-Coco et al.’s clinical trial, eligible patients were at low/intermediate risk APL.[6] However, ATO efficacy in newly diagnosed APL has been assessed in other risk populations. Powell et al. randomized 481 all-risk untreated APL patients either to a standard induction regimen of ATRA, cytarabine, and daunorubicin followed by two courses of consolidation therapy with ATRA plus daunorubicin or to the same induction and consolidation regimen plus two 25 day courses of ATO consolidation immediately after induction.[7] A complementary analysis was performed using data from Powell et al. to assess the economic impact of ATO consolidation for any risk group of newly diagnosed APL patients. Data from best-fitting curves were included in the model for 36 months only, which corresponds to the EFS and OS estimate times. Beyond this period, the mortality risk for the general population was applied to all patients remaining in any health state. Treatment costs were calculated as described above. Because no specific AE incidence data were reported in Powell et al., AEs were not considered in this complementary analysis. Moreover, according to Powell et al., the safety profile was very similar in both groups, and AEs were transient and manageable.[34] Other model parameters were the same as in the base-case analysis. The addition of maintenance treatment for the ATRA + IDA arm only, as described in Lo-Coco et al., was also considered in a complementary analysis.[6] In their study, maintenance treatment consisted of intramuscular or oral methotrexate at a dose of 15 mg/m2 per week and oral 6-mercaptopurine at a dose of 50 mg/m2 per day, alternating with ATRA at a dose of 45 mg/m2 per day for 15 days every 3 months for 2 years. As these treatments were given orally, no additional administration costs were considered, and only treatment costs associated with maintenance were added to the model.
Sensitivity analyses Several one-way analyses were performed to confirm the robustness of the base-case results. In addition, a probabilistic sensitivity analysis was performed by simultaneous parameter variation using Monte Carlo simulation. In all, 10,000 Monte Carlo simulations were performed using a triangular probability distribution. One-way and probabilistic sensitivity analyses were performed on key parameters, including target population, AE incidence, mortality risk, costs, ATO wastage in consolidation phase, and utility (Tables 1 and 2).
Results Base-case analysis Over a lifetime horizon, the ATO + ATRA combination was associated with 14.68 quality-adjusted life years (QALYs) Copyright © 2014 John Wiley & Sons, Ltd.
Table 3. Cost-effectiveness results—base-case analysis
Number of QALYs Costs, $CAD Drug acquisition cost Drug administration cost Cost of relapse Cost of follow-up Cost of AEs Productivity losses due to APL Productivity losses due to follow-up Total cost MoH perspective Total cost Societal perspective Incremental cost, $CAD/QALY MoH perspective Incremental cost, $CAD/QALY Societal perspective
ATO + ATRA
ATRA + IDA
Incrementala
14.68
13.24
1.44
79,953 60,792 3,347 1,870 0 20,755
16,467 47,016 8,282 2,003 0 20,452
63,486 13,776 -4,935 -133 0 303
1,326
1,420
-94
145,962
73,768
72,194
168,043
95,640
72,403
–
–
$CAD50,193/ QALY
–
–
$CAD50,338/ QALY
AE, adverse events; APL, acute promyelocytic leukaemia; ATO, arsenic trioxide; ATRA, all-trans retinoic acid; IDA, idarubicin; MoH, Ministry of Health; QALY, quality-adjusted life years. a May not sum to total due to rounding.
Table 4. Cost-effectiveness results—all-risk groups +ATO in Standard consolidation consolidation Incrementala
Number of QALYs Costs, $CAD Drug acquisition cost Drug administration cost Cost of relapse Cost of follow-up Productivity losses due to APL Productivity losses due to follow-up Total cost MoH perspective Total cost Societal perspective Incremental cost, $CAD/QALY MoH perspective Incremental cost, $CAD/QALY Societal perspective
14.79
14.46
0.33
41,784 118,126
14,755 115,903
27,029 2,223
24,086 1,817 22,597
48,500 1,875 23,162
-24,414 -58 -565
1,288
1,329
-41
185,813
181,033
4,780
209,698
205,525
4,174
–
–
$CAD14,703/ QALY
–
–
$CAD12,838/ QALY
APL, acute promyelocytic leukaemia; ATO, arsenic trioxide; MoH, Ministry of Health; QALY, quality-adjusted life years a May not sum to total due to rounding. Hematol Oncol 2015; 33: 229–238 DOI: 10.1002/hon
Cost-effectiveness of arsenic trioxide in APL
compared to 13.24 QALYs with the ATRA + IDA combination (Table 3), for a gain of 1.44 QALYs per patient with the ATO + ATRA combination. From a MoH perspective, ATO + ATRA and ATRA + IDA were associated with total costs of $CAD145,962 and $CAD73,768, respectively. The incremental cost for ATO + ATRA compared to ATRA + IDA was $CAD72,194, for an ICER of $CAD50,193 (€35,665)/QALY. From a societal perspective, ATO + ATRA and ATRA + IDA were associated with total costs of $CAD168,043 and $CAD95,640, respectively. The incremental cost was $CAD72,403, for an ICER of $CAD50,338 (€35,769)/QALY for ATO + ATRA compared to ATRA + IDA.
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Complementary analysis When all-risk groups were considered, the ICER for ATO in consolidation compared to standard consolidation was estimated at $CAD14,703/QALY and $CAD12,838/ QALY from MoH and societal perspectives, respectively (Table 4). In addition, when a maintenance treatment was added for the ATRA + IDA arm, as described in Lo-Coco et al., the ICER for ATO + ATRA compared to ATRA + IDA was estimated at $CAD38,954/QALY and $CAD39,099/QALY from a MoH and a societal perspective, respectively, due
Figure 2. Results of the one-way sensitivity analysis. Bars represent the variation in the base-case cost-effectiveness ratio due to changes in the input parameters, as described in Tables 1 and 2. Results from (a) a MoH perspective and (b) a societal perspective Copyright © 2014 John Wiley & Sons, Ltd.
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to an overall increase of $CAD16,165 in treatment costs for the ATRA + IDA arm.
Sensitivity analyses According to the one-way sensitivity analysis results, the ICER for ATO + ATRA compared to ATRA + IDA varied from $CAD23,045/QALY to $CAD60,759/QALY from a MoH perspective and from $CAD23,120/QALY to $CAD60,905/QALY from a societal perspective. Tornado diagrams show that the parameters that wielded the greatest impact on base-case ICERs from both perspectives were (1) actualization rate, (2) drug administration costs, and (3) mortality risk after relapse (Figures 2a and 2b). Results of the probabilistic sensitivity analysis indicated that the ICER remains below $CAD50,000 in 48.33% of the Monte Carlo simulations from a MoH perspective (similar from a societal perspective) (Figure 3).
Discussion This economic evaluation indicates that compared to the ATRA + IDA combination, the ATO + ATRA combination is associated with ICERs of $CAD50,193 (€35,665)/ QALY and $CAD50,338 (€35,769)/QALY from MoH and societal perspectives, respectively. Results of the exhaustive sensitivity analyses confirm the robustness of the base-case results. The parameter that had the greatest impact on the base-case results was the discount rate. This can be explained by the long life expectancy for APL patients (model starting age = 46 years). The CADTH recommends discounting costs and effects at a rate of 5%.[12] This discount rate is higher than that recommended by several other countries.[35,36] Thus, the discount rate used in this analysis (5%) is more conservative than those used in other countries: a lower discount rate
would improve the ICERs and consequently favour the ATO + ATRA combination. To our knowledge, this is the first economic evaluation conducted in APL. Because no economic information was available on this disease, the present analysis will facilitate an understanding of its economic impact and particularly the impact of ATO in patients with newly diagnosed APL from a Canadian perspective. The model is based on clinical data taken from a direct comparison trial, which strengthens the results. Moreover, a more complete analysis is provided by accounting for AEs associated with treatment as well as productivity losses associated with cancer before and after progression. Furthermore, a complementary analysis considering all-risk APL groups allowed a better estimate of the economic impact of ATO in different populations of newly diagnosed APL patients. As for any model-based analysis, and especially for rare diseases, many assumptions were made due to very limited data, which may increase the uncertainty of the results. However, a conservative approach was adopted to define each model assumption, which was validated by clinical experts. For example, the utilities associated with health states were estimated for AML.[24] According to clinical experts, APL treatment is associated with higher hospitalization rates and more serious adverse events than AML treatment, which has been associated with lower utilities. Despite these limitations, exhaustive sensitivity analyses were performed to assess the uncertainty associated with some of the study parameters. It is worth mentioning that anthracycline and conventional chemotherapy-based regimens are associated with long-term toxicity.[37] This cardiotoxicity usually occurs after the completion of anthracycline treatment and may become apparent within 1 year of treatment completion or many years after chemotherapy completion.[38] There is also evidence that anthracycline cardiotoxicity is cumulative dose dependent.[39] In addition, several studies have found risks of developing therapy-related myeloid neoplasms with anthracyclines and conventional chemotherapies.[9–11] Although these treatment-related toxicities may play a role in the survival and morbidity associated with APL treatment, it was difficult to take them into account in the present model. As a conservative assumption, these toxicities were not included in the analysis. However, as the ATO + ATRA combination allows avoiding the use of anthracyclines or conventional chemotherapies, therefore minimizing the development of these complications, the ICERs reported here may be overestimated.
Conclusion Figure 3. Cost-acceptability curves. The graph represents the probability (y-axis) that the ICER generated by the Monte Carlo simulation is equal to or lower than the ceiling ICER (x-axis) Copyright © 2014 John Wiley & Sons, Ltd.
This economic evaluation demonstrates that ATO + ATRA can be considered a cost-effective strategy over standard treatment for APL from a Canadian perspective. This is Hematol Oncol 2015; 33: 229–238 DOI: 10.1002/hon
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the first chemotherapy-free regimen to show significant clinical benefits compared to the current standard APL therapy. Given that conventional chemotherapy is associated with toxicities that increase the risk of mortality associated with APL and that ATO has been identified as a potential cure by the majority of clinical experts, the ATO + ATRA regimen should be taken into consideration in the treatment algorithm for newly diagnosed APL.
Conflict of interest JL, KM, and ACS have received consulting fees from Lundbeck Canada Inc. SB is an employee of Lundbeck Canada Inc.
Ethics statement Given the nature of this study (no human or animal subjects), it has not been approved by an Ethics Committee.
Acknowledgements We would like to thank Dr. Francesco Lo-Coco (University Tor Vergata, Rome, Italy) for reviewing the manuscript from a clinical standpoint and Dr. John Storring (McGill University Health Centre, Montreal) and Dr. Geneviève Gallagher (Hôpital de l’Enfant-Jésus, Quebec), haemato-oncologists, for validating the model assumptions. The study sponsor participated in the study design, in the collection of data, and in the decision to submit the paper for publication.
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9. Latagliata R, Petti MC, Fenu S, et al. Therapy-related myelodysplastic syndrome-acute myelogenous leukemia in patients treated for acute promyelocytic leukemia: an emerging problem. Blood 2002; 99: 822–824. 10. Lobe I, Rigal-Huguet F, Vekhoff A, et al. Myelodysplastic syndrome after acute promyelocytic leukemia: the European APL group experience. Leukemia 2003; 17: 1600–1604. 11. Montesinos P, Gonzalez JD, Gonzalez J, et al. Therapy-related myeloid neoplasms in patients with acute promyelocytic leukemia treated with all-trans-retinoic Acid and anthracycline-based chemotherapy. J Clin Oncol 2010; 28: 3872–3879. 12. Canadian Agency for Drugs and technologies in health (CADTH). Guidelines for the economic evaluation of health technologies: Canada, 2006. 13. Estey E, Garcia-Manero G, Ferrajoli A, et al. Use of all-trans retinoic acid plus arsenic trioxide as an alternative to chemotherapy in untreated acute promyelocytic leukemia. Blood 2006; 107: 3469–3473. 14. Ravandi F, Estey E, Jones D, et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 2009; 27: 504–510. 15. Lo-Coco F, Avvisati G, Vignetti M, et al. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood 2010; 116: 3171–3179. 16. Muchtar E, Vidal L, Ram R, Gafter-Gvili A, Shpilberg O, Raanani P. The role of maintenance therapy in acute promyelocytic leukemia in the first complete remission. Cochrane Database Syst Rev 2013; 3: CD009594. 17. Statistics Canada. Deaths and mortality rate, by selected grouped causes, age group and sex, Catalogue no. 84F0209X Table 102-0551, 2009. 18. Esteve J, Escoda L, Martin G, et al. Outcome of patients with acute promyelocytic leukemia failing to front-line treatment with all-trans retinoic acid and anthracycline-based chemotherapy (PETHEMA protocols LPA96 and LPA99): benefit of an early intervention. Leukemia 2007; 21: 446–452. 19. Thomas X, Dombret H, Cordonnier C, et al. Treatment of relapsing acute promyelocytic leukemia by all-trans retinoic acid therapy followed by timed sequential chemotherapy and stem cell transplantation. APL study group. Acute promyelocytic leukemia. Leukemia 2000; 14: 1006–1013. 20. Archimbaud E, Leblond V, Michallet M, et al. Intensive sequential chemotherapy with mitoxantrone and continuous infusion etoposide and cytarabine for previously treated acute myelogenous leukemia. Blood 1991; 77: 1894–1900. 21. Iland HJ, Bradstock K, Supple SG, et al. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 2012; 120: 1570–1580. 22. Burnett AK, Hills RK, Grimwade D, et al. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia 2013; 27: 843–851. 23. Efficace F, Rambaldi A, Di Bona E, et al. Long-term health related quality of life and symptom burden in patients with acute promyelocytic leukemia treated with all-trans retinoic acid (ATRA) and chemotherapy. Blood 2013; 122(21): 770. 24. Kurosawa S, Yamaguchi T, Miyawaki S, et al. A Markov decision analysis of allogeneic hematopoietic cell transplantation versus chemotherapy in patients with acute myeloid leukemia in first remission. Blood 2011; 117: 2113–2120. 25. Beusterien KM, Davies J, Leach M, et al. Population preference values for treatment outcomes in chronic lymphocytic Hematol Oncol 2015; 33: 229–238 DOI: 10.1002/hon
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37. Von Hoff DD, Layard MW, Basa P, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979; 91: 710–717. 38. Volkova M, Russell R 3rd.. Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr Cardiol Rev 2011; 7: 214–220. 39. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 2003; 97: 2869–2879. 40. Cancer Care Ontario Formulary. Drug monograph: Mitoxantrone, 2011. 41. Cancer Care Ontario Formulary. Drug monograph: Idarubicin, 2011. 42. Cancer Care Ontario Formulary. Regimen monograph: FLUD + R Regimen, 2012. 43. Cancer Care Ontario Formulary. Drug monograph: Tretinoin, 2012. 44. Cephalon Inc. Product monograph: Trisenox®, 2010. 45. Government of Canada. Working in Canada tool: registered nurse (NOC 3152). [cited 2012 March 1]; Available from: http://www.workingincanada.gc.ca 46. Government of Canada. Working in Canada tool: pharmacists (NOC 3131). [cited 2012 March 1]; Available from: http:// www.workingincanada.gc.ca 47. Ministry of Health and Long-Term Care of Ontario. Schedule of benefits for physician services under the health insurance act, 2012. 48. Ontario Case Costing Initiative. OCCI costing analysis tool. [cited 2013 May 3]; Available from: http://www.occp.com/ mainPage.htm 49. Coyte PC, Dobrow MJ, Broadfield L. Incremental cost analysis of ambulatory clinic and home-based intravenous therapy for patients with multiple myeloma. Pharmacoeconomics 2001; 19: 845–854.
Hematol Oncol 2015; 33: 229–238 DOI: 10.1002/hon
Original Research Article
Economic evaluation of arsenic trioxide for treatment of newly diagnosed acute promyelocytic leukaemia in Canada Jean Lachaine1*, Karine Mathurin1, Stéphane Barakat2 and Andre C. Schuh3 1 2 3
Faculty of Pharmacy, University of Montreal, Montreal, QC, Canada Market Access and Health Outcomes, Lundbeck Canada Inc., Montreal, QC, Canada Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
*Correspondence to: Jean Lachaine, PhD, Faculty of Pharmacy, University of Montreal, P.O. Box 6128, Station CentreVille, Montreal, QC, Canada H3C 3 J7. E-mail: [email protected]
Received 10 September 2014 Accepted 30 September 2014
Abstract To assess, from a Canadian perspective, the economic impact of arsenic trioxide (ATO) + all-trans retinoic acid (ATRA) for treating newly diagnosed acute promyelocytic leukaemia (APL), the cost-effectiveness of ATO + ATRA compared to ATRA + idarubicin (IDA) was assessed over a lifetime horizon using a time-dependent Markov model. The model considers four health states: complete remission, treatment failure or relapse, post-failure, and death. Markov cycle length was 1 month for the first 48 months and 1 year thereafter. Efficacy outcomes in terms of event-free survival and overall survival were taken from a head-to-head clinical trial. Costs were associated with drug and administration, adverse events (AEs), treatment of relapses, follow-up visits, and productivity losses. Utilities and disutilities associated with health states and AEs were derived from the literature. Compared to ATRA + IDA, ATRA + ATO is associated with incremental costeffectiveness ratios (ICERs) of $CAD50,193/quality-adjusted life years (QALY) and $CAD50,338/QALY from a Canadian Ministry of Health (MoH) and societal perspectives, respectively. Results of the one-way sensitivity analysis show that ICER varied from $CAD23,045 to $CAD60,759/QALY (MoH perspective) and from $CAD23,120 to $CAD60,905/QALY (societal perspective). ATO in the first-line therapy for patients with APL can be considered a more cost-effective strategy than standard treatment from a Canadian perspective. Copyright © 2014 John Wiley & Sons, Ltd. Keywords: arsenic trioxide; all-trans retinoic acid; acute promyelocytic leukaemia; Canada; cost-effectiveness; cost-utility
Introduction Acute promyelocytic leukaemia (APL) is a rare and distinct subtype of acute myeloid leukaemia (AML) characterized by acute coagulopathy and/or excessive fibrinolysis, resulting in death at early treatment stages. If left untreated, APL is the most fatal leukaemia, but if promptly diagnosed and treated, it is the most frequently curable AML subtype.[1] Although the Canadian incidence and prevalence of APL remain unknown, it has been estimated to account for approximately 10% to 15% of all AMLs, which amounts to from 0.2 to 0.3 cases per 100,000 Canadians per year [2]. Newly diagnosed APL in adults is usually treated in three successive steps: remission induction, consolidation, and maintenance therapy, all accompanied by supportive care as needed.[3–5] In the absence of Canadian guidelines, APL treatment has not been standardized across provinces. However, all-trans retinoic acid (ATRA) plus anthracycline is available for APL treatment in several Copyright © 2014 John Wiley & Sons, Ltd.
provinces and is recognized by most Canadian experts as the standard of care for patients with newly diagnosed APL, in line with international guidelines. Arsenic trioxide (ATO) has been approved in Canada for remission induction and consolidation in patients with APL who are refractory to or have relapsed from retinoid and anthracycline chemotherapy. The indication of ATO is the same as for other countries. More recently, the efficacy and safety of ATO plus ATRA has been assessed as first-line treatment in phase III randomized clinical trials, [6–8] in which ATO administration during induction and/or consolidation cycles showed clinical benefits in terms of survival and toxicity profile for patients with newly diagnosed APL. Given that the cytotoxic effects of chemotherapy treatments are a concern for these patients, ATO plus ATRA is a valuable option for first-line APL treatment. Indeed, conventional chemotherapy is associated with a myelosuppressive effect and other toxicities, increasing the risk of mortality not only during induction, but in complete remission as well. Moreover, according
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to a panel of Canadian experts and clinical research, the need to use less or no conventional chemotherapy is particularly important in APL, in which coagulopathy (which can be exacerbated by chemotherapy) and consequently the risk of early death are concerns. Furthermore, several studies have found associations between conventional chemotherapies and risks for developing secondary malignancies.[9–11] ATO provides an alternative treatment with significant benefits and a unique toxicity profile that is transient and manageable. To date, no economic study has been performed in APL. The aim of this study was therefore to assess, from a Canadian perspective, the economic impact of ATO + ATRA in treating newly diagnosed APL.
Methods A cost-utility analysis was conducted according to the most recent Canadian Agency for Drugs and Technologies in Health (CADTH) [12] guidelines for the economic evaluation of health technologies.
Model structure A Markov model simulating the course of newly diagnosed APL patients receiving induction therapy followed by consolidation therapy in case of a complete response (CR) was developed. It considered the following health states: event-free survival (EFS), treatment failure (TF), post-treatment failure (PF), and death (D). According to the survival data, the length of each Markov cycle was 1 month during the 48 month study period and 1 year thereafter.[6] In the first treatment month, patients could experience treatment-induced adverse events (AEs) according to the incidence reported in a pivotal clinical trial (Figure 1).[6]
Interventions The model compared the ATO + ATRA combination to the ATRA + chemotherapy combination. Both treatment regimens were taken from standard induction and consolidation treatments.[3] Dosages were taken from a pivotal clinical trial by Lo-Coco et al., which was used as the main data source for the clinical outcomes modelled here.[6] Patients in the ATO + ATRA group received ATO 0.15 mg/kg plus ATRA 45 mg/m2 daily until CR, followed by ATO 5 days/week, 4 weeks on and 4 weeks off, for a total of four courses, followed by ATRA 2 weeks on and 2 weeks off, for a total of seven courses.[13,14] Patients in the ATRA + idarubicin (IDA) group received the standard induction followed by three cycles of anthracyclinebased chemotherapy plus ATRA for consolidation, as Copyright © 2014 John Wiley & Sons, Ltd.
Figure 1. Model structure. *Treatment failure includes relapse or incomplete treatment response
described previously.[15] According to clinical experts and the research, the need for maintenance therapy remains controversial.[16] As a conservative assumption, it was considered to be the same in both treatment groups, and therefore was not included in the model, as validated by Canadian experts. However, in Lo-Coco et al.’s trial, the ATRA + IDA group received maintenance treatment, unlike the ATRA + ATO group.[6] This scenario was considered in a complementary analysis.
Clinical data Clinical data for both regimens were taken from a study conducted in 162 adult patients with newly diagnosed, genetically confirmed, low/intermediate risk (white blood cells ≤ 10x109/L) APL.[6] Of 156 patients evaluable for induction response, CR was achieved in 97.4%: 100% in the ATRA + ATO arm versus 95% in the ATRA + IDA arm (P.12). After a median follow-up of 34.4 months, the 2 year EFS was 97% and 86% (P < .001 for noninferiority) in the ATRA + ATO and ATRA + IDA arm, respectively. Post-remission events included one all-cause death in CR and two relapses in the ATRA + ATO arm, with seven deaths (four in induction, three in CR) and five relapses in the ATRA + IDA arm. The secondary endpoint rates, including overall survival (OS), disease-free survival, and cumulative incidence of relapse rates, were 99% versus 91% (P.02), 97% versus 90% (P.11), and 1% versus 6% (P.24) in the ATRA + ATO and ATRA + IDA arm, respectively. Hematol Oncol 2015; 33: 229–238 DOI: 10.1002/hon
Cost-effectiveness of arsenic trioxide in APL
Transition probabilities The transition probabilities between health states were taken from Kaplan–Meier curves for EFS and OS in LoCoco et al.’s study.[6] After the 48 month study period, the mortality risk for newly diagnosed APL patients in EFS (in CR) was considered to be similar to that observed in the general population.[17] Because the TF state is transient, patients in this state automatically moved from TF to PF state during the cycle following relapse or TF. Patients who did not respond to their first-line therapy or who relapsed after a response received a subsequent therapy. ATO is recognized by Canadian experts as the standard of care for this condition. Before the use of ATO in relapsed/refractory APL, salvage therapy usually consisted of re-administration of induction ATRA and chemotherapy, generally containing high-dose cytarabine and an anthracycline, followed by further chemotherapy and/or haematopoietic stem cell transplantation (HSCT). [18] Thomas et al. assessed the safety and efficacy of HSCT (mainly autologous) as consolidation therapy in APL patients who relapsed and achieved a second complete remission (CR2).[19] These patients had been previously treated with ATRA as first-line treatment and achieved CR2 with ATRA followed by timed sequential chemotherapy (combining etoposide, mitoxantrone, and cytarabine).[20] Data from Thomas et al.’s study were used to estimate the transition probabilities between PF and D (Table 1). After the 48 month study period, the mortality risk for survivors in PF state was considered to be similar to that observed in the general population.[17]
Adverse events Incidences of AEs were based on incidences reported in Lo-Coco et al.’s trial.[6] Only severe AEs (grade ≥ 3) with significantly different incidence between the two groups were taken into account (Table 1), including fever, thrombocytopenia, neutropenia, hepatotoxicities, and QTc interval prolongation. As the AEs included in the model were punctual, they were considered for the first model month only. Moreover, as fewer AEs were reported in consolidation than in induction,[21] it was assumed that AEs occurred during the induction phase only.
Utilities Few publications have reported quality of life data specifically for APL patients.[22,23] However, these data are insufficient to estimate the utilities associated with the model’s health states. Therefore, the utilities for the present economic evaluation were derived from a study conducted in adult AML patients who achieved a first remission on allo-HSCT or chemotherapy (Table 1).[24] Because APL is Copyright © 2014 John Wiley & Sons, Ltd.
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an AML subtype, these values were assumed to best represent the target population, as validated by a Canadian expert. Utilities associated with AEs were assigned after conducting a literature review of published utility scores associated with cancer treatment-related AEs.[25–30] The weighted average of disutilities reported for a same AE was thereafter calculated to estimate the disutility associated with each AE considered in the model (Table 1). No utility loss was considered for patients who experienced a QTc interval prolongation or hepatotoxicities, as management associated with these events was not likely to be associated with utility loss.
Cost data Analyses were conducted from a Canadian Ministry of Health (MoH) and a societal perspective. Table 2 presents the different costs included in the model. Treatment regimens for both therapeutic arms were taken from Lo-Coco et al.’s trial.[6] The median time to CR for each treatment arm was used to determine the number of ATO and ATRA induction doses.[6] Drug wastage was not taken into account in the base-case analysis but was considered in the sensitivity analyses. According to Canadian clinical experts, induction treatments are administered to inpatients and consolidation treatments are administered to outpatients. Therefore, drug administration costs during induction corresponded to inpatient costs. Consolidation drug administration costs were estimated based on nursing and pharmacy workloads as well as physician care and chair time for chemotherapy treatment. Treatment and administration costs were imputed based on Markov cycles according to calendar time. The cost of autologous HSCT was taken from Couban et al. and included all costs incurred during and 100 days after transplantation. These costs included clinic and daycare visits, professional haematologist fees, laboratory and diagnostic tests, medications, hospital readmission costs, and intensive care unit visits.[31] Follow-up costs were added after the treatment period, based on clinical experts’ opinions and follow-up directives in the Canadian AML management guidelines.[3] Costs associated with AEs were assumed to be included in the hospitalization fees incurred during the induction phase. For the societal perspective, the costs of productivity loss associated with APL were added. According to clinical experts, APL patients are off work for about 6 months following their diagnosis, due to the disease itself and the APL treatments. Therefore, a 6 month period of productivity loss was applied for all patients in both treatment arms, based on the mean national hourly wage in April 2013 ($CAD24.28).[32] In the case of relapse or treatment failure, another 6 month period of productivity loss was added. In addition, 1 hour of work loss was added for each Hematol Oncol 2015; 33: 229–238 DOI: 10.1002/hon
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Table 1. Model inputs—clinical parameters Description
Target population Age at onset, years Proportion of males, % Incidence of AEs, %a Neutropenia ATO + ATRA ATRA + IDA Thrombocytopenia ATO + ATRA ATRA + IDA Fever episodes ATO + ATRA ATRA + IDA Hepatotoxicity ATO + ATRA ATRA + IDA QTc prolongation ATO + ATRA ATRA + IDA Mortality risk with subsequent treatment (after relapse), % Parameters associated with drug administration, min ATO Nursing workload Pharmacy workload Chair time ATRA Nursing workload Pharmacy workload Chair time IDA Nursing workload Pharmacy workload Chair time MTZ Nursing workload Pharmacy workload Chair time Utilities/Disutilitiesb Health state EFS Relapse CR2 Death AEs Neutropenia Thrombocytopenia Fever episodes Hepatotoxicity QTc prolongation Discount rate Costs and effects, %
Base case
Lower bound
Upper bound
– –
– –
46.0 79.0
34.5 59.3
57.5 98.8
59.0 88.0
44.3 66.0
73.8 100.0
33.8 74.7
25.3 56.0
42.2 93.4
63.0 6.0
47.3 4.5
78.8 7.5
16.0 0.0 53.0
12.0 – 0.0
20.0 – 100.0
37 10 120
– – –
– – –
0 0 0
– – –
– – –
37 10 10
– – –
– – –
37 10 30
– – –
– – –
0.900 0.500 0.800 0
0.800 0.200 0.400 –
1.00 0.800 0.950 –
0.135 0.095 0.088 0 0
0.300 0.108 0.195 0.136 0.136
0.090 0.081 0 0 0
5
0
3
46 49
Reference
Lo-Coco et al. [6]
Lo-Coco et al. [6]
Thomas et al. [19]
Cancer Care Ontario, Product monographs [40–44]
Kurosawa et al. [24] Literature review [25–30]
CADTH [12]
AE, adverse events; ATO, arsenic trioxide; ATRA, all-trans retinoic acid; CADTH, Canadian Agency for Drugs and Technologies in Health; CR2, second complete remission; EFS, event-free survival; IDA, idarubicin; MTZ, mitoxantrone. a A ±25% variation in the base-case parameter was applied to the incidence of AEs to determine the lower and upper bounds used for sensitivity analyses. b The lower and upper bounds of the confidence interval (95% CI) were included in the sensitivity analyses of the health state utilities and disutilities.
Copyright © 2014 John Wiley & Sons, Ltd.
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Table 2. Model inputs—costs Cost parameter
Treatment Costs ATO ATRA IDA MTZ
Base case (2013$CAD)
Lower bound
Upper bound
Reference
$530.00/10 mg ampule $13.11/10 mg capsule $423.03/10 mg per 10 mL Vial $548.15/20 mg per 10 mL Vial
– – – –
– – – –
Lundbeck Canada Inc Wholesale price, Ontario Wholesale price, Ontario Wholesale price, Ontario
Cost parameters associated with drug administrationa Registered nurse Pharmacist Specialist visit Inpatient cost Overhead cost Follow-up costsa 0–4 years
$34.13/hour $46.57/hour $31.00/control visit $1,343/inpatient day $11.06/hour
$25.60 $34.93 $23.25 $1,007 $8.30
$42.66 $58.21 $38.75 $1,678 $13.83
Working in Canada[45] Working in Canada[46] OHIP[47] OCCI[48] Coyte et al. [49]
$34.25/month
$25.69
$42.81
OHIP[47], Guidelines for AML management[3]
5–9 years 10 years and +
$137.00/year $34.25/year
$102.7 5 $25.60
$171.2 5 $292.65
$9,005
–
–
$58,432 $71,159
$73,03 9 $88,94 9 $6,908 $8,350 $3,401 $12,90 5 $4,488
Couban et al. [31] OCCI[48]
Statistics Canada[32] Expert opinion Statistics Canada[32] Expert opinion
Costs associated with relapsea Reinduction therapy (ATRA + CT) HSCT Hospitalization (during reinduction) Costs associated with AEsb Neutropenia Thrombocytopenia Fever episodes Hepatotoxicity QTc prolongation Costs associated with productivity lossesa Productivity losses due to APL treatment (6 months) Productivity losses due to follow-up
$0 $0 $0 $0 $0
$43,82 3 $53,36 9 – – – – –
$3,399
$2,549
$4,249
$24.28/month
$18.21
$30.35
0–4 years 5–9 years 10 years and +
$97.12/year $24.28/year
$72.84 $18.21
$121.4 0 $30.35
Wholesale price, Ontario
Expert opinion OCCI[48]
AE, adverse events; AML, acute myeloid leukaemia; APL, acute promyelocytic leukaemia; ATO, arsenic trioxide; ATRA, all-trans retinoic acid; CT, chemotherapy; HSCT, haematopoietic stem cell transplantation; IDA, idarubicin; MTZ, mitoxantrone; OCCI, Ontario Case Costing Initiative; OHIP, Ontario Health Insurance Plan. a When applicable, a ±25% variation in the base-case parameter was applied to costs to determine the lower and upper bounds used for sensitivity analyses. b Specific costs according to the diagnosis of interest were obtained from the OCCI and were used as lower bounds for the costs associated with AEs in sensitivity analyses.
follow-up visit after the treatment period. Informal care was not included because patients are hospitalized during the induction phase and unlikely to require additional assistance, as validated by clinical experts. All costs estimated before 2013 were adjusted to April 2013 levels based on the health component of the Canadian Consumer Price Index.[33] Copyright © 2014 John Wiley & Sons, Ltd.
Incremental cost-effectiveness ratio The incremental cost-effectiveness ratios (ICERs) were calculated by dividing the difference in total costs for the ATO + ATRA and ATRA + IDA treatment arms by the difference in quality-adjusted survival between the two treatment arms. Hematol Oncol 2015; 33: 229–238 DOI: 10.1002/hon
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Complementary analysis In Lo-Coco et al.’s clinical trial, eligible patients were at low/intermediate risk APL.[6] However, ATO efficacy in newly diagnosed APL has been assessed in other risk populations. Powell et al. randomized 481 all-risk untreated APL patients either to a standard induction regimen of ATRA, cytarabine, and daunorubicin followed by two courses of consolidation therapy with ATRA plus daunorubicin or to the same induction and consolidation regimen plus two 25 day courses of ATO consolidation immediately after induction.[7] A complementary analysis was performed using data from Powell et al. to assess the economic impact of ATO consolidation for any risk group of newly diagnosed APL patients. Data from best-fitting curves were included in the model for 36 months only, which corresponds to the EFS and OS estimate times. Beyond this period, the mortality risk for the general population was applied to all patients remaining in any health state. Treatment costs were calculated as described above. Because no specific AE incidence data were reported in Powell et al., AEs were not considered in this complementary analysis. Moreover, according to Powell et al., the safety profile was very similar in both groups, and AEs were transient and manageable.[34] Other model parameters were the same as in the base-case analysis. The addition of maintenance treatment for the ATRA + IDA arm only, as described in Lo-Coco et al., was also considered in a complementary analysis.[6] In their study, maintenance treatment consisted of intramuscular or oral methotrexate at a dose of 15 mg/m2 per week and oral 6-mercaptopurine at a dose of 50 mg/m2 per day, alternating with ATRA at a dose of 45 mg/m2 per day for 15 days every 3 months for 2 years. As these treatments were given orally, no additional administration costs were considered, and only treatment costs associated with maintenance were added to the model.
Sensitivity analyses Several one-way analyses were performed to confirm the robustness of the base-case results. In addition, a probabilistic sensitivity analysis was performed by simultaneous parameter variation using Monte Carlo simulation. In all, 10,000 Monte Carlo simulations were performed using a triangular probability distribution. One-way and probabilistic sensitivity analyses were performed on key parameters, including target population, AE incidence, mortality risk, costs, ATO wastage in consolidation phase, and utility (Tables 1 and 2).
Results Base-case analysis Over a lifetime horizon, the ATO + ATRA combination was associated with 14.68 quality-adjusted life years (QALYs) Copyright © 2014 John Wiley & Sons, Ltd.
Table 3. Cost-effectiveness results—base-case analysis
Number of QALYs Costs, $CAD Drug acquisition cost Drug administration cost Cost of relapse Cost of follow-up Cost of AEs Productivity losses due to APL Productivity losses due to follow-up Total cost MoH perspective Total cost Societal perspective Incremental cost, $CAD/QALY MoH perspective Incremental cost, $CAD/QALY Societal perspective
ATO + ATRA
ATRA + IDA
Incrementala
14.68
13.24
1.44
79,953 60,792 3,347 1,870 0 20,755
16,467 47,016 8,282 2,003 0 20,452
63,486 13,776 -4,935 -133 0 303
1,326
1,420
-94
145,962
73,768
72,194
168,043
95,640
72,403
–
–
$CAD50,193/ QALY
–
–
$CAD50,338/ QALY
AE, adverse events; APL, acute promyelocytic leukaemia; ATO, arsenic trioxide; ATRA, all-trans retinoic acid; IDA, idarubicin; MoH, Ministry of Health; QALY, quality-adjusted life years. a May not sum to total due to rounding.
Table 4. Cost-effectiveness results—all-risk groups +ATO in Standard consolidation consolidation Incrementala
Number of QALYs Costs, $CAD Drug acquisition cost Drug administration cost Cost of relapse Cost of follow-up Productivity losses due to APL Productivity losses due to follow-up Total cost MoH perspective Total cost Societal perspective Incremental cost, $CAD/QALY MoH perspective Incremental cost, $CAD/QALY Societal perspective
14.79
14.46
0.33
41,784 118,126
14,755 115,903
27,029 2,223
24,086 1,817 22,597
48,500 1,875 23,162
-24,414 -58 -565
1,288
1,329
-41
185,813
181,033
4,780
209,698
205,525
4,174
–
–
$CAD14,703/ QALY
–
–
$CAD12,838/ QALY
APL, acute promyelocytic leukaemia; ATO, arsenic trioxide; MoH, Ministry of Health; QALY, quality-adjusted life years a May not sum to total due to rounding. Hematol Oncol 2015; 33: 229–238 DOI: 10.1002/hon
Cost-effectiveness of arsenic trioxide in APL
compared to 13.24 QALYs with the ATRA + IDA combination (Table 3), for a gain of 1.44 QALYs per patient with the ATO + ATRA combination. From a MoH perspective, ATO + ATRA and ATRA + IDA were associated with total costs of $CAD145,962 and $CAD73,768, respectively. The incremental cost for ATO + ATRA compared to ATRA + IDA was $CAD72,194, for an ICER of $CAD50,193 (€35,665)/QALY. From a societal perspective, ATO + ATRA and ATRA + IDA were associated with total costs of $CAD168,043 and $CAD95,640, respectively. The incremental cost was $CAD72,403, for an ICER of $CAD50,338 (€35,769)/QALY for ATO + ATRA compared to ATRA + IDA.
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Complementary analysis When all-risk groups were considered, the ICER for ATO in consolidation compared to standard consolidation was estimated at $CAD14,703/QALY and $CAD12,838/ QALY from MoH and societal perspectives, respectively (Table 4). In addition, when a maintenance treatment was added for the ATRA + IDA arm, as described in Lo-Coco et al., the ICER for ATO + ATRA compared to ATRA + IDA was estimated at $CAD38,954/QALY and $CAD39,099/QALY from a MoH and a societal perspective, respectively, due
Figure 2. Results of the one-way sensitivity analysis. Bars represent the variation in the base-case cost-effectiveness ratio due to changes in the input parameters, as described in Tables 1 and 2. Results from (a) a MoH perspective and (b) a societal perspective Copyright © 2014 John Wiley & Sons, Ltd.
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to an overall increase of $CAD16,165 in treatment costs for the ATRA + IDA arm.
Sensitivity analyses According to the one-way sensitivity analysis results, the ICER for ATO + ATRA compared to ATRA + IDA varied from $CAD23,045/QALY to $CAD60,759/QALY from a MoH perspective and from $CAD23,120/QALY to $CAD60,905/QALY from a societal perspective. Tornado diagrams show that the parameters that wielded the greatest impact on base-case ICERs from both perspectives were (1) actualization rate, (2) drug administration costs, and (3) mortality risk after relapse (Figures 2a and 2b). Results of the probabilistic sensitivity analysis indicated that the ICER remains below $CAD50,000 in 48.33% of the Monte Carlo simulations from a MoH perspective (similar from a societal perspective) (Figure 3).
Discussion This economic evaluation indicates that compared to the ATRA + IDA combination, the ATO + ATRA combination is associated with ICERs of $CAD50,193 (€35,665)/ QALY and $CAD50,338 (€35,769)/QALY from MoH and societal perspectives, respectively. Results of the exhaustive sensitivity analyses confirm the robustness of the base-case results. The parameter that had the greatest impact on the base-case results was the discount rate. This can be explained by the long life expectancy for APL patients (model starting age = 46 years). The CADTH recommends discounting costs and effects at a rate of 5%.[12] This discount rate is higher than that recommended by several other countries.[35,36] Thus, the discount rate used in this analysis (5%) is more conservative than those used in other countries: a lower discount rate
would improve the ICERs and consequently favour the ATO + ATRA combination. To our knowledge, this is the first economic evaluation conducted in APL. Because no economic information was available on this disease, the present analysis will facilitate an understanding of its economic impact and particularly the impact of ATO in patients with newly diagnosed APL from a Canadian perspective. The model is based on clinical data taken from a direct comparison trial, which strengthens the results. Moreover, a more complete analysis is provided by accounting for AEs associated with treatment as well as productivity losses associated with cancer before and after progression. Furthermore, a complementary analysis considering all-risk APL groups allowed a better estimate of the economic impact of ATO in different populations of newly diagnosed APL patients. As for any model-based analysis, and especially for rare diseases, many assumptions were made due to very limited data, which may increase the uncertainty of the results. However, a conservative approach was adopted to define each model assumption, which was validated by clinical experts. For example, the utilities associated with health states were estimated for AML.[24] According to clinical experts, APL treatment is associated with higher hospitalization rates and more serious adverse events than AML treatment, which has been associated with lower utilities. Despite these limitations, exhaustive sensitivity analyses were performed to assess the uncertainty associated with some of the study parameters. It is worth mentioning that anthracycline and conventional chemotherapy-based regimens are associated with long-term toxicity.[37] This cardiotoxicity usually occurs after the completion of anthracycline treatment and may become apparent within 1 year of treatment completion or many years after chemotherapy completion.[38] There is also evidence that anthracycline cardiotoxicity is cumulative dose dependent.[39] In addition, several studies have found risks of developing therapy-related myeloid neoplasms with anthracyclines and conventional chemotherapies.[9–11] Although these treatment-related toxicities may play a role in the survival and morbidity associated with APL treatment, it was difficult to take them into account in the present model. As a conservative assumption, these toxicities were not included in the analysis. However, as the ATO + ATRA combination allows avoiding the use of anthracyclines or conventional chemotherapies, therefore minimizing the development of these complications, the ICERs reported here may be overestimated.
Conclusion Figure 3. Cost-acceptability curves. The graph represents the probability (y-axis) that the ICER generated by the Monte Carlo simulation is equal to or lower than the ceiling ICER (x-axis) Copyright © 2014 John Wiley & Sons, Ltd.
This economic evaluation demonstrates that ATO + ATRA can be considered a cost-effective strategy over standard treatment for APL from a Canadian perspective. This is Hematol Oncol 2015; 33: 229–238 DOI: 10.1002/hon
Cost-effectiveness of arsenic trioxide in APL
the first chemotherapy-free regimen to show significant clinical benefits compared to the current standard APL therapy. Given that conventional chemotherapy is associated with toxicities that increase the risk of mortality associated with APL and that ATO has been identified as a potential cure by the majority of clinical experts, the ATO + ATRA regimen should be taken into consideration in the treatment algorithm for newly diagnosed APL.
Conflict of interest JL, KM, and ACS have received consulting fees from Lundbeck Canada Inc. SB is an employee of Lundbeck Canada Inc.
Ethics statement Given the nature of this study (no human or animal subjects), it has not been approved by an Ethics Committee.
Acknowledgements We would like to thank Dr. Francesco Lo-Coco (University Tor Vergata, Rome, Italy) for reviewing the manuscript from a clinical standpoint and Dr. John Storring (McGill University Health Centre, Montreal) and Dr. Geneviève Gallagher (Hôpital de l’Enfant-Jésus, Quebec), haemato-oncologists, for validating the model assumptions. The study sponsor participated in the study design, in the collection of data, and in the decision to submit the paper for publication.
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