AbstractAsparaginase is an expensive drug, but important in childhood acute lymphoblastic leukemia. In order to compare costs of PEGasparaginase, Erwinia asparaginase and native E. coli asparaginase, we performed a cost-analysis in the Dutch Childhood Oncology Group ALL-10 medium-risk group intensification protocol. Treatment costs were calculated based on patient level data of 84 subjects, and were related to the occurrence of allergy to PEGasparaginase. Simultaneously, decision tree and sensitivity analyses were conducted. The total costs of the intensification course of 30 weeks were $57,893 in patients without PEGasparaginase allergy (n=64). The costs were significantly higher ($113,558) in case of allergy (n=20) necessitating a switch to Erwinia asparaginase. Simulated scenarios (decision tree analysis) using native E. coli asparaginase in intensification showed that the costs of PEGasparaginase were equal to those of native E. coli asparaginase. Also after sensitivity analyses, the costs for PEGasparaginase were equal to those of native E. coli asparaginase. Intensification treatment with native E. coli asparaginase, followed by a switch to PEGasparaginase, and subsequently to Erwinia asparaginase in case of allergy had similar overall costs compared to the treatment with PEGasparaginase as the first-line drug (followed by Erwinia asparaginase in the case of allergy). PEGasparaginase is preferred over native E. coli asparaginase, because it is administered less frequently, with less day care visits. PEGasparaginase is less immunogenic than native E. coli asparaginase and is not more expensive. Asparaginase costs are mainly determined by the percentage of patients who are allergic and require a switch to Erwinia asparaginase.
Acute lymphoblastic leukemia (ALL) is the most common type of childhood cancer.1 Annually, approximately 120 new cases of childhood ALL are diagnosed in the Netherlands. The treatment of childhood ALL has improved dramatically and survival increased from 0–5% in the 1960s to 80–85% nowadays.1 Treatment consists of induction, consolidation, intensification and continuation phases. Asparaginase is one of the key drugs in this treatment.2–4 Asparaginase is a non-human enzyme which hydrolyses asparagine into aspartic acid and ammonia. Given that leukemic blasts depend heavily on asparagine, deprived of this amino acid, they undergo apoptosis.5
Currently, several asparaginase preparations are available on the market: these are derived from Escherichia coli in its native form (Paronal or Asparaginase medac) or as a pegylated enzyme (PEGasparaginase, Oncaspar) or extracted from Erwinia chrysanthemi (Erwinia asparaginase, Erwinase). Many studies have shown that intensification by asparaginase is essential to improve the event-free survival of children with ALL.2–4,6–8
Unfortunately, asparaginase can cause an allergic reaction leading to inactivation of the drug or silent inactivation. Silent inactivation is the formation of anti-asparaginase antibodies which neutralize asparaginase without their being clinical symptoms of an allergy.9 In the case of allergic reactions to PEGasparaginase, Erwinia asparaginase is given instead. Erwinia asparaginase is given three times per week. The different dose schedules for native E. coli asparaginase, PEGasparaginase and Erwinia asparaginase are based on differences in the pharmacokinetics of the three products.
Compared to native E. coli asparaginase, PEGasparaginase is expensive,10 and Erwinia asparaginase is even more expensive. Little information is available on the exact costs of asparaginase in the treatment of ALL.11–12 Recently, Litsenburg et al.13 concluded that medication and diagnostics were the major contributors to the increased costs of the ALL-10 protocol compared to the previous ALL-9 protocol. However, in this study the costs of asparaginase were not analyzed separately and the costs were not related to the occurrence of allergies. Since native E. coli asparaginase was not administered during intensification in the ALL-10 protocol, we used hypothetical scenarios to study this strategy. The trial data of the ALL-10 protocol were used to compare PEGasparaginase to native E. coli asparaginase. Because of hospital budget restrictions and increasing costs of treatment of childhood ALL more insight into costs of asparaginase preparations is desired.
In the present study, we studied the costs of asparaginase in childhood ALL patients treated with PEGasparaginase or Erwinia asparaginase during the first 30 weeks of the intensification phase of the ALL-10 medium-risk (MR) protocol. The aim was to assess whether there are savings from using PEGasparaginase as the first-line drug rather than the native E.coli asparaginase.
Design and Methods
Overall study design
For this cost-analysis, we compared the costs of asparaginase related to allergy in three treatment scenarios. Scenario 1 is based on trial data from the ALL-10 MR protocol. Scenarios 2 and 3 are based on assumptions. A decision tree model was also used to relate costs for each scenario to different allergy rates.
Patients and the acute lymphoblastic leukemia treatment protocol
From November 2004 to April 2012, children with ALL were enrolled on the DCOG ALL-10 protocol14 approved by the Institutional Review Board. Patients were stratified into three risk groups after induction treatment: standard risk (SR), MR and high risk (HR).15 The intensification/continuation scheme for the ALL-10 MR patients, including asparaginase (administered intravenously) is shown in Online Supplementary Figure S1 and described in the Online Supplementary Design and Methods section. For this cost-analysis between April 2005 and October 2009, only MR patients from two pediatric oncology centers were included. Allergic reactions were graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
Description of three scenarios
The ALL-10 MR protocol was used as scenario 1 (Figure 1). Due to the fact that native E. coli asparaginase was not administered during intensification in this protocol, we used two hypothetical scenarios. In scenarios 2 and 3, patients were hypothetically treated with native E. coli asparaginase (5,000 IU/m, twice weekly) for a duration of 30 weeks (Figure 1). In scenario 2, in case of an allergic reaction to native E. coli asparaginase, Erwinia asparaginase was given. In scenario 3, patients were switched to PEGasparaginase in case of an allergic reaction to native E. coli asparaginase. Scenario 3 was based, among others, on the ALL-10 induction and the ALL-BFM 200016 protocols which prescribed PEGasparaginase as second-line and Erwinia asparaginase as third-line therapy. In this scenario, it was assumed that an allergy to PEGasparaginase after an allergic reaction to native E. coli asparaginase will occur at the second dose which is the case in practically all allergic reactions according to the interim results of the ALL-10 protocol.
Data on volumes were adapted from hospital electronic databases and medical files. For the unit prices, we applied the microcosting method17 and Dutch tariffs. More details are given in the Online Supplementary Design and Methods section.
Statistical, decision tree, sensitivity analyses
The data were analyzed with the software package SPSS for Windows version 17.0.2 (SPSS, Chicago, IL, USA). The mean total costs were not normally distributed (as shown by the Shapiro-Wilk test). The non-parametric Mann-Whitney U-test was used to compare the subgroups with or without an allergy to asparaginase. A two-sided P-value <0.05 was considered statistically significant. Data are presented as mean ± standard deviation and median (range) where appropriate.
We developed a decision tree model to compare costs of PEGasparaginase or Erwinia asparaginase to those of native E.coli asparaginase, while taking into account the incidence of allergy to asparaginase and the different associated costs (Figure 2). To account for uncertainty in the used prices and calculated costs, sensitivity analyses were performed. More details are given in the Online Supplementary Design and Methods section.
In total 84 children with ALL (33 girls) were included in this study. The median age was 5.2 years (range, 1.8–18.6 years) at the start of the intensification. The baseline characteristics of each subgroup are presented in Table 1. In total 20 patients (24%) were switched to Erwinia asparaginase because of a proven allergic reaction to PEGasparaginase (grade 2 or higher according to the CTCAE criteria). No grade 1 allergies were seen. Two patients had an allergy to PEGasparaginase in a period (June 2005) that no Erwinia asparaginase was commercially available in the Netherlands. Five patients were switched to twice weekly Erwinia asparaginase based on sufficient trough asparaginase levels.
Calculated costs (scenario 1)
Table 2 presents the costs per subgroup for all patients. The total mean treatment costs of all patients treated according to the first 30 weeks of the ALL-10 MR protocol were $ 71,147±35,763 per patient. The distribution of these costs was mainly accounted for by asparaginase use (47%) calculated per used vial. Day care treatment and inpatient care accounted for 15% of the total costs. The mean treatment costs for patients with no allergy to PEGasparaginase were $ 57,893±16,247 per patient, which was significantly lower than the costs of the subgroup with an allergy to PEGasparaginase ($ 113,558±47,187 per patient). The total costs were calculated per 2 weeks of asparaginase exposure; for PEGasparaginase ($ 3,860±1,083 per patient), and for Erwinia asparaginase ($ 7,571±3,146 per patient).
Simulated costs (scenario 2 and 3)
Table 3 shows the mean costs of the two hypothetical scenarios with native E. coli asparaginase administered. The mean costs would be $ 47,610±13,317 for the subgroup with no allergy to native E. coli asparaginase. These costs were significantly lower than for patients who developed an allergy to native E. coli asparaginase and switched to Erwinia asparaginase with mean costs of $ 133,554±31,252 (P<0.001, scenario 2). A switch from native E. coli asparaginase to PEGasparaginase was accompanied by mean costs of $ 53,978±24,538, which are higher but not statistically significantly so, than the costs in the group without an allergy to native E. coli asparaginase. A second switch in the intensification to Erwinia asparaginase after an allergy to PEGasparaginase had a cost of $ 125,719±30,623 (P<0.001, scenario 3).
Decision tree and sensitivity analyses
The decision tree analysis was used to relate costs for each scenario to different probabilities of allergy. Figure 2 shows that the treatment costs using either native E. coli asparaginase as the first-line preparation (scenario 3: $ 70,402) or PEGasparaginase as the first-line preparation (scenario 1: $ 71,810) were the lowest. The costs of using native E. coli asparaginase in the first-line followed by Erwinia asparaginase second line (scenario 2) would be higher ($ 103,474).
One-way sensitivity analysis (Figure 3) showed that the largest range in treatment costs was in the subgroup with allergy to native E. coli asparaginase (scenario 2). Furthermore, Figure 3 illustrates that when treatment costs were calculated with the new price of Erwinia asparaginase, treatment with PEGasparaginase as the first-line preparation (scenario 1) would be less expensive ($ 100,199) than treatment with the native E. coli asparaginase scenario 2 ($ 190,284) and scenario 3 ($ 103,089).
Two-way sensitivity analysis (Figure 4) revealed that treatment with PEGasparaginase (scenario 1) is less expensive than treatment with native E. coli asparaginase (scenario 2) for probabilities of allergy to PEGasparaginase ranging from zero to 0.8 with a fixed allergy rate to native E. coli asparaginase of 0.65 (Figure 4A). This also holds true if a fixed allergy rate to native E. coli asparaginase of 0.4 is used, which is frequently found in studies using less native E. coli asparaginase in intensification after native E. coli asparaginase in induction.16,18 The treatment with PEGasparaginase (scenario 1) carries equal costs compared to the treatment with native E. coli asparaginase (scenario 3) at a fixed rate of allergy to PEGasparaginase of 0.25 (Figure 4B,C). This holds true if the probabilities for a second allergy to PEGasparaginase allergy are lower than the base case value of 0.4 (Figure 4B) or if the allergy probabilities for native E. coli asparaginase are higher than the base case value of 0.65 (Figure 4C).
The aim of this study was to assess whether there could be savings from using PEGasparaginase as the first-line drug compared to native E.coli asparaginase during the first 30 weeks of the intensification phase of the ALL-10 MR protocol in the Netherlands. We showed that overall costs of treatment with native E. coli asparaginase, followed by a switch to PEGasparaginase, and subsequently to Erwinia asparaginase in case of allergy were $ 70,402. This sum was equivalent to that of treatment with PEGasparaginase as the first-line drug (followed by Erwinia asparaginase in case of allergy) which had overall costs of $ 71,810 (scenario 1), as applied in the ALL-10 MR protocol. Because of the comparable costs of these two scenarios, the latter one is preferable, because PEGasparaginase is administered less frequently (once every 2 weeks versus four times every 2 weeks), resulting in a reduced burden for the patient and family. Treatment with native E. coli asparaginase, followed by a switch to Erwinia asparaginase is the most expensive alternative with overall costs of $ 103,474 (scenario 2).
We have shown that the distribution of the calculated and simulated costs was mainly accounted for by asparaginase use (47%) and that these asparaginase costs were mainly determined by allergy percentages necessitating a switch to Erwinia asparaginase. So, reducing the number of allergies by using PEGasparaginase would also reduce costs. Furthermore, PEGasparaginase is administered less frequently than native E. coli asparaginase or Erwinia asparaginase and is less immunogenic.19,20 Scenarios 1 and 3 were less expensive than scenario 2; scenario 1 with PEGasparaginase as first-line treatment is the most patient-friendly option. For these reasons, PEGasparaginase is being used as the first-line drug in induction and intensification in the new DCOG ALL-11 protocol (opened in April 2012).
Two earlier studies investigated the costs of PEGasparaginase. Both found that treatment costs with PEGasparaginase were similar or slightly less than those with native E. coli asparaginase.11,12 This is in line with our observations. However these studies did not study costs related to asparaginase allergy and in these studies asparaginase was given less intensively. Litsenburg et al. also studied costs in the ALL-10,13 but they calculated costs for the total period of treatment and did not study the exact role of asparaginase-related costs.
The costs in the different scenarios were based on actual resource utilization in childhood ALL patients. We also accounted for the costs of discarding unused asparaginase vials by calculating the costs per used vial. Despite of the sensitivity analysis to account for different percentages of asparaginase-related allergy, it is important to note that these percentages depend on several factors such as dose schedule and the type of asparaginase, earlier exposure to asparaginase in induction and the route of asparaginase administration (intravenous or intramuscular).21 PEGasparaginase has been shown to result in less antibody formation than native E. coli asparaginase.22 The percentage of patients switching to another asparaginase preparation can also depend on silent inactivation of asparaginase.9 With monitoring of asparaginase activity levels, more cases of inactivation will be detected, necessitating a switch in asparaginase preparations more often.
This study had some limitations. First, we had to simulate part of the treatment in order to calculate costs. To achieve reliable simulations for treatment with native E. coli asparaginase, simulations were based on the allergy rates in the ALL-9 HR and ALL-10 MR protocols. Furthermore, some satellite hospitals were not visited to collect data, which were retrieved from academic hospital files. A mean cost based on data collected from satellite hospitals was imputed for the missing data. We did not evaluate silent inactivation of asparaginase; this is now being done in a prospective setting. The generalizability of this study might be limited, because there is tremendous heterogeneity across the world in dose, frequency and type of asparaginase used in the treatment of childhood ALL. Nowadays, the new childhood ALL treatment protocols also include PEGasparaginase, for instance in Germany23 and the United Kingdom,24 while native E. coli asparaginase and Erwinia asparaginase are used in different countries. We studied the costs of asparaginase preparations which were related to different allergy probabilities. Additionally, the costs were presented for 2 weeks of exposure to asparaginase. Taken together, our results could be generalized for these countries using different asparaginase preparations.
To conclude, we have shown that the costs of PEGasparaginase and native E.coli asparaginase in intensification therapy are comparable. However, PEGasparaginase is preferred, because it is administered less frequently, requiring fewer daycare visits and is, therefore, more patient-friendly. PEGasparaginase is less immunogenic than native E. coli asparaginase and is not more expensive. Since the price of Erwinia asparaginase has been doubled, the saving of costs will be clearly in favor of PEGasparaginase. Finally, asparaginase costs are mainly determined by allergy rates, necessitating a switch to Erwinia asparaginase.
The authors would like to thank all the cooperating pediatric oncology satellite hospitals and the Dutch Childhood Oncology Group (DCOG) for collecting clinical and laboratory information of the studied children with acute lymphoblastic leukemia. This work was supported by the KiKa foundation.
- The online version of this article has a Supplementary Appendix.
- Authorship and Disclosures Information on authorship, contributions, and financial & other disclosures was provided by the authors and is available with the online version of this article at www.haematologica.org.
- Received July 2, 2012.
- Accepted January 23, 2013.
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