Powered by EHA Article OPEN ACCESS Health Economic Aspects of Chimeric Antigen Receptor T-cell Therapies for Hematological Cancers: Present and Future Renaud Heine1, Frederick W. Thielen1, Marc Koopmanschap1, Marie José Kersten2, Hermann Einsele3, Ulrich Jaeger4, Pieter Sonneveld5, Jorge Sierra6, Carin Smand7, Carin A. Uyl-de Groot1,8 Correspondence: Renaud Heine (heine@eshpm.eur.nl). Abstract Since 2018, 2 chimeric antigen receptor (CAR) T-cell therapies received approval from the European Medicine Agency, with list prices around 320 000 Euro (€) (EUR) per treatment. These high prices raise concerns for patient access and the sustainability of healthcare systems. We aimed to estimate the costs and budget impact associated with CAR T-cell therapies for current and future indications in hematological cancers from 2019 to 2029. We focused on the former France, Germany, Spain, Italy and the United Kingdom (EU-5) and the Netherlands. We conducted a review of list prices, health technology assessment reports, budget impact analysis dossiers, and published cost-effectiveness analyses. We forecasted the 10-year health expenditures on CAR T-cells for several hematological cancers in selected European Union countries. Nine cost-effectiveness studies were identified and list prices for CAR T-cell thera- pies ranged between 307 200 EUR and 350 000 EUR. Estimated additional costs for pre- and post-treatment were 50 359 EUR per patient, whereas the incremental costs of CAR T-cell therapy (when compared with care as usual) ranged between 276 086 EUR and 328 727 EUR. We estimated market entry of CAR T-cell therapies for chronic mantle cell lymphoma, follicular lymphoma, chronic lym- phocytic leukemia, multiple myeloma, and acute myeloid leukemia in 2021, 2022, 2022, 2022, and 2025, respectively. Cumulative expenditure estimates for existing and future indications from 2019 to 2029 were on average 28.5 billion EUR, 32.8 billion EUR, and 28.9 billion EUR when considering CAR T-cell therapy costs only, CAR T-cell therapy costs including pre- and post-treatment, and incremental CAR T-cell therapy costs, respectively. CAR T-cell therapies seem to be promising treatment options for hematological cancers but the financial burden on healthcare systems in the former EU-5 and the Netherlands will contribute to a substantial rise in healthcare expenditure in the field of hematology. Introduction approval of tisagenlecleucel (Kymriah) and axicabtagene ciloleu- It took almost 40 years from the time chimeric antigen recep- cel (Yescarta) by both the Food and Drug Administration (FDA) tor (CAR) T-cell therapy was first described in the 1980s to the and the European Medicines Agency (EMA) in 2017 and 2018, respectively.1 Thus far, the EMA approved tisagenlecleucel for the treatment of pediatric and young adult patients up to 25 1 Erasmus School of Health Policy and Management, Erasmus University, Rotterdam, The Netherlands years of age with B-cell acute lymphoblastic leukemia (ALL) that 2 Department of Haematology, Cancer Center Amsterdam and LYMMCARE are refractory, in relapse post-transplant or in second or later (Lymphoma and Myeloma Center Amsterdam), Amsterdam UMC, University of relapse as well as for adult patients with relapsed or refractory Amsterdam, Amsterdam, The Netherlands diffuse large B-cell lymphoma (DLBCL) after 2 or more lines of 3 Department of Internal Medicine II, Universitätsklinikum Würzburg, Germany systemic therapy. Axicabtagene ciloleucel is currently approved 4 Department of Medicine I, Division of Hematology and Hemostaseology, Medical by the EMA for the treatment of adult patients with relapsed University of Vienna, Austria or refractory DLBCL and primary mediastinal large B-cell lym- 5 Erasmus MC Cancer Institute, Department of Haematology, Rotterdam, The phoma after 2 or more lines of systemic therapy. Both therapies Netherlands are autologous treatments and second-generation CAR-Ts. 6 Department of Haematology, Hospital de la Santa Creu I Sant Pau, Josep Carreras Leukaemia Research Institute, Universitat Autonoma of Barcelona, Spain After novel drugs receive central approval by the EMA, each 7 European Hematology Association, The Hague, The Netherlands European member state handles its own approval and reimburse- 8 Institute for Medical Technology Assessment, Rotterdam, The Netherlands. ment procedure. With list prices of approximately 289 550 Euro (€) RH and FWT contributed equally to this study. (EUR) (373 000 United States dollars [$] [USD]) in the United States Supplemental digital content is available for this article. and 320 000 EUR in Europe, CAR T-cell therapies belong to the Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. most expensive cancer treatments at the moment. This has conse- on behalf of the European Hematology Association. This is an open-access quently raised concerns regarding patient access to these therapies article distributed under the terms of the Creative Commons Attribution-Non and the financial sustainability of healthcare systems in general. Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible CAR T-cell therapies are expected to bring substantial health bene- to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. fits but also exposes healthcare systems to very large expenditures. HemaSphere (2021) 5:2(e524). http://dx.doi.org/10.1097/ Simultaneously, an increase in trial activity heralds an expansion of HS9.0000000000000524. CAR T-cell therapies to many more indications in the near future, Received: 3 June 2020 / Accepted: 24 November 2020 of which hematological cancers currently play the most significant 1 Heine et al Health Economic Aspects of Chimeric Antigen Receptor T-cell Therapies role.2 Therefore, these therapies may have a considerable incremen- reimbursement authorities. In addition, we searched for tal budget impact on healthcare expenditures, especially in the field published CEA studies to complement potential missing or of hematology-oncology. Moreover, the costs associated with these unpublished data. These publications were searched through therapies are not limited to acquisition costs alone. Other costs that Excerpta Medica dataBASE on May 9, 2019, with an update will have a substantial impact on healthcare expenditures are hos- search on April 20, 2020 (see Appendix 1, http://links.lww. pitalization, intensive care unit (ICU) stays, as well as other costs com/HS/A130 for the full search strategy). Only economic related to the treatment of adverse events (AEs) and laboratory evaluations for hematological diseases were included. work. Furthermore, patients who live longer will also incur future medical costs unrelated to their condition for which they received CAR T-cell therapy. Conversely, longer survival may also lead to a Identification of future indications and estimation return to productive work of survivors in remission. of the eligible patient population In addition, substitution effects may reduce the financial impact of CAR T-cells such as avoiding the current standard To identify future indications for CAR T-cells, we searched of care treatment and a potential reduction in the numbers of ClinicalTrials.gov for all registered studies on CAR T-cell autologous and/or allogeneic stem cell transplantation follow- therapies (search term: “chimeric antigen receptor”) for ing treatment. hematological cancers on May 3, 2019. This search included Overall, the application of CAR T-cell therapies may result in early phase 1, phase 1, phase 2, phase 3, and phase 4 trials. higher overall healthcare spending and opportunity costs—money All studies were ranked according to the indication studied can only be spent once—leading to a change in the allocation of the (most to least often studied indication). Through a semi-struc- available healthcare budget. Without any formal assessment with tured interview, several clinical experts were asked to validate regards to the financial aspects of these therapies, their costs remain this ranking and to (re)arrange it according to the sequence of intangible and vague. Even though economic evaluations and bud- expected market entry. get impact analyses can shed light on the economic burden of new To estimate the eligible patient population for CAR T-cells, therapies in general, such assessments are not formally required in we focused on the 2 indications for which CAR T-cells already most countries (in Europe and elsewhere) for drug reimbursement have market authorization (pediatric ALL [pALL] and DLBCL) decision making, and therefore, such data are scarce. and the top 5 potential future indications identified by the The European Hematology Association (EHA) is concerned clinical experts. The eligible patient population was calculated about the sustainability of the pricing of new oncological treat- based on previous population forecasts by using 2 data sources, ments, and in particular of CAR T-cell therapy, possibly exposing namely Eurostat and Globocan.3 health systems to very large expenditures. Therefore, the EHA has In the Eurostat forecast, several assumptions were made on commissioned the Institute for Medical Technology Assessment the future development for fertility, mortality, and net migration (iMTA) to forecast future health expenditures, based on the to predict the population of European member states to the year adoption of CAR T-cell therapies in hematological cancers. 2080 (based on the population in 2016).4 We assumed a linear This study aimed to estimate the costs and budget impact trend between the 2016 and 2080 Eurostat data and calculated associated with CAR T-cell therapies for current and future the yearly population per country of interest. For our purpose, indications in hematological cancers in Europe from 2019 we defined the “disease incident population” by estimating the to 2029. The results of this study can be used by healthcare yearly crude incidence rate (IR) per 100 000 for each disease and decision-makers in their budgetary planning as they elucidate country of interest. For pALL and DLBCL, the yearly disease the future economic burden of CAR T-cell therapies in several IRs were taken from HTA/BIA reports. For future indications, European countries. or in the absence of published data from HTA/BIA reports, we used data from the European Cancer Information System (ECIS).5 Subsequently, the crude IRs were applied to projected Materials and Methods population data by Eurostat.4 The online database Global Cancer Incidence, Mortality We followed a 4-stepped approach and focused on 6 and Prevalence offers information on projected IRs of dif- European member states: the former EU-5 (ie, Germany, Spain, ferent cancer types for the time between 2018 and 2040 for France, United Kingdom, and Italy) and the Netherlands. several countries.6 To derive the number of patients for each First, we conducted a review of list prices, health technology cancer subtype of interest, we applied proportions based on assessment (HTA) reports, budget impact analysis (BIA) dos- the literature.3,7-9 siers, and published cost-effectiveness analyses (CEA). Second, Both forecast approaches are depicted in Figure 1. we identified potential future indications and estimated the The proportion of “patients eligible for CAR T-cell ther- eligible patient population for both registered and selected apy” per country was calculated based on HTA/BIA reports. upcoming indications. Third, we validated our findings with Most publications stated the yearly number of incident cases international clinical experts in the field of hematology-on- and the total number of patients eligible for CAR T-cell ther- cology. Finally, based on the gathered information in the pre- apy. From these numbers, we calculated the proportion of vious steps, we predicted the 10-year health expenditures on eligible patients and applied this rate to all incident cases to CAR T-cells for several hematological cancers in the selected derive the total yearly number of eligible patients for CAR European Union (EU) member states. The forecast entails dif- T-cells per disease and country. The CAR T-cell therapy eligi- ferent cost calculations, namely: (1) costs of CAR T-cell ther- ble patient population for all future indications was based on apies only; (2) costs of CAR T-cell therapies and costs of care, expert opinion. as well as (3) incremental costs associated with the substitu- tion of former therapies by CAR T-cell therapies. All costs are expressed in 2018 Euro. Validation with clinical experts Clinical experts in the field of hematology-oncology were Review of list prices and cost-effectiveness asked to validate our intermediate findings via semi-structured publications interviews. Respondents were asked about their experience with CAR T-cell therapies, possible future hematological indications, We retrieved list prices for tisagenlecleucel and axicabta- resource use during pre-treatment, treatment, and post-treat- gene ciloleucel from HTA/BIA reports published by national ment with CAR T-cell therapies in their own country, and the 2 (2021) 5:2 www.hemaspherejournal.com Figure 1. Flowchart of forecast approaches. CAR-T = chimeric antigen receptor T cell. plausibility for CAR T-cell therapies to be manufactured within Results specialized hospitals (point-of-care manufacturing). Results of list prices and cost-effectiveness Expenditure estimation of CAR T-cell therapies for publications current and selected future indications HTA reports and BIA dossiers were found for Germany,18-20 Expenditures were estimated for 3 scenarios. In “Scenario 1,” France,21-23 the United Kingdom,24-26 the Netherlands,27-29 and the CAR T-cell therapy eligible patient population was multi- Spain. Only in German publications, list prices were stated for plied with the average list price for the currently approved CAR all indications. In France, all prices were marked as confidential, T-cell therapies in the former EU-5 and the Netherlands. For and in the United Kingdom, prices were stated for all indications all new indications, the costs for CAR T-cell therapies were treated with tisagenlecleucel. The UK price for axicabtagene cil- assumed to be similar to the average list price. oleucel was marked confidential, that is, it was concealed in the For “Scenario 2,” we added costs for pre-treatment, concom- report. Dutch prices were available for axicabtagene ciloleucel itant medication, AEs, and hospitalization (including follow-up) and tisagenlecleucel. to the price of CAR T-cell therapy. Information on resource For Italy and Spain, HTA/BIA reports were not publicly use (ie, medication dosage and the number of hospital days) available. List prices for these countries were retrieved from were taken from available HTA/BIA reports or based on expert documents of the Italian Medicines Agency (AIFA),30,31 and the opinion. Prices for medication, hospitalization (including ICU Spanish Ministry of Health.32,33 Table 1 presents an overview of admission), and AEs were based on costs reported in HTA/BIA all list prices. reports or the literature.10-16 In case country-specific prices could The initial literature search detected 9 CEA,34-41 and the not be found, the average of available prices was used. Finally, search for gray literature found 3 HTA reports42-44 and 1 report clinical experts were asked to validate these data. from an Evidence Review Group (ERG) for a National Institute For “Scenario 3,” we calculated the incremental costs of CAR for Health and Care Excellence, Single technology appraisal.37 T-cell therapy, that is, the costs of “Scenario 2” minus the costs of Two publications were added following the update search.38,39 care as usual. These incremental costs were derived from the pub- The publication by Walton et al37 presented results from the lished CEAs identified for this study. Thereafter, we multiplied Incremental Cost-Effectiveness Ratio (ICER) HTA report and is the eligible patient population with incremental costs of CAR therefore included in the following summary instead of the HTA T-cell therapy. Average incremental costs observed in DLBCL report. Most studies focused on pALL patients, while 3 publi- were used to estimate incremental costs for future indications. cations40,41,45 studied relapsed/refractory (r/r) DLBCL as indica- For all scenarios and indications, we assumed a market pen- tion. The ICER report42 presented results for both r/r pALL and etration rate of 45% in the first year after registration and 90% r/r DLBCL. thereafter.17 The results are summarized in Table 2. 3 Heine et al Health Economic Aspects of Chimeric Antigen Receptor T-cell Therapies Table 1 Overview of List Prices. List Price (Excl. VAT) Axicabtagene ciloleucel (Yescarta) Tisagenlecleucel (Kymriah) Country DLBCL pALL DLBCL France 350 000 EUR 320 000 EUR 320 000 EUR Germany 327 000 EUR 320 000 EUR 320 000 EUR Italy 327 000 EUR 300 000 EUR 300 000 EUR The Netherlands 327 000 EUR 320 000 EUR 320 000 EUR Spain 327 000 EUR 320 000 EUR 320 000 EUR United Kingdom 318 773 EUR (300 000 GBP) 318 773 EUR (282 000 GBP) 318 773 EUR (282 000 GBP) DLBCL = diffuse large B-cell lymphoma; EUR = Euro; GBP = Pound sterling; pALL = pediatric acute lymphoblastic leukemia; VAT = value added tax. Identification of future CAR T-cell indications For the period 2019–2029, we estimated a total average of 103 750 patients being eligible for CAR T-cell therapies, rang- The search on clinicaltrials.gov resulted in a total of 246 stud- ing from 95 954 patients (Eurostat forecast) to 111 545 patients ies, of which most were attributed to non-Hodgkin’s lymphoma (Globocan forecast) for the indications pALL, DLBCL, MCL, (n = 97), followed by ALL (n = 84), multiple myeloma (MM) FL, AML, CLL, and MM. (n = 38), chronic lymphocytic leukemia (CLL) (n = 22), acute myeloid leukemia (AML) (n = 19), and others (n = 35). Several studies addressed multiple indications and targets. The 3 most Expenditure estimation of CAR T-cell therapies studied target antigens were CD19 (n = 161), followed by B-cell for current and selected future indications per maturation antigen (n = 19) and CD22 (n = 20). scenario The clinical experts expected that mantle cell lymphoma (MCL), follicular lymphoma (FL), MM, CLL, and AML, would Scenario 1: Estimation based on list prices be the first indications for which CAR T-cell therapy would Multiplying costs for CAR T-cell therapies with the number of become available in the near future. Based on phases of the clin- eligible patients in the former EU-5 and the Netherlands resulted in ical trials and clinical expert opinion, we estimated market entry average cumulative expenditures varying between 1.4 billion EUR of CAR T-cell therapies for MCL in 2021. For the indications for the Netherlands and 6.7 billion EUR for Germany. Cumulative of MM, CLL, and FL market entry was estimated for the year expenditure estimates in our base-case for pALL, DLBCL, MCL, 2022. Finally, it was expected that CART T-cell therapies for FL, AML, CLL, and MM for all included countries from 2019 to AML would be available in 2025. 2029 were on average 0.8 billion EUR, 13.7 billion EUR, 2.3. bil- lion EUR, 6.4 billion EUR, 1.2 billion EUR, 0.9 billion EUR, and 3.5 billion EUR, respectively (total average: 28.6 billion EUR). Estimation of the eligible patient population Figure 2 depicts the yearly average forecasted expenditure per Reported yearly IRs varied not only across but also within country for scenario 1 across all indications. countries. Although targeting the same indication, HTA/ BIA reports for DLBCL stated different yearly incidences for Scenario 2: Total CAR T-cell therapy costs, including the same indication and hence different numbers of eligible pre- and post-costs patients within the same country. For our analysis, we used Resource use and prices for the cost items considered country averages for pALL and DLBCL in case more than 1 for scenario 2 could partly be retrieved from sources for the estimate was available. IRs for MCL, FL, AML, MM, and CLL Netherlands, the United Kingdom, Germany, and France (see were taken from ECIS (see Appendix VII, http://links.lww.com/ Table 4 for an overview of the average resource use and cost HS/A130). prices). The additional costs for CAR T-cell therapy amounted The proportion of eligible patients for CAR T-cell therapies to 50 359 EUR for each patient receiving CAR T-cell therapy, were available for pALL in Germany, France, and the Netherlands with a substantial amount necessary for lymphodepletion and and varied between 6% (France) and 11% (Germany). For administering CAR T-cells, namely 26 615 EUR. In Table 4, DLBCL, the proportions were known for Germany, France, the these costs are shown. Cumulative expenditure estimates in our United Kingdom, and the Netherlands, varying between 12% base-case for pALL, DLBCL, MCL, FL, AML, CLL, and MM (France) and 22% (United Kingdom). Missing data for these for all included countries from 2019 to 2029 were on average indications (ie, pALL and DLBCL) in all other countries were 0.9 billion EUR, 15.8 billion EUR, 2.5 billion EUR, 7.4 billion imputed with the mean proportion from countries with avail- EUR, 1.4 billion EUR, 1.1 billion EUR, and 4 billion EUR, able data (see for details Appendix VII, http://links.lww.com/HS/ respectively (total average: 32.9 billion EUR). A130). Multiplying the total costs of pre- and post-CAR T-cell care To estimate the number of patients for the different cancer with the number of eligible patients per indication and country subtypes from Globocan, we used United States (US) figures resulted in total cumulative expenditures between 7.7 billion since European data were not available. As proportions were not EUR (Germany) and 1.6 billion EUR (Netherlands). Figure 3 available from 1 single source, data for pALL were based on the depicts average forecasted costs (all indications) per country for Surveillance, Epidemiology, and End Results (SEER) Program of scenario 2. the US National Cancer Institute.46 Most recent data for ALL and CLL were taken from the 2019 facts and figures sheet pub- Scenario 3: Incremental costs of introducing CAR T-cell lished by the American Cancer Society,7 and DLBCL estimates therapy were based on Li et al.9 Proportions of MCL and FL patients Of all CEA studies reviewed, the total average incremental from non-Hodgkin lymphoma were taken from Sandoval-Sus et costs of CAR T-cell therapies when compared to care as usual al8 and Cerhan,3 respectively. were 276 086 EUR and 328 727 EUR for patients with pALL 4 (2021) 5:2 www.hemaspherejournal.com Table 2 Overview of Cost-effectiveness Analysis Publications. Indication, Total Effects References Treatment Base-case Settings Scenario Analysis Total Costs in QALYs ICER: CAR T-cell vs Lin et al34 pALL, tisagen- Perspective: healthcare Yes, 5-y relapse-free survival rates (2017 USD) Clo-M: 3.12 (USD/QALY) lecleucel Horizon: lifetime (ie, 40%-0%) Clo-M: 314 000 Clo-C: 3.52 Best-case scenario (40% 5-y relapse-free survival rate) Discount rate (costs/effects): Clo-C: 374 000 Blina: 3.57 Clo-M: 61 315, Clo-C: 43 103, 3%/3% Blina: 282 000 CAR T-cell: 8.74 Blina: 50 712 CAR T-cell: 599 000 Whittington pALL, tisagen- Perspective: healthcare Yes, other discount rates, different (2017 USD) Clo-M: 2.10 (USD/QALY) et al35 lecleucel Horizon: lifetime survival curve fitting, future health- Clo-M: 337 256 CAR T-cell: 9.28 Base-case scenario: 46 000 Discount rate (costs/effects): care cost (included/not included CAR T-cell: 666 754 3%/3% Sarkar pALL, tisagen- Perspective: healthcare No (2017 USD) Clo-C: 8.58 (USD/QALY) et al36 lecleucel Horizon: lifetime Clo-C: 440 600 CAR T-cell: 16.76 Payer perspective: 64 600 Discount rate (costs/effects): CAR T-cell: 968 800 3%/3% Walton pALL, tisagen- Perspective: NA No (2017 GBP) Salvage chemo: NA (GBP/QALY) et al37 lecleucel Horizon: lifetime Salvage chemo: NA Blin: NA Deterministic: Salvage chemo Discount rate (costs/effects): Blina: NA CAR T-cell: NA 45 397, Blina: 27 732 3.5%/3.5% CAR T-cell: NA Furzer pALL, tisagen- Perspective: Public insurer Yes, long-term cure rates varying (2018 USD) Comparator: 5.05 (USD/QALY) et al38 lecleucel Horizon: 60 y between 10% and 40% Comparator (combi- Optimistic scenario: 53 933 nation of chemo and HSCT): 86 597 Discount rate (costs/effects): CAR T-cell: 442 098 CAR T-cell: 14.90 1.5%/1.5% Thielen pALL, tisagen- Perspective: Societal Yes, different perspectives, shorter (2018 EUR) Clo-M: 0.74 (EUR/QALY) et al39 lecleucel Horizon: lifetime plateau phase, different time Clo-M: 160 803 Clo-C: 1.70 Base-case Discount rate (costs/effects): horizons, alternative standardized Clo-C: 193 920 Blina: 2.25 Clo-M: 36 378 EUR/QALY 4%/1.5% mortality rate input, vial sharing BlinaL 267 259 CAR T-cell: 11.26 Clo-C: 31 052 EUR/QALY assumed, longer duration of IVIG CAR T-cell: 552 679 Blina: 31 682 EUR/QALY administration, different parametric extrapolation models resulting in different cure rates Roth et al40 DLBCL, Perspective: healthcare Yes, patients in long-term remission (2018 USD) R-DHAP: 1.13 (USD/QALY) axicabtagene Horizon: lifetime experience 10% or 20% lower sur- R-DHAP: 172 737 CAR T-cell: 7.67 Base-case scenario: 58 146 ciloleucel Discount rate (costs/effects): vival compared with age-matched CAR T-cell: 552 921 3%/3% US general population Lin et al45 DLBCL, Perspective: healthcare Yes, PFS at 5 y: Axicabtagene: 40% (2018 USD) Combination: R-DHAP, (USD/QALY) tisagenlec- to 20% and tisagenlecleucel: 35% R-GDP, R-GEMOX, leucel, and to 15% R-ICE, SCT: 1.78 axicabtagene Horizon: lifetime Combination: R-DHAP, Axicabtagene Axicabtagene ciloleucel vs ciloleucel R-GDP, R-GEMOX, ciloleucel: 5.50 combination (40% 5-y progres- R-ICE, SCT: 169 000 sion-free survival): 129 570 Discount rate (costs/effects): Axicabtagene ciloleucel: Tisagenlecleucel: Tisagenlecleucel vs combina- 3%/3% 651 000 3.92 tion (35% 5-y progression-free Tisagenlecleucel: survival): 168 224 529 000 Whittington DLBCL, Perspective: public payer care Yes, different extrapolation of OS (Year not clear USD) R-DHAP: 3.37 (USD/QALY) et al41 axicabtagene Horizon: lifetime and PFS curves, different perspec- R-DHAP: 151 200 CAR T-cell: 9.19 Public payer perspective, stan- ciloleucel Discount rate (costs/effects): tives, different time horizons CAR T-cell: 554 700 dard parametric: 230 900 3%/3% CAR T = chimeric antigen receptor T cell; DLBCL = diffuse large B-cell lymphoma; EUR = Euro; GBP = Pound sterling; HSCT = autologous haematopoietic stem cell transplantation; ICER = incremental cost-effectiveness ratio; IVIG = intravenous immunoglobulin; pALL = pediatric acute lymphoblastic leukemia; NA = not available; OS = overall survival; PFS = progression-free survival; QALY = quali- ty-adjusted life year; R-DHAP = rituximab dexamethasone cytarabine cisplatin; R-GDP = rituximab gemcitabine dexamethasone cisplatin; R-GEMOX = rituximab gemcitabine oxaliplatin; R-ICE = rituximab ifosfamide carboplatin etoposide; SCT = stem cell transplantation; USD = United States dollar. and DLBCL, respectively. Cumulative expenditure estimates in are the estimates based on the Globocan and Eurostat approach, our base-case for pALL, DLBCL, MCL, FL, AML, CLL, and respectively. MM for all included countries from 2019 to 2029 were on average 0.7 billion EUR, 13.8 billion EUR, 2.3 billion EUR, 6.5 billion EUR, 1.2 billion EUR, 0.9 billion EUR, and 3.5 billion Discussion EUR, respectively (total average: 28.9 billion EUR). Figure 4 depicts the average expenditure across all countries In our analysis, we estimated future expenditures associated and indications of all 3 scenarios. The upper and lower bounds with CAR T-cell therapies for a set of hematological indications 5 Heine et al Health Economic Aspects of Chimeric Antigen Receptor T-cell Therapies Figure 2. Total average costs per country in scenario 1 (all indications). in 6 European member states between 2019 and 2029. The aver- our projection due to unforeseen events and assumptions. Our age cumulative costs in all 6 countries for all included indications assumptions and results were validated by clinical experts, but were estimated at 28.5 billion EUR (scenario 1) with a steady forecasts are sensitive to changes in outcomes and business increase in yearly average costs across the time range studied. strategies. Besides, future clinical pathways may also change, Average yearly costs increased in a stepwise manner, which can accommodating for new treatments that are currently in the be explained by the assumed drug penetration rate and predicted pipeline. Advancements in other immunotherapies and targeted new indication launches. For the year 2019, we assumed pene- therapies could affect future uptake of CAR T-cell therapies as tration rates of 45% for current CAR T-cell therapies for DLBCL well. Currently, available CAR T-cell therapies (ie, tisagenlecleu- and pALL. This penetration rate peaks in 2020 (90%) and cel and axicabtagene ciloleucel) are being investigated for the remains stable thereafter. We assumed new product launches for second-line treatment of patients with DLBCL (NCT03570892, MCL for the year 2021 and FL, MM, and CLL in the year 2022. NCT03391466), which will make those therapies available Even with an initial penetration rate of 45% for the first year of to an even larger patient population. Moreover, lisocabtagene the product launch, this is a major cost driver that more than maraleucel is also being investigated in a second-line setting for doubled the yearly average costs. Finally, the product launch patients with B-cell non-Hodgkin lymphomas (NCT03575351). for AML was estimated for the year 2025 and is responsible for If CAR T-cell therapies are utilized in second-line settings, this another stepwise increase in predicted yearly cumulative costs. would considerably increase the eligible patient population. It seems obvious that new product launches have a consider- Besides the uncertainties regarding the number of patients able impact on any expenditure. Therefore, the methodology for eligible for CAR T-cell therapies, the price of the therapy itself estimating the expenditure of these launches is crucial. However, is associated with a high degree of uncertainty. For our anal- there is no reliable way of knowing at what time exactly new ysis, we used list prices whenever available. However, actual CAR T-cell therapies will be available for treatment. For product prices for CAR T-cell therapies are mostly subject to confi- launches of future indications, we used data on available clinical dential negotiations. Hence, the actual price per country is trials on clinicaltrials.gov and estimated their future availability unknown. For our analysis, the price of CAR T-cell therapies based on the time between the trial start date and the published for future indications was assumed to be 323 500 EUR per date of the respective HTA reports for tisagenlecleucel and axi- treatment, based on an average of the known list prices for cabtagene ciloleucel. In case several trials were currently running, DLBCL patients. This estimation could be inaccurate due to we selected studies from the biggest sponsor in terms of market existing and future competing treatment options. Moreover, capitalization. However, this approach neglects the possibility of clinical experts already reported a new and lower price for tis- failing trials that would not lead to market access of a drug, the agenlecleucel in Germany of 275 000 EUR per treatment. Such possibility of smaller companies to be the first to receive market a price reduction could be the result of the 2 CAR T-cell thera- access for their drug, or the possibility of postponing market access pies (ie, tisagenlecleucel and axicabtagene ciloleucel) currently due to internal decisions. Therefore, we validated our findings competing for DLBCL. The expected approval of lisocabta- with clinical experts who suggested CAR T-cell therapy launches gene maraleucel47 (Celgene) could drive up competition even in the years 2021 and 2022 for MCL and FL, respectively. more. To allow competition with the 2 existing CAR T-cell The eligible patient population for CAR T-cell therapies in therapies could lead to an even further reduction in prices. Per the different EU member states was based on the population contra, Celgene might price lisocabtagene maraleucel higher projection by Eurostat4 with fixed IRs, and the incidence pro- than its competitor considering the possibility of being best- jection from Globocan, over the period 2019 to 2029. Both in-class.48 Yet another scenario that could affect prices of CAR strategies were used to congregate an average patient popula- T-cell therapies is the point-of-care production within hospi- tion. The factual eligible patient population could deviate from tals, leaving healthcare payers with only the manufacturing 6 (2021) 5:2 www.hemaspherejournal.com Table 3 possibly lower cost for healthcare payers. Lastly, the possi- Cost Components and Resource Use of Pre- and Post-CAR bility of in vivo reprogramming of T cells, to, for example, be T-cell Therapy. active against CD19 positive cells, could potentially reduce treatment costs by circumventing ex vivo manufacturing of Item Type Value in EUR T cells.50 Leukapheresis and cryopreservation Costs 4947 While the price for CAR T-cell therapies may be subject to CAR T-cell administration + lymphodepletion Costs 15 033 changes, the cost of care associated with CAR T-cell therapy ICU stay (per day) Costs 1444 could also decrease over time. This may be due to possible reduc- Hospital stay at hematology/oncology ward (per day) Costs 628 tions in side-effects or different AE profiles with future CAR IVIG (per dose) Costs 2032 T-cell therapies. Likewise, our forecasted incremental costs may Tocilizumab (per event) Costs 1483 differ. Our estimates are based on relatively scarce cost-effec- Treatment of febrile neutropenia (per event) Costs 4953 tiveness data on both tisagenlecleucel and axicabtagene ciloleu- Treatment of anemia (average costs per event, incl. Costs 2961 cel. For future indications, we assumed an average of the known transfusion) costs. However, according to clinical experts, the incremental Treatment of thrombocytopenia (per event) Costs 2417 costs associated with CAR T-cell therapies for MM could be Oncologist/hematologist (per visit) Costs 145 much lower when compared with DLBCL, for instance. This Neurologist (per visit) Costs 103 may be caused by the chronic nature of MM and its current high MRI scan (per scan) Costs 214 costs for the standard of care, which could be redundant after PET-CT scan (per scan) Costs 1110 CAR T-cell therapies. Percentage of patients receiving tocilizumab Resource use 60%a Other cell and gene therapies that have regenerative or cura- Percentage of patients receiving IVIG Resource use 24% tive potential are currently being developed for various indica- Assumed average number of days in hospital Resource use 14 tions.51 The limited duration of clinical trials is coincidentally (including pre- and post-treatment) accompanied by uncertainty in long-term effects. Moreover, the Assumed average number of ICU days (including Resource use 2 possibility to cure patients with a single administration pres- pre- and post-treatment) ents a new challenge for pricing and reimbursement of these Percentage of patient admitted to ICU Resource use 20%a therapies.52 Current pricing of gene therapies ought to reflect Probability of patients with CRS ≥ 3 Resource use 18% expected long-term effects and its curative potential. For Probability of patients with FN Resource use 23% instance, Novartis has priced Zolgensma, a gene therapy med- Probability of patients with neurological events ≥ 3 Resource use 20% ication used to treat spinal muscular atrophy in children less Probability of patients with anemia Resource use 27% than 2 years old, at approximately 1.887 million EUR (2.125 Probability of patients with thrombocytopenia Resource use 19% million USD), which makes it the most expensive drug currently Duration of follow-up (y) Resource use 15a available.53 Spark Therapeutics Inc’s Luxturna gene therapy for patients with inherited retinal disease was priced at approxi- a Based on clinical experts. mately 754 817 EUR (850 000 USD) for both eyes. One aspect CAR T = chimeric antigen receptor T cell; CRS = cytokine release syndrome; EUR = Euro; FN = febrile neutropenia; ICU = intensive care unit; IVIG = intravenous immunoglobulin; PET-CT = these cell and gene therapies share is their high prices, which are positron emission tomography and computed tomography. often justified by significant treatment effects. However, long- term efficacy results are not yet available, and some patients may need subsequent CAR T-cell therapies or allogeneic stem cell transplantation. In addition, some patients might need addi- Table 4 tional (other) gene therapies in the future. It remains unclear Average Total Costs Pre- and Post-CAR T-cell Administration in who should bear the financial risk stemming from the uncer- Former EU-5 and NL. tainty in the clinical value. Consequently, reimbursement deci- Item Value in EUR sion-makers in many EU member states seem to be reluctant in applying “standard” reimbursement criteria to CAR T-cell Average cost of care pre-CAR T-cell administration 7147 therapies. Average cost lymphodepletion and administering CAR-T 26 615 Several EU member states and the United Kingdom adopted Average cost of care managing AEs 10 524 various pricing and reimbursement schemes. While France and Average cost of follow-up 6074 the United Kingdom opted for coverage with evidence develop- Total cost of pre- and post-CAR-T care 50 359 ment schemes, both Italy and Spain negotiated outcomes-based AE = adverse event; CAR T = chimeric antigen receptor T cell; EU-5 = France, Germany, Spain, staged payment agreements. Outcomes-based rebates were Italy and the United Kingdom; EUR = Euro; NL = the Netherlands. negotiated in Germany, and in Austria, different cost-sharing agreements are in place, varying between provinces. In the Netherlands tisagenlecleucel for pALL, patients are reimbursed costs. Specialized hospitals in several countries are exploring through standard criteria, since its estimated budget impact the possibility to make their own CAR T-cell treatments in was found to be relatively low (approximately 10 children per the future. We have asked clinical experts whether they think year were estimated to be eligible). Axicabtagene ciloleucel for it would be an option for lowering the price and improving DLBCL patients, on the other hand, was placed in the so-called the access to CAR T-cells for patients. In Germany and the “lock” for 421 days before being reimbursed. The different Netherlands, the probability was estimated above 50% and reimbursement schemes for the former EU-5 are analyzed and the cost of own production was estimated to be 50 000-70 000 discussed in depth elsewhere.54 EUR per CAR T-cell treatment. This means that 1 treatment At the 2020 EHA/European Society for Blood and Marrow may cost approximately 80 000 EUR (including pre- and Transplantation CAR T-cell Meeting in Sitges, manufacturers post-care costs) instead of 375 000 EUR. In the literature, the signaled a willingness to further cooperate with payers reaching manufacturing costs have been estimated at 65 000 USD.49 reimbursement agreements. Presented options were discounts Moreover, companies such as Cellectis or Servier are cur- of list prices, price-volume agreements, outcome-based agree- rently working on the development of allogeneic CAR T-cell ments based on patient-level outcomes, value-based agreements therapies (NCT03190278, NCT02808442). These off-the- based on additional clinical evidence, or a price by indication. shelf CAR T-cell therapies could be manufactured in batches Despite this, CAR T-cell therapies are still not affordable for instead of on-demand, resulting in economies of scale, and many countries. 7 Heine et al Health Economic Aspects of Chimeric Antigen Receptor T-cell Therapies Figure 3. Total average costs per country in scenario 2 (all indications). Figure 4. Expenditure forecast per scenario (all countries and indications). CAR-T = chimeric antigen receptor T cell. We limited our study to the former EU-5 and the Netherlands, The decision resources group (DRG), for instance, published all of which are already reimbursing CAR T-cell therapies. a report on CAR T-cell therapies in the pipeline and a forecast However, difficulties regarding reimbursement are even greater snapshot. Without revealing the employed methodology, the in Eastern Europe, resulting in many patients currently lacking DRG estimated the CAR T-cell therapy market at approximately access to these promising treatments. 1.5 billion EUR (1.7 billion USD) by 2026 for the hematological The future market of CAR T-cell therapies has been malignancies. It is not clear whether these figures ought to reflect studied previously, although not with a specific focus on the United States, European, or a global market. Our estimation hematology-oncology. exceeds the DRG figures by far, but since the methodological 8 (2021) 5:2 www.hemaspherejournal.com approaches cannot be compared, it remains open which fore- cost analysis of the treatment of anaemia, neutropenia and thrombo- casted aspects differ. cytopenia in patients with chronic myeloid leukaemia. J Med Econ. Another study estimated 114 737 cumulative treated 2009;12:164–169. 11. Hakkaart-van Roijen L, van der Linden N, Bouwamans C, et al. patients in the United States between the years 2019 and 2029 Kostenhandleiding: methodologie van kostenonderzoek en referentie- for all hematological cancers.17 This is relatively close to our prijzen voor economische evaluaties in de gezondheidszorg. Bijlage estimate considering a fundamentally different methodological 1. 2016. approach and the inclusion of different cancer types. In terms 12. Weycker D, Danel A, Marciniak A, et al. Economic costs of chemo- of costs, Quinn et al17 mention a range between 11.1 billion therapy-induced febrile neutropenia among patients with non-Hod- EUR (12.5 billion USD) and 88.8 billion EUR (100 billion gkin’s lymphoma in European and Australian clinical practice. BMC USD) for all hematological cancers. Our estimates fall within Cancer. 2012;12:362. this range. However, it needs to be noted that although the US 13. Bock JO, Brettschneider C, Seidl H, et al. Ermittlung standardisierter population is comparable to the studied population in terms Bewertungssätze aus gesellschaftlicher Perspektive für die gesund- heitsökonomische evaluation. Gesundheitswesen. 2014;77:53–61. of size (US population is roughly 96% of the former EU-5 14. Högy B, Keinecke HO, Borte M. Pharmacoeconomic evaluation of + Netherlands), costs for CAR T-cell therapies are generally immunoglobulin treatment in patients with antibody deficiencies higher in the United States. from the perspective of the German statutory health insurance. Eur J Finally, we conclude that, although current and future CAR Health Econ. 2005;6:24–29. T-cell therapies seem promising in hematological cancers, with 15. Lefrant JY, Garrigues B, Pribil C, et al. The daily cost of ICU patients: the current price-setting, the financial burden on healthcare sys- a micro-costing study in 23 French intensive care units. Anaesth Crit tems in former EU-5 and the Netherlands is considerable. Some Care Pain Med. 2015;34:151–157. European countries are struggling with associated costs of pre- 16. Tan S, Martin J, Pezzi A, et al. Microcosting study of ICU costs in three and post-care for CAR T-cell therapies as these costs are reim- European countries. Crit Care. 2008;12:P526. 17. Quinn C, Young C, Thomas J, et al. Estimating the clinical pipeline of bursed insufficiently. Further, the pricing of CAR T-cell therapies cell and gene therapies and their potential economic impact on the is high, and it can be expected that new and commercial CAR US healthcare system. Value Health. 2019;22:621–626. T-cell therapies will be in a similar price range. Combined with 18. Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen. the expected expansion of indications, the financial burden on Tisagenlecleucel (akute lymphatische B-ZellLeukämie). Bewertung healthcare systems will increase substantially with direct effects gemäß § 35a Abs. 1 Satz 11 SGB V. Nr. 689. 2018. 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