ClinicoEconomics and Outcomes Research Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Cost-Effectiveness Of Midostaurin In The Treatment Of Acute Myeloid Leukemia With The FLT3 Mutation In Spain This article was published in the following Dove Press journal: ClinicoEconomics and Outcomes Research Ainhoa Arenaza 1 Purpose: The addition of midostaurin to standard chemotherapy (cytarabine and daunor- Raúl Diez 2 ubicin) has shown significant improvements in the survival of patients with acute myeloid Jordi Esteve 3 leukemia with the FLT3 mutation (FLT3-AML). The objective of this study was to determine Roberta Di Nicolantonio 4 whether this intervention would be cost-effective in Spain. Methods: A partitioned survival model with five health states was developed (diagnosis and Joana Gostkorzewicz 4 induction, complete remission, no complete remission, transplantation and death). A lifetime Carlos Martínez 5 time horizon and the Spanish National Health System perspective were adopted. During the Diana Martínez Llinàs 6 first three years, permanence in the different health states was determined according to the Joaquin Martinez-Lopez 7 results of the RATIFY study. In successive years, the death rates of the Spanish population Pau Montesinos 8 adjusted by a factor to reflect long-term disease-related mortality were used. Utilities were Aída Moure-Fernández 6 obtained from the literature. Pharmacological costs (first and second line) and the costs of Jorge Sierra 9 other health resources (hospitalizations, visits and tests) were included. The robustness of the Joan Lluís Vinent 10 model was evaluated by deterministic and probabilistic sensitivity analyses. 1 Pharmacy Department, Clínico San Results: The addition of midostaurin resulted in 1.46 life years gained (LYG) and 1.23 Carlos Hospital, Madrid, Spain; quality-adjusted life years (QALY) gained and implied an additional cost of € 47,955, 2 Pharmacy Department, University De resulting in an incremental cost-effectiveness ratio (ICER) of € 32,854/LYG and an incre- Getafe Hospital, Madrid, Spain; 3 Hematology Department, Clinic mental cost-utility ratio of € 38,985/QALY. In the univariate sensitivity analysis, the thresh- Hospital, Barcelona, Spain; 4Health old of € 50,000/QALY was not exceeded in any case; taking into consideration potential Economics and Outcome Research, discounts of 20-40% in the PVL of midostaurin the ICER would be below € 30,000/QALY, a Novartis Farmacéutica S.A., Madrid, Spain; 5Pharmacy Department, University commonly accepted threshold in Spain. In the probabilistic analysis, when the threshold was Hospital Araba, Vitoria, Spain; 6Oblikue € 50,000/QALY, midostaurin was cost-effective in 82.3% of simulations. Consulting, S.L., Barcelona, Spain; 7 Hematology Department, University Conclusion: According to our modeling, midostaurin, in combination with standard che- Hospital 12 de Octubre, CNIO, motherapy, could be an efficient alternative for the treatment of FLT3-AML in Spain. Complutense University, Madrid, Spain; Keywords: AML, modeling, efficiency, health economics, economic evaluation 8 Hematology Department, University Hospital La Fe, Valencia, & CIBERONC, Instituto Carlos III, Madrid, Spain; 9 Hematology Department, University Hospital Santa Creu i Sant Pau, Barcelona, Spain; 10Pharmacy Introduction Department, Sant Joan de Déu Hospital, Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy char- Barcelona, Spain acterized by the clonal expansion of myeloid blasts in peripheral blood, bone marrow and/or other tissues.1 AML is the most frequent type of acute leukemia in adults (5–8 cases per year per 100,000 persons)2 and leads to 4–6 deaths annually Correspondence: Diana Martínez Llinàs per 100,000 persons.3 Oblikue Consulting, S.L. C/Comte d’Urgell, 240, 2-D, Barcelona 08036, Spain Although the etiology of the disease is unknown, numerous cytogenetic and Tel +34 932521377 molecular abnormalities that have implications for the prognosis and treatment have Fax +34 93 737 9984 Email diana.martinez@oblikue.com been identified. These include mutations in the gene that encodes FMS-like tyrosine submit your manuscript | www.dovepress.com ClinicoEconomics and Outcomes Research 2019:11 683–694 683 DovePress © 2019 Arenaza et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. http://doi.org/10.2147/CEOR.S222879 php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Arenaza et al Dovepress kinase 3 (FLT3), which occur in approximately one third Spanish National Health System perspective and consider- of patients with AML (FLT3-AML) and result in a poor ing only direct health costs. prognosis.3 To capture all the costs and benefits of the introduction The therapeutic management of FLT3-AML depends of midostaurin in the treatment of FLT3-AML, a lifetime fundamentally on the patient’s physical state, which deter- time horizon was adopted. A discount rate of 3% per year mines whether they can receive intensive chemotherapy, was applied to costs and benefits, as recommended by and the cytogenetic/molecular profile of the disease, which national pharmacoeconomic guidelines when the time hor- determines the prognosis and the risk of relapse.1,4 izon of the analysis is > 1 year.7,8 Candidate patients for intensive chemotherapy gener- The model is an adaptation of the model presented to ally receive induction treatment with cytarabine and an NICE,9 and adaptations of this model were also submitted anthracycline (daunorubicin or idarubicin), followed by to CADTH10 and HAS.11 NICE recommendations on the consolidation strategies based on the use of high-dose economic evaluation of midostaurin9 and the opinion of a cytarabine.1 panel of Spanish clinical experts were taken into account Chemotherapy may be followed by allogeneic hemato- when carrying out the analysis. poietic stem cell transplantation (HSCT) when the patient has intermediate or high risk genetics and the benefit-risk Patients balance is in favor of HSCT.1 In general, allogeneic HSCT A population with the same clinical characteristics as the is recommended in patients with an expected incidence of RATIFY study population was analyzed − adult patients relapse of >35-40%.1 with recently diagnosed FLT3-AML who were candidates Midostaurin is an inhibitor of multiple kinases, includ- for standard chemotherapy. In the RATIFY study, the ing FLT3. One indication for midostaurin is the treatment mean age at diagnosis was 47.9 years and 55.5% of of adult patients with newly diagnosed FLT3-AML, in patients were female. The baseline characteristics of the combination with standard induction (daunorubicin and patients included in the RATIFY study are described cytarabine) and consolidation (high dose cytarabine) che- elsewhere6 and are summarized in the supplementary motherapy, followed by midostaurin monotherapy as material (Table S1). maintenance treatment in patients who have achieved a complete response.5 Therapy In the RATIFY study, a randomized, double-blind, In the base case, the therapeutic alternatives considered in phase III clinical trial which included 717 patients, the the RATIFY study were compared.6 Taking into account the addition of midostaurin to standard treatment provided study protocol, a maximum duration of 2 cycles was estab- significant reductions in the risk of death (hazard ratio lished for the induction phase, 4 cycles for the consolidation [HR] = 0.78; 95% CI = 0.63–0.96, p = 0.009) and events phase and 12 cycles for the maintenance phase.5,6 The (HR = 0.78, 95% CI = 0.66–0.93, p = 0.002).6 The use of proportion of patients achieving each treatment cycle within midostaurin also increased the rate of complete remission the RATIFY study is shown in Figure S2. (CR) when all-reported CRs within 30 days after the end Additionally, it was considered that all patients who of treatment were considered (68% vs 59%, P = 0.04).4 did not respond or relapsed after first-line treatment would The objective of this study was to determine whether receive salvage treatment. Based on the opinion of a panel the addition of midostaurin to standard induction che- of experts, it was considered that 75% of patients would motherapy and consolidation with cytarabine and daunor- receive a cycle of fludarabine, cytarabine and idarubicin ubicin, followed by maintenance treatment with (FLAG-IDA) and that the remaining 25% would receive a midostaurin monotherapy, would be a cost-effective inter- cycle of mitoxantrone, etoposide and cytarabine (MEC). vention compared with standard chemotherapy induction The regimens and doses of the therapies considered in and consolidation therapy in patients with FLT3-AML in each treatment phase are described in Table 1. For the induc- Spain. tion, consolidation and maintenance treatments, the regi- mens, doses and durations of treatment observed in the Materials And Methods RATIFY clinical trial6 were adopted. For the other treat- An economic evaluation was carried out, including cost- ments, the most frequent regimens and doses in clinical effectiveness and cost-utility analyses, adopting the practice (validated by clinical experts) were adopted. submit your manuscript | www.dovepress.com ClinicoEconomics and Outcomes Research 2019:11 684 DovePress Dovepress Arenaza et al Table 1 Regimens Considered In Each Treatment Phase Treatments Active Principle Regimen 1st line chemotherapy: intervention therapy Induction (cytarabine + daunorubicin + midostaurin) Cytarabine 200mg/m2/day (days 1–7) Daunorubicin 60mg/m2/day (days 1–3) Midostaurin 50 mg twice a day (days 8–21) Consolidation (high dose cytarabine + midostaurin) High dose cytarabine 3,000mg/m2/day twice a day (days 1, 3, 5) Midostaurin 50mg twice a day (days 8–21) Maintenance (midostaurin) Midostaurin 50mg twice a day (days 1–28) 1st line chemotherapy: Comparator treatment 7 + 3 (cytarabine + daunorubicin) Cytarabine 200mg/m2/day (days 1–7) Daunorubicin 60mg/m2/day (days 1–3) High dose cytarabine High dose cytarabine 3,000mg/m2/day twice a day (days 1,3,5) 2nd line chemotherapy FLAG-IDA (fludarabine + cytarabine + idarubicin) Fludarabine 30 mg/m2 (days 1–5) Cytarabine 2,000 mg/m2/day (days 1–7) Idarubicin 10 mg/m2/day (days 1–3) MEC (mitoxantrone + etoposide + cytarabine) Mitoxantrone 8 mg/m2/day, (days 1–6) Etoposide 80 mg/m2/day, (days 1–6) Cytarabine 1,000 mg/m2/day, (days 1–6) Other treatmentsa 7 + 3 (cytarabine + idarubicin) Cytarabine 200mg/m2/day (days 1–7) Idarubicin 12 mg/m2/day, (days 1–3) Notes: aIncluded in the sensitivity analysis. In the opinion of experts, regimens based on cytarabine and idarubicin are common in Spain as induction therapy, so a sensitivity analysis was also carried out in which the costs of induction treatment with idarubicin and daunorubicin were included. Analysis Effectiveness We used a partitioned survival model with five health Effectiveness was measured in life years gained (LYG) states (“diagnosis and induction”, “complete remission”, and quality-adjusted life years (QALY). LYG were “no complete remission”, “HSCT” and “death”). The pro- estimated from the overall survival data observed in portion of patients occupying each health state was derived the RATIFY study. QALYs were estimated by multi- directly from cumulative survival probabilities and was plying the time patients spent in each health state by determined by the area under the curves fitted to the the utility associated with the state and the treatment RATIFY trial outcomes. The structure of the model is phase. shown in Figure 1. Most utilities were obtained from the literature13-17 During the first three years of the model, mortality was except the utility associated with the state of relapse, which estimated from the uncensored overall survival transplant was calculated according to NICE recommendations.9 curves in the RATIFY study.6 From the fourth year, follow- Utilities were validated by a committee of Spanish clinical ing the recommendations issued by a panel of clinical experts and were represented with a value between 0 and 1, experts, mortality was estimated based on the mortality where 0 represents a state of health similar to death and 1 a rate of the Spanish general population,12 applying an adjust- state of perfect health. Table 2 shows the utilities included in ment (15% higher than that of the general population). the model. submit your manuscript | www.dovepress.com ClinicoEconomics and Outcomes Research 2019:11 685 DovePress Arenaza et al Dovepress Figure 1 Model structure. Use Of Resources And Health Costs hospital visits, emergency room visits, specialist visits, tests) The costs of first and second line pharmacological therapies were included. All costs were expressed in 2017 euros. and the costs of other health resources (hospitalizations, day Costs derived from the management of adverse events were not considered since, in the opinion of the experts, Table 2 Utilities Associated With The Treatment Phases the introduction of midostaurin would not imply any rele- vant change in the incidence of adverse events, and that State Value Source most adverse events would occur during induction and Inductiona 0.648 Uyl-DE Groot et al, 199813 consolidation and would thus already be included in the Consolidationa 0.710 Batty et al, 201414 cost of hospital admission. Even during the maintenance Maintenancea 0.810 Batty et al, 201414 CR post 1st line 0.830 Leunis et al, 201415 phase, the most frequent grade 3 or 4 adverse events (no relapse) (absolute neutrophil count and leukopenia) occurred at Relapse 0.780 NICE, 20189 similar rates in patients treated with midostaurin or with HSCTa,b 0.613 Crott (2010) & Grulke (2012)16,17 placebo;5 thus a similar use of resources at all stages for HSCT recoveryb 0.810 Crott (2010) & Grulke (2012)16,17 both treatment arms. HSCT follow up 0.826 Crott (2010) & Grulke (2012)16,17 b (after 1st line) Notes: aIncludes the disutility associated with treatment. bUtility values used in the Pharmacological Costs model for SCT treatment, recovery, and post-SCT recovery, were mapped from pub- The cost of the treatments was estimated from the mean ex- lished (EORTC) Quality of Life Core Questionnaire QLQ-C30 data (Grulke et al 2012) using an algorithm developed by Crott et al (2010) which calculated EQ-5D utility based factory price (in Spanish “Precio de Venta de Laboratorio” on QLQ-C30 scores. The QLQ-C30 data published by Grulke et al presented scores or PVL) of each drug in the database of the General Council specific to different stages of stem cell therapy (before SCT, during hospitalization, up to 6 months after SCT, and >1 year after SCT). The algorithm developed by Crott, et al was of Official Associations of Pharmacists (in Spanish then applied to this data in order to obtain EQ-5D utility scores: EQ-5D utility = “Consejo General de Colegios Oficiales de Farmacéuticos” 0.85927770–0.0069693*(Physical Functioning) – 0.0087346*(Emotional Functioning) – 0.0039935*(Social Functioning) + 0.0000355*(Physical Functioning)2 + 0.0000552* or CGCOF)18 after applying the discount according to (Emotional Functioning)2 + 0.0000290*(Social Functioning)2 + 0.0011453* (Constipation) +0.0039889*(Diarrhoea) + 0.0035614*(Pain) – 0.0003678*(Sleep) – Royal Decree Law (RDL) 8/201019 (Table 3), and adopting 0.0000540*(Diarrhoea)2+0.0000117*(Sleep)2. the regimens, doses and timings described in Table 1. submit your manuscript | www.dovepress.com ClinicoEconomics and Outcomes Research 2019:11 686 DovePress Dovepress Arenaza et al Table 3 Drug Prices Before And After The Discount According Table 4 Cost Per Treatment Cycle To RDL 8/201017 Treatments Cost/Cycle Drug PVL Discount. PVL- 1st line chemotherapy: intervention therapy RDL Discount. RDL Induction (cytarabine + daunorubicin + midostaurin) € 6,521.41 Consolidation (high dose cytarabine + midostaurin) € 6,859.79 Midostaurin (Rydapt®) € 6673.77 4% € 6406.82 Maintenance (midostaurin) € 12,813.65 (25 mg, 56 capsules) Cytarabine gpe € 7.19 - € 7.19 1st line chemotherapy: Comparator treatment (500 mg, 1 vial) 7 + 3 (cytarabine + daunorubicin) € 114.59 Cytarabine gpe € 14.38 - € 14.38 (1 g, 1 vial) High dose cytarabine € 452.97 Cytarabine gpe € 28.76 - € 28.76 (2 g, 1 vial) 2nd line chemotherapy Daunoblastin € 4.20 15% € 3.57 (daunorubicin) (20 mg, 1 FLAG-IDA (fludarabine + cytarabine + idarubicin) € 1,340.81 vial) Fludarabine gpe € 49.77 - € 49.77 MEC (mitoxantrone + etoposide + cytarabine) € 514.44 (25 mg/mL, 2 mL) Mitoxantrone gpe € 23.46 - € 23.46 Other treatmentsa (10 mg, 1 vial) Etoposide gpe € 10.06 - € 10.06 7 + 3 (cytarabine + idarubicin) € 786.53 (20 mg/mL, 1 vial, 2 mL) Idarubicin gpe € 81.80 - € 81.80 Notes: aIn the opinion of experts, regimens based on cytarabine and idarubicin are (10 mg, 1 vial)a also common in induction therapy in Spain, so a sensitivity analysis was carried out that included the costs of induction therapy with idarubicin and daunorubicin. Notes: aIncluded in the sensitivity analysis. In the opinion of experts, the schemes based on the use of cytarabine and idarubicin are also common in Spain induction, so a sensitivity analysis was also carried out in which the costs of the induction treatment with idarubicin and daunorubicin were considered. Table 5 Unit Costs Of The Health Resources Used In The Abbreviations: GPE, Generic Pharmaceutical Equivalent; PVL, ex-factory price; Analysis RDL, Royal Decree Law. Resource Unit Cost Following the recommendation of the panel of clinical Hospitalizations experts, all calculations were made taking into account the Hospitalization for chemotherapy (cost/stay)a € 23,362.91 Hospitalization for allogeneic HSCT (cost/ € 46,204.70 use of complete vials, using the combination of vials that process)b provided the dose closest to the dose required for an Additional hospitalization in a patient with no € 1,146.99 average patient with a body surface of 1.7 m2. Table 4 complete remission (cost/day)c shows the cost per treatment cycle. Additional hospitalization in a patient in remission € 1,383.03 (cost/day)d Costs Of Non-Pharmacological Health Mortality cost (cost/process)e € 7,635.51 Resources Other health resources FLT-3 test € 327.96 During the first three years of stay in the model, the costs Day hospital visit € 84.32 of non-pharmacological health resources were estimated Emergency visit € 177.82 from the use of resources in the different treatment states Specialist visit € 84.32 and phases. The use of resources in each health state was Bone marrow aspiration € 63.92 defined by a panel of clinical experts and the unit costs of Complete blood count and biochemistry € 94.86 health resources were obtained from the eSalud database20 a Notes: DRG 205.00: Acute myeloid leukemia with no mention of remission being achieved. bAllogeneic bone marrow transplant (cost/hospitalization). cEstimated (Table 5). from the cost of the stay equivalent to DRG 205.02 “Acute Myeloid Leukemia in Before starting treatment, it was considered that all Recurrence” and the length of stay for this DRG stipulated in the CMBD. d Estimated from the cost of the stay equivalent to DRG 205.01 “Acute Myeloid patients would undergo a diagnostic test to detect FLT3 Leukemia in Remission” and the length of stay for this DRG stipulated in the CMBD. e mutations. Average cost of hospitalization for a patient with a fatal termination (CMBD). submit your manuscript | www.dovepress.com ClinicoEconomics and Outcomes Research 2019:11 687 DovePress Arenaza et al Dovepress Taking into account the opinion of clinical experts, it was guidelines.7,8 Following the recommendations of clinical considered that all patients would be hospitalized during the experts, the effect of substituting daunorubicin for idar- induction phase. In the consolidation phase, it was considered ubicin for first line therapy was also evaluated. that 80% of patients would be hospitalized to receive the In addition, according to the NICE recommendations9 treatment and that the remaining 20% would receive treatment the following sensitivity analyses were carried out: consider in a day hospital – with a mean of 8 visits per cycle - and would a utility in the state of non-complete remission lower than be admitted for a mean of 5 days for possible complications. that considered in the base case (from 0.780 to 0.655) to The costs per day of hospitalizations in the “complete reflect the lower utility of patients receiving a second line of remission” and “no complete remission” states were calculated treatment; move the cure point (located in the fourth year of using the mean stay for these admissions included in the permanence in the model in the base case) to 6.2 years (80 ‘Conjunto Mínimo Básico de datos’ (CMBD) database.21 cycles) in line with the follow-up period of the RATIFY The use of resources used in the states of complete remission study; adjust the mortality rate after the fourth year in the and no complete remission are detailed in Table 6. model, considering a scenario where the mortality from that Finally, it was considered that patients who received an year onwards was equal to that of the general population allogeneic HSCT would be hospitalized during the entire and a scenario where this rate doubled. transplant process and would make a subsequent follow-up Additionally, potential reductions in the PVL of mid- specialist visit in each cycle during the first three years. ostaurin (−20%, −30% and −40%), increases in the cost of According to the NICE recommendations, it was HSCT (scenarios where the cost of HSCT would be assumed that patients who remained in the model after equivalent to the cost of the Diagnosis-Related Group three years would be considered cured and would not (DRG) associated with allogeneic transplantation and the incur additional costs from then onwards.9 highest cost of allogeneic HSCT in eSalud, respectively) and a modification of ±20% in the cost items (pharmaco- Sensitivity Analysis logical costs of second line therapy, mortality costs and A univariate deterministic analysis was performed to evaluate non-pharmacological health costs during first line treat- the effect of variations in the variables with greater uncertainty. ment) were analyzed. The variables included in this analysis are shown in Table 7. Finally, a probabilistic sensitivity analysis was carried Discount rates for the costs and benefits of 0% and out by performing 1,000 simulations using the Monte- 5%, respectively, were applied according to the recom- Carlo method; in this analysis, a log-normal distribution mendations of the main national pharmacoeconomic was used for the costs, duration of second line therapy, Table 6 Resource Use In The Complete Remission And No Complete Remission States Complete Remission No Complete Remission 0-6 Months 6-12 2-5 Years 6+ Years Months Specialist visits % patients 100% 100% 100% 100% 100% Frequency/cycle 2.0 0.4 0.2 0.1 3 Emergency room visits % patients 60% 15% 7.5% 0% 62.5% Frequency/cycle 0.25 0.25 0.03 0.0 1.5 Bone marrow aspiration % patients 100% 50% 20% 0% 100% Frequency/cycle 0.2 0.2 0.03 0.0 1 Complete blood count % patients 100% 100% 100% 0% 100% and biochemistry Frequency/cycle 2.0 0.4 0.2 0.0 3 Hospitalizations % patients 2.5% 2.5% 2.5% 0% 100% Frequency/cycle 1.0 2.5 0.2 0.0 1 Duration (days) 12.5 12.5 10 0.0 25–30 submit your manuscript | www.dovepress.com ClinicoEconomics and Outcomes Research 2019:11 688 DovePress Dovepress Arenaza et al Table 7 Univariate Deterministic Sensitivity Analysis Parameter Base Scenario Sensitivity Analysis Scenario Discount on benefits and costs 3% 0% 5% (0–5%)a,b Modification of the cost of HSCT € 46,204.70 € 61,001.07 (DRG 803: € 61,000.07)c Modification of the cost of HSCT (highest cost available: € € 46,204.70 € 110,276.59 110,276.59 )d Utility in the state of complete no remission (0.655)b 0.780 0.655 Different cure point (6.2 years)b,e 3 years 6.2 years, derived from the maximum follow-up of patients in RATIFY Different mortality adjustment after the fourth year (=/x2 15% higher than the Same as the general population. mortality, general population)b general population Twice as high as the general population PVL reduction for midostaurin (20-30-40%) 100% 60% 70% 80% Modification of 2nd line therapy costs (± 20%) 100% 80% 120% Modification of mortality costs (± 20%) 100% 80% 120% f Replacement of daunorubicin with idarubicin Daunorubicin 60mg/m2/day Idarubicin 12 mg/m2/day (days 1–3) (days 1–3) Modification of non-pharm health costs during 1st line 100% 80% 120% treatment (± 20%) Notes: aBased on economic evaluation guidelines. bBased on NICE recommendations. cCost of HSCTequivalent to the cost of DRG 803 (“Allogenic bone marrow transplant”). d The highest cost of allogeneic HSCT found in the available evidence (eSalud).18 eIn keeping with the follow-up time in the RATIFY study. fBased on expert opinion. Abbreviation: PVL, ex-factory price. patients’ body surface area and efficacy variables; a due to a reduction in the costs of relapses versus the gamma distribution for utilities; and beta distributions for comparator (€ 21,703 vs € 39,256). This resulted in a pharmacological doses and duration of first line therapy. total cost of non-pharmacological health resources that was approximately € 15,000 lower for midostaurin versus Results the comparator (Table 8). The addition of midostaurin to standard chemotherapy in The greatest between-group difference in costs was in the treatment of patients with FLT3-AML provided an the pharmacological costs (€ 61,250 vs € 1,798), which additional gain in effectiveness over standard chemother- were higher in the midostaurin group in all treatment apy. This gain translated into 1.46 LYG and 1.23 QALY phases except for second line therapy. From the total gained (Table 8). Outcomes during the first 120 cycles are drug costs incurred by the patients in the midostaurin shown in Figure S1. group, € 7,973 were associated to the induction phase, Treatment with midostaurin involved an additional cost € 12,881 to consolidation and € 39,870 to the maintenance of € 47,955 versus the comparator. The main cost deter- treatment while € 527 were second line therapy costs minants in the two treatments compared were the costs (Table 8). associated with non-pharmacological health resources, The reductions in costs associated with mortality especially hospitalization costs. Although, during treat- (€ 5,082 vs € 5,413), together with the reductions in ment, these costs were slightly higher for midostaurin the costs of non-pharmacological health resources, par- than for the comparator (€ 66,568 vs € 60,439), after tially offset the increases in pharmacological costs and treatment the hospitalization costs were considerably in the costs associated with HSCT in patients treated lower for midostaurin (€ 40,230 vs € 60,935), mainly with midostaurin (Table 8). In the base case, the incre- submit your manuscript | www.dovepress.com ClinicoEconomics and Outcomes Research 2019:11 689 DovePress Arenaza et al Dovepress Table 8 Results Of The Cost-Effectiveness And Cost-Utility Analyses. Base Case Midostaurin + Chemotherapy Chemotherapy Incremental Cost Pharmacological cost € 61,250 € 1,798 € 59,452 Induction € 7,973 € 466 € 7,507 Consolidation € 12,881 € 744 € 12,138 Maintenance € 39,870 €0 € 39,870 2nd line therapy € 527 € 589 € −62 Cost of healthcare resources € 106,798 € 121,374 € −14,576 (non-pharmacological) During treatment € 66,568 € 60,439 € 6,129 After treatment € 40,230 € 60,935 € −20,705 HSCT costs € 34,723 € 31,315 € 3,409 Costs of mortality € 5,082 € 5,413 € −331 TOTAL COST € 207,854 € 159,900 € 47,955 Effectiveness LYG 11.73 10.27 1.46 QALYs 9.45 8.22 1.23 ICER (€ per LYG): € 32,854 ICUR (€ per QALY gained): € 38,985 Note: The values that are not in bold are components of the items in bold. Abbreviations: QALY, Quality Adjusted Life Year; LYG, Life year gained; ICER, Incremental Cost Effectiveness Ratio; ICUR, Incremental Cost Utility Ratio. mental cost-utility ratio (ICUR) for midostaurin and eligibility criteria to receive an allogeneic HSCT, cannot chemotherapy treatment was € 38,985/QALY. receive it or cannot receive it in optimal conditions as they The univariate sensitivity analysis (Figure 2) showed have not achieved CR after first line therapy.22 Improving that the results of the model are robust. In addition, the clinical outcomes in first line therapy is an unmet medical application of potential discounts to the PVL of midos- need in the management of FLT3-AML. taurin produced cost-effectiveness results below € 30,000/ Midostaurin is the first targeted treatment which, in QALY; a 20% discount in the PVL of midostaurin trans- combination with standard induction and consolidation lated the RCUI into € 29,326/QALY, while RCUIs of chemotherapy and as maintenance therapy after induction € 24,496/QALY and € 19,666/QALY were obtained and consolidation, has shown benefits in the survival of under discounts of 30% and 40%, respectively. The results patients with newly-diagnosed FLT3-AML.6 Our results of the probabilistic sensitivity analysis show that, when the show that the addition of midostaurin to standard che- efficiency threshold was set at € 50,000/QALY, treatment motherapy based on cytarabine and daunorubicin, fol- with midostaurin was a cost-effective option in 82.3% of lowed by maintenance treatment with midostaurin, could the simulations (Figure 3). be a cost-effective intervention in Spain. In the base case, it was estimated that the introduction of Discussion midostaurin would produce gains of 1.46 LYG, 1.23 QALYs Currently, induction and consolidation therapy followed and an additional cost of € 47,955, resulting in an incremental by allogeneic HSCT constitute the basis of the manage- cost-effectiveness ratio (ICER) of € 32,854/LYG and an ment of intermediate or high risk FLT3-AML. Although ICUR of € 38,985/QALY. These results are similar to those this treatment is intended to cure, the prognosis of the observed in the economic evaluations of midostaurin in disease remains poor, especially in patients refractory to Canada and the United Kingdom, in which ICURs of primary treatment and in those who, despite meeting $ 66,937 and £ 34,327 were observed, respectively.23,24 submit your manuscript | www.dovepress.com ClinicoEconomics and Outcomes Research 2019:11 690 DovePress Dovepress Arenaza et al Figure 2 Univariate sensitivity analysis. a. Based on economic evaluation guidelines. b. Based on NICE recommendations. c. In keeping with the follow-up time in the RATIFY study. d. The highest cost of allogeneic HSCT found in the available evidence (eSalud). e. Cost of HSCT equivalent to the cost of DRG 803 (“Allogenic bone marrow transplantation”). f. Based on expert opinion. Abbreviations: AE, adverse events; PVL, ex-factory price. In addition, taking into account the potential of mid- ostaurin to increase the proportion of patients who are transplanted, the robustness of the results with respect to the variations in the cost of HSCT is also especially relevant. When the costs of the intervention were doubled (using a unit cost of > € 110,000), the results would still remain below € 42,000/QALY. In the probabilistic analysis, treatment would continue to be a cost-effective intervention in 82.3% of the simula- tions if a threshold of € 50,000/QALY was considered Figure 3 Probabilistic sensitivity analysis. (Figure 3). Given the lack of published evidence, it is difficult to Both the ICER and the ICUR are below the thresholds compare the efficiency of midostaurin with that of inter- used in orphan diseases in Spain,2 which may exceed ventions used in the management of other hematologic € 100,000/QALY,25,26 and below the efficiency thresholds neoplasms in Spain. stipulated by the World Health Organization (WHO), Our results also show that using midostaurin in combi- which is up to three times the gross domestic product per nation with standard induction and consolidation che- capita in Spain (77,400 €/QALY).27 motherapy would help to improve the efficiency of these The deterministic and probabilistic sensitivity analyses processes, which are very expensive due to the high costs demonstrate the robustness of the results. In the determi- incurred by hospitalizations for treatment. The results also nistic analysis, when a discount between 20% and 40% show that increases in pharmacological costs due to the was applied to the price of midostaurin and discounts on introduction of midostaurin would be partially compen- benefits and costs were not taken into account, the ICUR sated by cost reductions in the management of relapses, was below a threshold of € 30,000/QALY, which is a and especially by reductions in hospitalizations to receive commonly accepted threshold in Spain.28 second line therapy. submit your manuscript | www.dovepress.com ClinicoEconomics and Outcomes Research 2019:11 691 DovePress Arenaza et al Dovepress Although a front-line allogeneic HSCT is generally requirements of one of the main European health technol- recommended in FLT3-AML patients, especially in those ogy agencies. However, the study has some limitations. with higher risk disease, a large proportion of patients cannot One limitation is that only the direct costs of the disease finally be transplanted because there is no compatible donor and its treatment were analyzed, since the associated indir- or for other reasons. In the RATIFY study, both transplant ect costs should be taken into account in patients with and non-transplant patients benefited from the introduction FLT3-AML, especially those who relapse or receive of midostaurin. Therefore, maintenance treatment with mid- HSCT. Although, according to economic evaluation guide- ostaurin, in addition to promoting CR and possible HSCT in lines, the social perspective is the most appropriate,7 the CR, would be a treatment option in patients who have CR perspective most commonly used in GENESIS reports8 after induction and consolidation and have an indication for and in the cost-effectiveness analyses published for other allogeneic HSCT but cannot receive it, as well as for those drugs indicated for hematologic neoplasms in Spain29,30 is with low-intermediate risk of relapse. that of the Spanish National Health System. Another lim- As it is an orally-administered treatment with a good safety itation is the lack of quality of life results in patients and tolerability profile, the costs of maintenance treatment treated with midostaurin or the comparator, which forced with midostaurin are limited to the pharmacological costs. us to use utility values collected from the literature. Taking into account the treatment times observed in the However, in a sensitivity analysis in which the utility RATIFY study, it may be estimated that, in an average patient, associated with relapse was reduced, the results of the the cost of complete treatment with midostaurin would be ICUR were more favorable than those observed in the around € 60,000, of which € 40,000 would correspond to the base case. Finally, our analysis considered that the toxicity maintenance phase. In any case, it is worth noting that, while profile of midostaurin was similar to that of the compara- this study has considered the midostaurin treatment costs for tor. Therefore, data on adverse events were not included. all the phases included in the RATIFY study and approved by However, NICE considered it important to take into the EMA (induction, consolidation and maintenance), the account the adverse events derived from HSCT, given maintenance phase is not currently reimbursed in Spain. that certain events, such as graft-versus-host disease, Therefore, in clinical practice, patients would only incur the could have a significant impact on the results. Further pharmacological costs of induction and consolidation. Further research on this area is needed to ascertain the economic research is needed to determine the cost-effectiveness of mid- implications of HSCT-related adverse events. ostaurin when the maintenance phase is omitted. When comparing two potentially curative interven- Conclusions tions, and in line with the recommendations of pharma- This study shows that midostaurin, in combination with coeconomic guidelines, our study adopted a lifetime time standard chemotherapy, is emerging as an efficient alter- horizon. The availability of long-term overall survival and native for the treatment of recently-diagnosed FLT3-AML disease-free survival results from the RATIFY study in Spain. According to our modeling, the introduction of shows that the curves reached a plateau approximately midostaurin could reduce the costs associated with disease three years after study initiation, confirming that patients relapse and improve both life expectancy and quality of who remained alive would be virtually cured. In addition, life of Spanish patients with FLT3-AML. when the cure point was delayed to 6.2 years (maximum follow-up of the RATIFY study), the ICUR results are Abbreviations even more favorable than in the base case (€ 33,085/ AE, adverse event; AML, acute myeloid leukemia; QALY), which suggests that the establishment of a cure CADTH, Canadian Agency for Drugs and Technologies point at three years is a conservative assumption for mid- in Health; CGCOF, Consejo General de Colegios Oficiales ostaurin with respect to the comparator and that the effi- de Farmacéuticos; CI, confidence interval; CMBD, ciency of midostaurin could extend beyond the maximum Conjunto Mínimo Básico de Datos; CMV, cytomegalo- follow-up time observed in the clinical trial. virus; CR, complete remission; DRG, diagnosis-related This study incorporated the main NICE recommenda- group; FLAG-IDA, fludarabine, cytarabine, idarubicin; tions based on the authorization process of midostaurin in FLT3, FMS-like tyrosine kinase 3; GPE, generic pharma- the United Kingdom. This reinforces the validity and ceutical equivalent; GVHD, graft versus host disease; reliability of the model and its alignment with the HAS, Haute Autorité de Santé; HR, hazard ratio; HSCT, submit your manuscript | www.dovepress.com ClinicoEconomics and Outcomes Research 2019:11 692 DovePress Dovepress Arenaza et al hematopoietic stem cell transplantation; ICER, incremen- Carlos III. DML and AMF are employees of Oblikue tal cost-effectiveness ratio; ICU, intensive care unit; Consulting, an independent contract health economic orga- ICUR, incremental cost-utility ratio; LYG, life year nization that received consultancy fees from Novartis gained; MEC, mitoxantrone, etoposide, cytarabine; Farmacéutica, S.A. to conduct this research. AMF reports NICE, National Institute for Health and Care Excellence; grants from Oblikue Consulting, during the conduct of the PVL, ex-factory price; QALY, quality-adjusted life year; study. RDN and JG are employees of Novartis RDL, royal decree law; VZV, varicella-zoster virus; WHO, Farmacéutica, S.A., the marketing authorization holder World Health Organization. for Rydapt® (midostaurin). The funding body was not involved in the study design, collection and interpretation Acknowledgments of the data, or the decision to publish. The authors report The authors of the manuscript wish to thank Dr. Elena Amutio no other conflicts of interest in this work. for his participation in the panel of experts who validated the model inputs and assumptions, and Gabriel Tremblay for his References support during the performance of the sensitivity analyses. 1. O’Donnell MR, Tallman MS, Abboud CN, et al. Acute myeloid leukemia, version 3.2017, NCCN clinical practice guidelines in oncology. J Natl Compr Cancer Netw. 2017;15(7):926–957. Author Contributions doi:10.6004/jnccn.2017.0116 2. Infante MS, MÁ P, Hernández-Rivas JÁ. 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