ClinicoEconomics and Outcomes Research Dovepress open access to scientific and medical research Open Access Full Text Article ORIGINAL RESEARCH Cost-Effectiveness Analysis of Gemtuzumab Ozogamicin for First-Line Treatment of Patients with Cd-33 Positive Acute Myeloid Leukaemia in Spain ClinicoEconomics and Outcomes Research downloaded from https://www.dovepress.com/ on 28-Jan-2023 Maria Mareque 1 Objective: To assess the incremental cost–utility ratio (ICUR) of gemtuzumab ozogamicin Pau Montesinos 2 (GO) + standard of care (SOC) vs SOC alone for treatment of patients with de novo AML Patricia Font 3 from a Spanish Health Service perspective. José María Guinea 4 Methods: A cohort state-transition model, with 12 health-states, was used to estimate the For personal use only. lifetime accumulated cost and benefits in terms of quality-adjusted-life-years (QALYs) in Adolfo de la Fuente 5 AML patients with favourable, intermediate, and unknown cytogenetic profiles. Patient Javier Soto 6 profile was defined based on the ALFA-0701 trial. Therapeutic regimens were defined by Itziar Oyagüez 1 5 haematologists. SOC was assumed to be idarubicin and cytarabine, the combination most James Brockbank 7 used in Spain. QALYs were estimated by applying utilities for the time spent by the cohort in Tamara Iglesias 6 each health-state and utility decrements associated with adverse events (AE). Total cost Julia Llinares 6 (€,2020) included drug-acquisition, hematologic stem-cell transplantation, disease manage­ Jorge Sierra 8 ment, AE management and end-of-life costs. Unit costs were derived from local databases. 1 Pharmacoeconomics & Outcomes All parameters were validated by haematologist. Costs and outcomes were discounted (3%/ Research Iberia (PORIB), Madrid, Spain; year). 2 Hospital Universitario La Fe, Valencia, Results: Higher cost/patient (€177,618 vs €151,434) and greater QALYs (5,70 vs 4,62) were Spain; 3Hospital General Universitario Gregorio Marañón, Madrid, Spain; obtained with GO+SOC vs SOC. The ICUR was €24,203/QALY gained. 4 Organización Sanitaria Integrada Araba, Conclusion: This simulation suggests that GO + SOC could be a cost-effective option for País Vasco, Spain; 5Hospital MD Anderson, Madrid, Spain; 6Pfizer, Madrid, treatment of patients with de novo AML in first line. Spain; 7RTI Health Solutions, Manchester, Keywords: cost-effectiveness, gemtuzumab ozogamicin, acute myeloid leukaemia, Spain UK; 8Hospital Universitario de La Santa Creu i Sant Pau, Barcelona, Spain Introduction Acute myeloid leukaemia (AML) is a heterogeneous neoplasm characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow and/or other tissues.1 In Europe, the incidence of this disease is estimated at 3.7 per 100,000 inhabitants per year.2 The incidence increases progressively with age, with the highest rates in the oldest patients.2–4 AML is an aggressive and rapidly progressing disease with a 5-year survival rate for adults of less than 30%.5 In addition, AML is associated with an important clinical and economic burden to patients, their caregivers, and the healthcare system.6,7 Correspondence: Maria Mareque Pharmacoeconomics & Outcomes This disease is associated with different non-specific clinical manifestations, Research Iberia (PORIB), Paseo Joaquín such as fatigue, dyspnoea, anorexia, fever, weight loss, infections, and bleeding, Rodrigo 4-I, Pozuelo de Alarcón, Madrid, 28224, Spain which are present at diagnosis of AML and during all treatments.8,9 Therefore, Tel + 34 91 715 91 47 a proper diagnosis is clinically important in determining the appropriate therapeutic Fax + 34 91 715 94 69 Email mmareque@porib.com strategy for patients with AML. ClinicoEconomics and Outcomes Research 2021:13 263–277 263 © 2021 Mareque 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. 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). Mareque et al Dovepress The therapeutic management of AML depends funda­ The aim of the present analysis was to assess the cost- mentally on patients’ physical condition which determines effectiveness of adding GO to SOC first-line therapy in whether they can receive intensive chemotherapy, and on Spain, comparing the SOC alone for the management of the cytogenetic profile of the patient, which determines the patients with previously untreated de novo CD33-positive prognosis and the risk of relapse. With the advent of new AML. techniques for the molecular diagnostic and the European Leukemia Network 2017 guidelines,10 the determination Materials and Methods of genetic alterations which recurrently appear in AML (as NPM1 or FLT3) is becoming inceasingly important for the Model Structure A cost-effectiveness model was used to evaluate the effi­ risk classification of AML patients, and therefore, for the cacy of GO plus SOC vs SOC alone for the management selection of the best therapy for each type of AML.11 of patients with previously untreated de novo AML in Currently, the standard recommendation for patients with Spain. To perform the analysis in the Spanish setting, AML who are candidates to receive an intensive treatment a cohort state-transition model that had been previously consists of induction, consolidation therapy followed by validated was used.18–20 allogeneic (or less common autologous) hematologic stem The structure of the model used for the present analysis cell transplantation when appropriate and feasible.10 The captures the progression of the disease, using 12 mutually induction chemotherapy, aimed at achieving remission, is exclusive health states: induction chemotherapy, complete composed of cytarabine given by continuous infusion for 7 remission (CR) or complete remission with incomplete days and an anthracycline (such as daunorubicin or idar­ platelet recovery (CRp) (consolidation chemotherapy), ubicin) given daily for 3 days. Induction chemotherapy is CR or CRp (off treatment), relapse (salvage therapy), followed by consolidation chemotherapy to maintain relapse (noncurative therapy), refractory (salvage therapy), remission or eradicate any residual disease, which usually refractory (noncurative therapy), haematopoietic stem-cell consists of various courses of cytarabine in different transplant (HSCT) procedure, post-HSCT CR or CRp schemes.4,12 [without graft versus host disease (GVHD)], post-HSCT However, the therapeutic arsenal for AML has evolved CR or CRp (with GVHD), functionally cured (off treat­ rapidly in recent years, with the introduction of several ment) and dead (Figure 1). targeted therapies. These new drugs led to changes in the The analysis was performed for the patient cohort disease landscape, creating a wider range of treatment using monthly cycles over a lifetime horizon (40 years). options for these patients.13,14 One such example is Upon entering the model, patients were initiated with first- gemtuzumab ozogamicin (GO), a recombinant humanized line chemotherapy, receiving one or two induction courses, anti-CD33 monoclonal antibody linked to the antitumor depending on their initial response to treatment. At the end antibiotic calicheamicin, which permits the drug to be of induction chemotherapy, patients were assessed and targeted selectively to CD33-positive AML blast cells, either attained CR or CRp or failed induction chemother­ preserving normal cells, and thus limiting non- apy (refractory). Patients who achieved CR or CRp con­ haematological toxicity.15 GO administered in combina­ tinued with up to two courses of consolidation tion with standard of care (SOC) chemotherapy in chemotherapy; however, some patients received HSCT ALFA-0701, a randomised, open-label, phase III trial of because it is considered beneficial for patients with certain 278 patients aged 50–70 with previously untreated AML, risk profiles. Patients in CR or CRp who relapsed and significantly improved median event-free survival (EFS) patients who were refractory to induction chemotherapy and relapse-free survival (RFS) compared to SOC che­ moved to salvage or noncurative therapies (second-line motherapy alone.16 In April 2018, GO was approved by treatments). From this group of patients, those who were the European Medicines Agency (EMA), indicated for deemed fit enough could receive salvage therapy with the combination therapy with daunorubicin (DNR) and cytar­ aim of achieving a second-line CR or CRp and potentially abine (AraC) for the treatment of patients aged 15 years curative HSCT. Finally, some relapsed patients who and above with previously untreated, de novo CD33- achieved second-line CR or CRp who did not receive positive AML, except acute promyelocytic leukaemia HSCT but had prolonged survival were considered func­ (APL).17 tionally cured. 264 http://doi.org/10.2147/CEOR.S302097 ClinicoEconomics and Outcomes Research 2021:13 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Mareque et al Figure 1 Model structure diagram. Abbreviations: AML, acute myeloid leukaemia; CR, complete remission; CRp, complete remission with incomplete platelet recovery; GVHD, graft versus host disease; HSCT, haematopoietic stem cell transplantation. This analysis was performed from the perspective of the Population Spanish National Health System (NHS) and an annual dis­ The study population was selected based on those patients count rate of 3.0% was applied to both costs and health who had demonstrated benefit from adding GO to standard outcomes, according to the available recommendations for chemotherapy in the ALFA-0701 clinical trial.16,22 Based the development of a cost-effectiveness analysis in Spain.21 on the ALFA-0701 trial results, patients with unfavourable A lifetime horizon, 40 years, was applied to estimate cytogenetic profiles (including monosomy 5 or del(5q), life years gained (LYG) and quality-adjusted life years monosomy 7 or del(7q), t(6;11), t(9;22), 3q26 abnormal­ (QALYs) gained and the total costs of the two therapies ities but t(3;5), 11q23 abnormalities but t(9;11), and com­ considered in the analysis. plex karyotypes with 3 abnormalities or more) did not The model structure, population, adverse event (AE) show an apparent EFS benefit with GO added to SOC; management, disease management and resource consump­ therefore, previously untreated adult patients with de novo tion were validated and agreed on by a panel of five AML with favourable [t(8;21) and inv(16)/t(16;16)], inter­ haematologist experts with wide expertise and knowledge mediate (other anomalies as well as normal karyotypes), about AML. For this study, a structured questionnaire that and unknown cytogenetic profiles who were eligible to included the parameters identified in the scientific pub­ receive intensive chemotherapy were included in the lished literature was developed and completed by the analysis.16,22 expert panel. Subsequently, a face-to-face consensus meet­ Data for the simulated cohort were modelled on the ing was carried out with the panel of experts to validate mean characteristics of patients participating in the ALFA- and agree upon all the values used in the analysis to ensure 0701 trial.16 The baseline characteristics of the patients that it was representative of the Spanish setting. included in the analysis are described in Table 1. ClinicoEconomics and Outcomes Research 2021:13 http://doi.org/10.2147/CEOR.S302097 265 DovePress Powered by TCPDF (www.tcpdf.org) Mareque et al Dovepress Table 1 Inputs Included in the Model ALFA-0701 (2007–002933-36)16 was ap hase 3, open- Cytogenetic profile16 label multicenter study undertaken to investigate the addi­ Favourable 3.3% tion of GO to standard front-line chemotherapy in patients Intermediate 66.4% with CD33 positive de novo AML. The primary endpoint Unfavourable* 21.0% of the study was EFS. Unknown 9.2% Patients aged 50–70 years with previously untreated de Utility and utility decrement values novo AML were randomly assigned to a control group Induction chemotherapy31,32 0.6574 with standard treatment (N=139) or to therapy with five Consolidation chemotherapy31,32 0.6574** doses of intravenous GO (3 mg/m2 on days 1, 4, and 7 HSCT procedure31,32 0.6574** GVHD (post-HSCT)33 0.6700 during induction and day 1 of each of the two consolida­ CR or CRp31,32 0.7400 tion chemotherapy courses) (N=139).16 Relapse31,32 0.5680 Patients achieving complete response with or without Refractory31,32 0.5680*** incomplete platelet recovery after induction chemotherapy Functionally cured34 0.8199 was 104 (75%) in the control group and 113 (81%) in the Utility decrement for grade 3 or 4 AEs31 0.0024 Utility decrement for VOD35 0.208 GO group (odds ratio 1.46, 95% CI 0.20–2.59; p=0.25). At 2 years, EFS was estimated as 17.1% in the control group Notes: *These patients were only considered for sensitivity analysis; **assumed equal to induction chemotherapy; ***assumed equal to relapse. versus 40.8% in the GO group (HR 0.58, 0.43–0.78; Abbreviations: BSA, body surface area; AEs, adverse events; CR, complete remission; CRp, complete remission with incomplete platelet recovery; GVHD, p=0.0003), OS 41.9% versus 53.2%, respectively (0.69, graft versus host disease; HSCT, haematopoietic stem cell transplantation; VOD, 0.49–0.98; p=0.0368), and relapse-free survival (RFS) veno-occlusive disease. 22.7% versus 50.3%, respectively (0.52, 0.36–0.75; p=0.0003). Haematological toxicity, particularly persistent Treatment Strategies thrombocytopenia, was more common in the GO group The therapeutic alternatives compared in the model than in the control group (22 [16%] vs 4 [3%]; p<0.0001), included GO (Mylotarg®) combined with the most com­ without an increase in the risk of death from toxicity.16 mon SOC chemotherapy used in Spain (idarubicin and Additional publications of the trial results performed cytarabine) or SOC therapy alone. by a blinded independent review confirmed previous For induction and consolidation treatments, the regimens, results.22 The final OS on April 30, 2013, favoured GO doses, and durations of treatment observed in the ALFA-0701 but was not statistically significant (HR 0.81; 95% CI: clinical trial16 and the consensus established by an expert 0.60–1.09; P=0.16), and no differences in the early death panel according to clinical practice in Spain were adopted. rate were observed between arms. Moreover, the subgroup For the salvage and noncurative treatments, the most frequent analyses showed that patients with favourable or inter­ regimens and doses in clinical practice shown in the approved mediate cytogenetic risk (classified according to the summaries of product characteristics23–29 were assumed. All International System for Human Cytogenetic treatment regimens and doses considered in the model were Nomenclature criteria) at baseline had significantly longer validated by the clinical expert panel. EFS in the GO arm than in the control arm (HR: 0.46; Table 2 shows the regimens and doses of the therapies 95% CI: 0.31–0.68; p<0.0001); however, this advantage in considered in each treatment phase as well as the propor­ EFS with GO was not demonstrated for patients with poor tion of patients achieving each treatment cycle. cytogenetic risk (HR 1.11; 95% CI: 0.63–1.95; p=0.72). Grade 3 and 4 AEs most commonly observed in the Clinical Data ALFA-0701 clinical trial (skin toxicity, mucosal toxicity, To determine the distribution of patients across health pain, nausea, vomiting and diarrhoea, pulmonary toxicity, states over time, parametric survival models were fitted cardiac rhythm disorder, other cardiac toxicity, central to RFS and OS Kaplan–Meier curves from the ALFA- neurological toxicity, peripheral neurological toxicity, 0701 trial and extrapolated over the model time horizon. infections, haemorrhage and veno-occlusive disease An additive hazard ratio (HR) was applied to represent the (VOD)) were considered during the first model cycle15 excess mortality for cured patients with AML versus the (Table 3). Conservatively, no AEs related to subsequent- general population. line therapies were considered. 266 http://doi.org/10.2147/CEOR.S302097 ClinicoEconomics and Outcomes Research 2021:13 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Mareque et al Table 2 Treatment Regimens Considered in the Analysis Induction chemotherapy PVL - deduction per unit Induction course 1 Induction course 2 (if necessary)* (GO+SOC: 100%; SOC: 100%) (GO+SOC: 15%; SOC: 15%) 2 GO € 1,382.40 3 mg/m per day (maximum 5 mg per dose) on - days 1, 4 and 7 SOC Idarubicin € 8.18 12 mg/m2 per day on days 1–3 12 mg/m2 per day on days 1–3 Cytarabine € 0.0144 200 mg/m2 per day on days 1–7 200 mg/m2 per day on days 1–7 Consolidation chemotherapy PVL - deduction per unit Consolidation course 1 Consolidation course 2 (GO+SOC: 74%; SOC: 70.8%) (GO+SOC: 62.6%; SOC: 65%) GO € 1,382.40 3 mg/m2 per day (maximum 5 mg per dose) 3 mg/m2 per day (maximum 5 mg per on day 1 dose) on day 1 SOC Idarubicin € 8.18 - - Cytarabine € 0.0144 2,000 mg/m2 per 12 hours on days 1–3 2,000 mg/m2 per 12 hours on days 1–3 Salvage therapy PVL - deduction per unit Doses Number of doses Fludarabine € 1.99 30 mg/m2 5 Cytarabine € 0.0144 2,000 mg/m2 5 Filgrastim € 0.1137 5 µg/kg/day 6 Idarubicin € 8.18 10 mg/m2 3 Noncurative therapies PVL - deduction per unit Doses Number of doses Proportion of use Hydroxycarbamide € 0.0003 1,000 mg/day 28 20% Cytarabine € 0.0144 40 mg 10 10% Azacitidine € 3.54 75 mg/m2 7 50% Decitabine € 21.33 20 mg/m2 5 20% Notes: The proportion of patients for each treatment regimen was obtained from the ALFA-0701 clinical trial and from expert opinion; *GO should not be administered during second induction course. Abbreviations: GO, gemtuzumab ozogamicin; SOC, standard of care. In addition, acute and chronic GVHD was considered a higher risk of dying from causes other than the general in the analysis since it is a clinically important complica­ population; therefore, mortality related to AML and its asso­ tion that patients can develop after HSCT. The incidence ciated complications were considered in the analysis.16 of grade 3 or 4 acute GVHD for HSCT patients was estimated to be 15%, with a mean duration of 2.5 months, Utilities and Disutilities and the incidence of grade 3 or 4 chronic GVHD was To estimate the QALYs, different utility values were con­ estimated to be 20%, with a mean duration of 12 months sidered depending on the health states of the patients. The based on expert panel opinion. Probability of HSCT was term “utility” refers to the quality perceived by patients calculated from the ALFA-0701 clinical trial.16 based on their health status and receives a value between 1 (perfect health) and 0 (state of health equivalent to death). Mortality The utility values were obtained from the scientific All-cause mortality data were applied to show the annual literature31–34 using the scores of the EuroQol probability of death by age and sex, derived from the Spanish 5-Dimensions (EQ-5D) questionnaire were applied to the mortality tables.30 In addition, patients with AML carry different health states (Table 1). ClinicoEconomics and Outcomes Research 2021:13 http://doi.org/10.2147/CEOR.S302097 267 DovePress Powered by TCPDF (www.tcpdf.org) Mareque et al Dovepress Table 3 Healthcare Direct Costs (€, 2020) Disease Management Costs Resource Use* % Patients Unit Cost Cost Induction course 1 Hospital admissions Haematology unit 30 days 100% € 722.89 € 21,686.70 Tests** Blood count 1 100% € 4.15 € 4.15 Biochemistry 1 100% € 128.52 € 128.52 Coagulation 1 100% € 14.36 € 14.36 Bone marrow aspirate 1 100% € 244.84 € 244.84 Immunophenotyping 1 100% € 94.62 € 94.62 Molecular study 1 100% € 308.05 € 308.05 Myelogram 1 100% € 98.53 € 98.53 Karyotype 1 100% € 164.71 € 164.71 Chest radiography 1 75% € 17.43 € 13.07 HLA study 1 100% € 158.27 € 158.27 Abdominal ultrasound 1 50% € 104.99 € 52.49 Pharmaceutical treatment Meropenem (3,000 mg/day) 20 days 100% € 0,0142 € 852.00 Total cost € 23,820.32 Induction course 2 Hospital admissions Haematology unit 30 days 100% € 722.89 € 21,686.70 Tests** Blood count 1 100% € 4.15 € 4.15 Biochemistry 1 100% € 128.52 € 128.52 Coagulation 1 100% € 14.36 €14.36 Bone marrow aspirate 1 100% € 244.84 € 244.84 Immunophenotyping 1 100% € 94.62 € 94.62 Molecular study 1 70% € 308.05 € 215.64 Myelogram 1 100% € 98.53 € 98.53 Karyotype 1 100% € 164.71 € 164.71 Chest radiography 1 75% € 17.43 € 13.07 Abdominal ultrasound 1 50% € 104.99 € 52.49 Pharmaceutical treatment Meropenem (3,000 mg/day) 20 days 100% € 0,0142 € 852.00 Total cost € 23,569.63 Consolidation course 1 Hospital admissions Haematology unit 24 days 100% € 722.89 € 17,349.36 Tests** Blood count 1 100% € 4.15 € 4.15 Biochemistry 1 100% € 128.52 € 128.52 Coagulation 1 100% € 14.36 € 14.36 Pharmaceutical treatment Meropenem (3,000 mg/day) 20 days 100% € 0,0142 € 852.00 Total cost € 18,348.39 (Continued) 268 http://doi.org/10.2147/CEOR.S302097 ClinicoEconomics and Outcomes Research 2021:13 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Mareque et al Table 3 (Continued). Disease Management Costs Resource Use* % Patients Unit Cost Cost Consolidation course 2 Hospital admissions Haematology unit 24 days 100% € 722.89 € 17,349.36 Tests** Blood count 1 100% € 4.15 € 4.15 Biochemistry 1 100% € 128.52 € 128.52€ Coagulation 1 100% € 14.36 € 14.36 Bone marrow aspirate 1 100% € 244.84 € 244.84 Immunophenotyping 1 100% € 94.62 € 94.62 Molecular study 1 100% € 308.05 € 308.05 Myelogram 1 100% € 98.53 € 98.53 Karyotype 1 100% € 164.71 € 164.71 Pharmaceutical treatment Meropenem (3,000 mg/day) 20 days 100% € 0,0142 € 852.00 Total cost € 19,259.14 Complete remission off treatment Specialist visits Haematology 0.33 100% € 159.08 € 53.03 Tests** Blood count 1 100% € 4.15 € 4.15 Biochemistry 1 100% € 128.52 € 128.52 Coagulation 1 100% € 14.36 € 14.36 Bone marrow aspirate 1 100% € 244.84 € 244.84 Myelogram 1 100% € 98.53 € 98.53 Karyotype 1 100% € 164.71 € 164.71 Immunophenotyping 1 100% €94.62 €94.62 Molecular study 1 100% € 308.05 € 308.05 Total cost € 1,110.81 Salvage therapy Hospital admissions Haematology unit 30 days 100% € 722.89 € 21,686.70 Test** Blood count 1 100% € 4.15 € 4.15 Biochemistry 1 100% € 128.52 € 128.52 Coagulation 1 100% € 14.36 € 14.36 Bone marrow aspirate 1 100% € 244.84 € 244.84 Immunophenotyping 1 100% € 94.62 € 94.62 Molecular study 1 100% € 308.05 € 308.05 Myelogram 1 100% € 98.53 € 98.53 Karyotype 1 100% € 164.71 € 164.71 Chest radiography 1 100% € 17.43 € 17.43 Abdominal ultrasound 1 50% € 104.99 € 52.49 Pharmaceutical treatment Meropenem (3,000 mg/day) 20 days 100% € 0,0142 € 852.00 Total cost € 22,814.40 (Continued) ClinicoEconomics and Outcomes Research 2021:13 http://doi.org/10.2147/CEOR.S302097 269 DovePress Powered by TCPDF (www.tcpdf.org) Mareque et al Dovepress Table 3 (Continued). Disease Management Costs Resource Use* % Patients Unit Cost Cost Non-curative therapies Specialist visits Haematology 3 100% € 159.08 € 477.24 Hospital admissions Haematology unit 10 days 30% € 722.89 € 2,168.67 Test** Blood count 1 100% € 4.15 € 4.15 Biochemistry 1 100% € 128.52 € 128.52 Total cost € 2,778.58 End-of life cost Hospital admissions 20 days 60% € 986.00 € 11,832 Total cost € 11,832 HSCT COST Cost HSCT procedure € 65,514.92 Mean number of transfusions TRANSFUSION COST Costs GO+SOC SOC Red blood cell transfusion Per induction course 1 8.0 7.1 Per induction course 2 7.5 6.8 Per consolidation course 1 4.6 3.9 Per consolidation course 2 4.1 4.3 € 234.27/transfusion Per salvage course 7.0 7.0 Per non-curative course 5.0 5.0 Platelet transfusion Per induction course 1 12.9 6.1 Per induction course 2 10.8 7.4 Per consolidation course 1 8.1 2.9 Per consolidation course 2 7.8 3.8 € 83.26/transfusion Per salvage course 8.0 7.0 Per non-curative course 4.0 4.0 AE MANAGEMENT COSTS Cost Skin toxicity € 3,440.59 Mucosal toxicity € 3,456.06 Pain € 3,301.36 Nausea, vomiting, and diarrhoea € 3,308.34 Pulmonary toxicity € 4,205.10 Cardiac rhythm disorder € 6,426.90 Other cardiac toxicity € 6,426.90 Central neurological toxicity € 4,344.30 Peripheral neurological toxicity € 4,344.30 Infections € 6,381.54 Haemorrhage € 6,804.31 (Continued) 270 http://doi.org/10.2147/CEOR.S302097 ClinicoEconomics and Outcomes Research 2021:13 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Mareque et al Table 3 (Continued). Disease Management Costs Resource Use* % Patients Unit Cost Cost Veno-occlusive disease € 24,524.66 Graft versus host disease € 6,852.47 Notes: *Resource consumption was provided by the expert panel; **additional tests not included in the inpatient period. Abbreviations: HLA, human leukocyte antigen; AEs, adverse events; GO, gemtuzumab ozogamicin; SOC, standard of care; HSCT, haematopoietic stem-cell transplant. Moreover, a decrease in utility (disutility) was applied for End-of-life costs were estimated from the consumption of AEs. A mean one-off utility decrement of 0.0024 for all healthcare resources provided by a clinical expert panel grade 3 or 4 AEs apart from VOD was applied in the (Table 3). model.32 For VOD, a decrease in utility of 0.20835 was All unitary costs were obtained from a local national applied for a mean duration of 26.8 days.36 database of healthcare costs.39 Costs were expressed in Euros for the year 2020 and adjusted for inflation using the Resource Use and Costs Spanish healthcare consumer price index as necessary.40 In line with the perspective of the analysis, only costs related to direct healthcare resource consumption were Sensitivity Analysis considered. These included pharmaceutical costs, disease One-way sensitivity analysis (OWSA) and probabilistic management costs per health state, HSCT costs, AE man­ sensitivity analysis (PSA) were performed to assess the agement costs and end-of-life costs. robustness of the model and the uncertainty of the base The pharmaceutical costs reflected drug acquisition, case results for each of the treatment strategies analysed. which was estimated based on ex-factory prices published For the OWSA, the following parameters were varied: in the Spanish General Council of Official Pharmaceutical time horizon (20 years), discount rate (0% and 5%), mean Colleges catalogue,37 applying the national mandatory BSA of 1.70 m2 which is representative of the Spanish deductions38 (Table 2). population,41 proportion of patients for all cytogenetic Disease management costs were estimated based on the profiles (3.32% favourable, 66.42% intermediate, 21.03% healthcare resource consumption for referral to specialist visits, hospital admissions, diagnostic and laboratory tests, unfavourable and 9.23% unknown), costs such as health and concomitant treatments, which were provided by state medical resources and AEs were varied by ±20%, a haematology expert panel with wide expertise and and health-state utility values were modified by ±20%. knowledge about AML (Table 3). In the PSA, 1,000 Monte Carlo simulations were per­ In relation to transfusion costs, red blood cell and formed. The value of each key model parameter was varied platelet transfusions were considered in the analysis. within a specific probability distribution assigned to each Total costs were estimated by multiplying the mean num­ parameter. Bayesian posterior distributions were applied for ber of transfusions reported in the ALFA-0701 study16 by survival function parameters, log-normal distributions for HR, the cost per transfusion (Table 3). and gamma distributions for costs and utility values. Regarding HSCT costs, only the cost of the transplan­ tation procedure was considered, assuming that it covers Results complications and follow-up and the post-transplantation recovery period. The model applied a one-time cost for the Base Case transplantation procedure and recovery period whenever Over a lifetime horizon, GO in combination with anthra­ patients entered the HSCT health state (Table 3). cycline and cytarabine was associated with 7.81 LYG and Grade 3 or 4 AE-related costs were calculated by 5.70 QALYs gained per patient, which were higher than multiplying the number of AEs reported in the ALFA- the results obtained in patients treated with SOC alone 0701 study16 with the estimates of the cost per event. (6.37 LYG/patient and 4.62 QALYs/patient). The cost of VOD was calculated from the healthcare The estimated total cost for achieving these gains in resource consumption incurred for hospitalizations, health outcomes was € 177,618 and € 15,134 per patient which was provided by an expert panel (Table 3). with GO plus SOC and SOC alone, respectively. ClinicoEconomics and Outcomes Research 2021:13 http://doi.org/10.2147/CEOR.S302097 271 DovePress Powered by TCPDF (www.tcpdf.org) Mareque et al Dovepress Table 4 Base Case Results of the Cost-Effectiveness Analysis GO + SOC SOC Incremental LYG 7.81 6.37 1.44 QALYs 5.70 4.62 1.08 TOTAL COST € 177,618.13 € 151,434.33 € 24,203.42 Induction health state cost Course 1 € 48,080.02 € 26,567.04 € 21,512.98 Course 2 € 4,020.20 € 3,953.15 € 67.05 CR/CRp health state cost Consolidation 1 € 20,222.78 € 14,676.78 € 5,546 Consolidation 2 € 17,588.54 € 13,584.06 € 4,004.48 Off treatment € 22,537.26 € 14,491.30 € 8,045.96 Relapse health state cost Salvage therapy € 5,407.65 € 7,978.82 - € 2,571.16 Non-curative therapy € 8,031.54 € 11,889.66 - € 3,858.12 Best supportive care € 7,365.01 € 10,902.94 - € 3,537.93 Refractory health state cost Salvage therapy € 4,296.89 € 4,283.87 € 13.02 Non-curative therapy € 5,443.31 € 5,443.31 - Best supportive care € 4,942.19 € 4,942.19 - HSCT health state cost € 17,937.96 € 23,371.74 - € 5,433.78 CR/CRp with GVHD health state cost € 656.03 € 854.76 - € 198.73 Adverse event cost € 11,088.74 € 8,494.72 € 2,594.02 ICER (€/LYG) € 18,234.55 ICUR (€/QALY gained) € 24,203.42 Abbreviations: CR, complete remission; CRp, complete remission with incomplete platelet recovery; GO, gemtuzumab ozogamicin; GVHD, graft versus host disease; HSCT, haematopoietic stem-cell transplant; ICER, incremental cost-effectiveness ratio; ICUR, incremental cost utility ratio; QALY, quality adjusted life year; LYG, life years gained; SOC, standard of care. The incremental cost–utility ratio (ICUR) for GO plus influence on the results were the inclusion of the unfavourable SOC versus the SOC alone was € 24,203 per additional cytogenetic profile, followed by the discount rate (Figure 2). QALY (Table 4). The results of the PSA showed that of 1,000 iterations Therefore, according to the most widely accepted willing­ carried out, 55.9% showed an ICUR below a willingness- ness-to-pay threshold in Spain (€ 10,000–30,000/QALY),42 to-pay threshold of €30,000/QALY. The GO plus SOC the treatment of AML patients with GO added to standard therapy can be considered a cost-effective alternative induction chemotherapy (anthracycline and cytarabine) can with a mean ICUR of € 25,556 (95% CI € 23,698 – € be considered a cost-effective strategy compared with SOC 27,710) compared to SOC alone (Figure 2). alone (Table 4). The results of both the deterministic and probabilistic analyses are described in Figure 2. Sensitivity Analysis In the OWSA, the addition of GO to SOC (anthracycline and Discussion cytarabine) was a cost-effective in eight of nine scenarios Economic evaluations aim to provide information to health tested. The ICUR values ranged between € 17,703 and € decision-makers that could be useful for the adoption of 34,418 for each additional QALY gained with the GO+SOC new therapies and their inclusion in the reimbursement treatment versus SOC alone. The parameters having the most process of health systems. 272 http://doi.org/10.2147/CEOR.S302097 ClinicoEconomics and Outcomes Research 2021:13 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Mareque et al A One-way sensitivity analysis B Probabilistic sensitivity analysis Figure 2 Results of one-way and probabilistic sensitivity analysis. (A) One-way sensitivity analysis. (B) Probabilistic sensitivity analysis. In 2018, the EMA granted the authorization of GO to be which can be compensated for or even lead to savings in used for the treatment of previously untreated, de novo the total costs by a lower use of resources for patient CD33-positive AML, except APL, for patients aged 15 management. In the case of GO, previous studies have years and above, in combination with daunorubicin and been performed with different higher dose concerns in cytarabine, and in July 2019, marketing authorization was terms of safety.44,45 To minimize toxicity, the ALFA- issued.43 0701 study16 presented a new fractionated dose regimen Usually, the inclusion of new treatment options fre­ in combination with 3+7, using 3 mg/m2 of GO on D1, quently represents an increase in pharmaceutical costs, D4, D7, allowing safer administration of higher ClinicoEconomics and Outcomes Research 2021:13 http://doi.org/10.2147/CEOR.S302097 273 DovePress Powered by TCPDF (www.tcpdf.org) Mareque et al Dovepress cumulative doses (9 mg/m2). The ALFA-0701 study clas­ 30,000 per QALY, a threshold frequently used as reference sified patients according to the current European Leukemia value in economic evaluations performed in Spain.42 Net (ELN) 2010 at the moment of the study. Under cyto­ To our knowledge, this is the first cost-effectiveness genetic risk classification, only 3% of the total patients /utility analysis of GO plus SOC in newly diagnosed included in the study were classified as favourable cyto­ patients with CD-33 positive AML conducted from the genetic risk (t(8;21) and inv(16)/t(16;16)).16 Subgroup perspective of the Spanish NHS. Therefore, in the analysis showed that patients with favourable or inter­ Spanish context, it is not possible to compare the results mediate cytogenetic risk had a significantly longer EFS with other studies. Nevertheless, the results of the study in the GO arm versus the control arm (HR: 0.46, are in line with those from other published economic p>0.0001), which was not observed in patients with poor analyses in other settings. A cost-effectiveness study was cytogenetic risk (HR: 1.11, p=0.72).22 published recently in the United Kingdom using the same Recently, Fournier et al. retrospectively analysed data model as in the present analysis.48 This study showed that from patients enrolled in the ALFA-0701 trial using the GO in combination with SOC (daunorubicin + cytarabine) most recent ELN 2017 risk classification. In this work, the is a cost-effective first-line treatment option for adult benefit of GO was confirmed in patients with favourable patients with AML versus SOC alone, leading to an and intermediate risk, while it did not influence the out­ ICUR of £13,561/QALY gained. come of patients within the adverse risk subgroup.11 A conservative assumption was made, in that the base Another study46 has examined post-transplant outcomes case patients with favourable, intermediate, and unknown cytogenetic profiles were considered. This cytogenetic and the occurrence of hepatic VOD or sinusoidal obstruc­ subgrouping was employed since, based on the ALFA- tion syndrome (SOS) in patients who received HSCT as 0701 study,16 the addition of GO was not associated with follow-up therapy in ALFA-0701, which was recom­ an additional survival benefit for patients with an unfa­ mended for patients in first complete remission with vourable cytogenetic profile. Nevertheless, a sensitivity matched donor, except those with AML with core- analysis was performed to test the results in the total binding factor or normal karyotype and AML NPM1 population with AML, which was slightly above the will­ +/FLT3-ITDwt or CEBPA+. The results indicate that frac­ ingness-to-pay threshold used as a reference.43 tionated dose GO as part of induction and consolidation The present model has several limitations, some of chemotherapy for AML does not induce excess VOD/SOS which are inherent to this type of pharmacoeconomic after transplantation or mortality and therefore does not analysis. Primarily, the theoretical nature of any model­ preclude the use of HSCT as consolidation therapy. ling might not be an accurate representation of daily Furthermore, a meta-analysis of individual patient data clinical practice. In this study, the source used to include from 5 randomized controlled trials showed the benefit efficacy in the model was the ALFA-0701 clinical trial,16 of GO added to conventional induction therapy. In this a study that only considered the intensive treatment article, the addition of GO significantly reduced the risk of candidate population (excluding patients with comorbid­ relapse (OR 0.81 p=0.0001) and, at 6 years, the absolute ities or other conditions that doesn´t allow to receive survival benefit was especially significant in patients with intensive chemotherapy) and de novo AML (excluding favourable cytogenetic features (20.7% p=0.0006) but also patient had secondary or post-treatment AML). RFS and with intermediate cytogenetic features (5.7% p=0.005).47 OS data are limited at a median follow-up of 60 months, In the present study, the addition of GO to SOC for and parametric survival functions were required to extra­ first-line treatment for CD33+ AML patients with favour­ polate the Kaplan-Meier trial curves. Additionally, in the able/intermediate or unknown cytogenetics increased the analysis, equivalence was assumed between SOC che­ pharmaceutical cost (€ 31,179); however, due to its higher motherapy used in the ALFA-0701 trial16 (daunorubicin effectiveness, the final management costs were reduced (€ + cytarabine) and the most common combination used in 5,715), mainly by transplantations avoided (32 GO+SOC Spain (idarubicin + cytarabine). Several studies identi­ vs 53 SOC).22 The results obtained with the present simu­ fied in the literature, using either daunorubicin at 60 or lation suggest that the cost per additional QALYs gained 90 mg/m2 or idarubicin at 12 mg/m2 have shown similar with GO in combination with SOC compared to SOC rates of CR and survival.49,50 These data were validated alone (€ 24,203/QALYs) remains between € 10,000 - € and agreed upon by the panel of experts. 274 http://doi.org/10.2147/CEOR.S302097 ClinicoEconomics and Outcomes Research 2021:13 DovePress Powered by TCPDF (www.tcpdf.org) Dovepress Mareque et al Another possible limitation is related to the use of data Pharmaceuticals, and AbbVie, during the conduct of the extracted from the literature of studies conducted in other study. María Mareque and Itziar Oyagüez are currently countries, where studies conducted, specifically in Spain employed at PORIB, a consultant company specialized in were not identified. The utility and disutility values used in economic evaluation of health interventions, which received the model were derived from international literature,32–35 financial support from Pfizer for the development of this which were validated by the expert panel to ensure that these study. Javier Soto, Tamara Iglesias and Julia Llinares are values are representative of the Spanish AML population. employees of Pfizer Spain. James Brockbank is employed Finally, the parameters used in the analysis have been of RTI Health Solutions. The authors report no other conflicts extracted from different sources; however, all variables are of interest in this work. based on official sources or on publications with a high level of clinical evidence and have been validated by an expert panel. Regarding the consumption of healthcare resources References included for the consolidation courses, a conservative sce­ 1. Tallman MS, Wang ES, Altman JK, et al. 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