Cost-effectiveness analysis of KTE-X19 CAR T therapy versus real-world standard of care in patients with relapsed/refractory mantle cell lymphoma post BTKi in England.

AIMS: The objective of this study is to estimate the cost-effectiveness of KTE-X19 versus standard of care (SoC) in the treatment of patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) post-Bruton tyrosine kinase inhibitor (BTKi) treatment from a UK healthcare perspective. MATERIALS AND METHODS: A three-state partitioned survival model (pre-progression, post-progression and death) with a cycle length of one month was used to extrapolate progression-free and overall survival over a lifetime horizon. Population inputs along with KTE-X19 (brexucabtagene autoleucel) efficacy and safety data were derived from the single-arm trial ZUMA-2 (NCT02601313). The composition of SoC was informed by a literature-based meta-analysis, SoC efficacy data were obtained from the SCHOLAR-2 real-world study. Survival was modelled using standard parametric curves for SoC and a mixture-cure methodology for KTE-X19. It was assumed that patients whose disease had not progressed after five years experienced long-term remission. Costs, resource use and utility, and adverse event disutility inputs were obtained from published literature and publicly available data sources. An annual discount rate of 3.5% was applied to costs and health outcomes. Modelled outcomes for KTE-X19 and SoC included expected life years (LY), quality-adjusted life years (QALY) and total costs. Deterministic and probabilistic sensitivity analyses and scenario analyses were performed. RESULTS: Estimated median survival was 5.96 years for KTE-X19 and 1.38 for SoC. Discounted LYs, QALYs and lifetime costs were 8.27, 5.99 and £385,765 for KTE-X19 versus 1.98, 1.48 and £79,742 for SoC, respectively. The KTE-X19 versus SoC cost per QALY was £67,713 and the cost per LY was £48,645. Influential scenario analyses use alternative KTE-X19 survival curves and discount rates, and shorter time horizons. CONCLUSION: Considering the survival and quality of life benefits compared to SoC, KTE-X19 for R/R MCL appears as a cost-effective treatment in the real-world UK setting.

Health Care Resource Utilization and Total Costs of Care Among Patients with Diffuse Large B Cell Lymphoma Treated with Chimeric Antigen Receptor T Cell Therapy in the United States.

The use of chimeric antigen receptor (CAR) T-cell therapy after a second relapse of diffuse large B-cell lymphoma (DLBCL) has shown favorable efficacy in clinical trials; however, little is known about health care resource utilization (HCRU) and costs of CAR T cell therapy for patients treated in real-world settings. We assessed treatment patterns, HCRU, costs, and safety in patients receiving CAR T cell therapy for relapsed or refractory DLBCL across 3 US commercial claims databases. Adults with DLBCL treated with CAR T cell therapy were identified in the following 3 claims databases: Optum® Clinformatics® Data Mart, IBM MarketScan® Commercial & Medicare Database, and IQVIA PharMetrics® Plus. Mean total costs were calculated and adjusted to 2019 US dollars. HCRU and costs within 3 months of infusion were stratified by safety events of interest, including neurological events (NEs) and cytokine release syndrome (CRS), identified via unvalidated algorithms designed based on expert medical opinion. A total of 191 patients receiving CAR T cell therapy were identified across the databases; their median age ranged from 56 to 67 years, and 63% to 75% were male. Most patients (88% to 98%) received CAR T cell infusions in the inpatient setting; 30% to 75% received bridging therapy. CRS was reported in 75% to 84% of patients (severe CRS, 15% to 32%), and NEs were reported in 58% to 69% (severe NEs, 25% to 43%). Mean total inpatient hospital days ranged from 17 to 22 days and increased with severe CRS (19 to 27 days) or severe NEs (22 to 29 days). Mean total health care expenditures ranged from $380,000 to $526,000 and were generally higher with severe CRS or NEs (∼$406,000 to $679,000). HCRU and costs associated with CAR T cell therapy may vary in the real world depending on several factors, including occurrence and severity of adverse events.

[CAR-T CELLS: How does the EBMT registry monitor European activities, identify hurdles and prepare for changes in regulations]. / CAR-T cells : comment le registre de l'EBMT monitore les activités en Europe, identifie les contraintes et prépare l'évolution des régulations.

CAR-T Cells are gene therapy medicinal products, a subcategory of Advanced Therapy Medicinal Products as defined in the EC Regulation 1394/2007. They may represent the first example of such medicinal products that are industry-manufactured and commercialized on a large scale. Their very nature, their manufacturing processes, pricing and conditions upon which they were approved by regulatory agencies, all lead the latter to require long-term follow-up after marketing approval with a view for a better definition of CAR-T Cells safety profile and efficacy profile in real world conditions. Collection and analysis of data over a 15-year period of time represents a technical and political challenge. So does the a priori definition of data to be collected for a wealth of forthcoming analyses that focus on the interests of a variety of stakeholders. EBMT has been collecting and analyzing data on hematopoietic cell transplants for decades. EBMT currently works with many interested parties to collect data on patients treated with CAR-T Cells.

Challenges raised by the economic evaluation of CAR-T-cell therapies. The review by the French National Authority for Health.

Since 2013, the process of pricing of innovative drugs by the French National Health Insurance has considered both cost-effectiveness and budget impact. CAR-T cell therapies were first subject to economic evaluation from 2019 in France. We aim to describe the process and results of the economic evaluation of tisagenlecleucel and axicabtagene ciloleucel as well as the challenges these evaluations raised. Evaluations submitted by the firms were reviewed by HAS and submitted to the Committee of Economic Evaluation and Public Health (CEESP). The CEESP issued opinions related to: (1) the methodological quality of economic evidence and, (2) the cost-effectiveness and budget impact of the drugs. The CEESP invalidated the estimated incremental cost-utility ratios (ICUR) of tisagenlecleucel due to the insufficient clinical evidence and methodological quality to extrapolate the long-term progression of the disease after treatment and compare tisagenlecleucel with alternatives. The CEESP concluded that tisagenlecleucel was not proven cost-effective. The estimated ICUR of axicabtagene ciloleucel at €114,509/QALY vs. chemotherapies was associated with an acceptable level of methodological quality despite being based on a weak indirect comparison and limited data on quality of life. The CEESP considered axicabtagene ciloleucel ICUR to be "very high" and questioned the societal/community willingness-to-pay of the claimed price. The primary source of uncertainty surrounding the ICUR estimates of both drugs was the lack of hindsight on effectiveness. The economic evaluation of CAR-T cell therapies highlights the risk of inefficient resource allocation driven by limited clinical data. It calls for payment schemes accounting for this risk and effective collection of post-marketing data.

How much does the hospital stay for infusion of anti-CD19 CAR-T cells cost to the French National Health Insurance?

Chimeric antigen receptor T-cells (CAR-T cells) have the potential to be a major innovation as a new type of cancer treatment, but are associated with extremely high prices and a high level of uncertainty. This study aims to assess the cost of the hospital stay for the administration of anti-CD19 CAR-T cells in France. Data were collected from the French Medical Information Systems Program (PMSI) and all hospital stays associated with an administrated drug encoded 9439938 (tisagenlecleucel, Kymriah®) or 9440456 (axicabtagene ciloleucel, Yescarta®) between January 2019 and December 2020 were included. 485 hospital stays associated with an injection of anti-CD19 CAR-T cells were identified, of which 44 (9%), 139 (28.7%), and 302 (62.3%) were for tisagenlecleucel in acute lymphoblastic leukaemia (ALL), tisagenlecleucel in diffuse large B-cell lymphoma (DLBCL), and axicabtagene ciloleucel respectively. The lengths of the stays were 37.9, 23.8, and 25.9 days for tisagenlecleucel in ALL, tisagenlecleucel in DLBCL, and axicabtagene ciloleucel, respectively. The mean costs per hospital stay were € 372,400 for a tisagenlecleucel in ALL, € 342,903 for tisagenlecleucel in DLBCL, and € 366,562 for axicabtagene ciloleucel. CAR T-cells represented more than 80% of these costs. n=13 hospitals performed CAR-T cell injections, with two hospitals accounting for more than 50% of the total number of injections. This study provides original data in a context of limited information regarding the costs of hospitalization for patients undergoing CAR-T cell treatments. In addition to the financial burden, distance may also be an important barrier for accessing CAR T-cell treatment.

Anti B-cell maturation antigen CAR T-cell and antibody drug conjugate therapy for heavily pretreated relapsed and refractory multiple myeloma.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Beinfeld, Fluetsch, and Pearson are employed by ICER. Ollendorf received funding from ICER for work on this summary and reports consulting and other personal fees from EMD Serono, Amgen, Analysis Group, Aspen Institute/University of Southern California, GalbraithWight, Cytokinetics, Executive Insight, Sunovion, University of Colorado, World Health Organization, and Eli Lilly, unrelated to this work. Lee and McQueen received funding from ICER for work on this summary.

Obstacles and Coping Strategies of CAR-T Cell Immunotherapy in Solid Tumors.

Chimeric antigen receptor (CAR) T-cell immunotherapy refers to an adoptive immunotherapy that has rapidly developed in recent years. It is a novel type of treatment that enables T cells to express specific CARs on their surface, then returns these T cells to tumor patients to kill the corresponding tumor cells. Significant strides in CAR-T cell immunotherapy against hematologic malignancies have elicited research interest among scholars in the treatment of solid tumors. Nonetheless, in contrast with the efficacy of CAR-T cell immunotherapy in the treatment of hematologic malignancies, its general efficacy against solid tumors is insignificant. This has been attributed to the complex biological characteristics of solid tumors. CAR-T cells play a better role in solid tumors, for instance by addressing obstacles including the lack of specific targets, inhibition of tumor microenvironment (TME), homing barriers of CAR-T cells, differentiation and depletion of CAR-T cells, inhibition of immune checkpoints, trogocytosis of CAR-T cells, tumor antigen heterogeneity, etc. This paper reviews the obstacles influencing the efficacy of CAR-T cell immunotherapy in solid tumors, their mechanism, and coping strategies, as well as economic restriction of CAR-T cell immunotherapy and its solutions. It aims to provide some references for researchers to better overcome the obstacles that affect the efficacy of CAR-T cells in solid tumors.

Does Cost-Effectiveness Analysis Overvalue Potential Cures? Exploring Alternative Methods for Applying a "Shared Savings" Approach to Cost Offsets.

OBJECTIVES: To evaluate alternative methods to calculate and/or attribute economic surplus in the cost-effectiveness analysis of single or short-term therapies. METHODS: We performed a systematic literature review of articles describing alternative methods for cost-effectiveness analysis of potentially curative therapies whose assessment using traditional methods may suggest unaffordable valuations owing to the magnitude of estimated long-term quality-adjusted life-year (QALY) gains or cost offsets. Through internal deliberation and discussion with staff at the Health Technology Assessment bodies in England and Canada, we developed the following 3 alternative methods for further evaluation: (1) capping annual costs in the comparator arm at $150 000 per year; (2) "sharing" the economic surplus with the health sector by apportioning only 50% of cost offsets or 50% of cost offsets and QALY gains to the value of the therapy; and (3) crediting the therapy with only 12 years of the average annual cost offsets or cost offsets and QALY gains over the lifetime horizon. The impact of each alternative method was evaluated by applying it in an economic model of 3 hypothetical condition-treatment scenarios meant to reflect a diversity of chronicity and background healthcare costs. RESULTS: The alternative with greatest impact on threshold price for the fatal pediatric condition spinal muscular atrophy type 1 was the 12-year cutoff scenario. For a hypothetical one-time treatment for hemophilia A, capping cost offsets at $150 000 per year had the greatest impact. For chimeric antigen receptor T-cell treatment of non-Hodgkin's lymphoma, capping cost offsets or using 12-year threshold had little impact, whereas 50% sharing of surplus including QALY gains and cost offsets greatly reduced threshold pricing. CONCLUSIONS: Health Technology Assessment bodies and policy makers will wrestle with how to evaluate single or short-term potentially curative therapies and establish pricing and payment mechanisms to ensure sustainability. Scenario analyses using alternative methods for calculating and apportioning economic surplus can provide starkly different assessment results. These methods may stimulate important societal dialogue on fair pricing for these novel treatments.

[Economics and management of CAR T- cell therapy : Status quo and future perspectives]. / Ökonomie und Management bei der CAR-T-Zell-Therapie : Status quo und Ausblick.

BACKGROUND: Virtually no other topic has attracted more attention in oncology in recent years than chimeric antigen receptor (CAR) T­cell therapy (CAR T). On the one hand it opens up completely new treatment options for cancer patients, while on the other it generates treatment costs exceeding € 300,000 per treatment. OBJECTIVES: The aim of this work is to analyze the economic, procedural and organizational challenges of CAR T­cell therapy from the perspective of the service provider, the cost-bearer and the pharmaceutical manufacturer. MATERIAL AND METHODS: The current German diagnosis-related-group (G-DRG) catalog, the G­DRG tariff, of the German Federal Joint Committee (G-BA) guidelines and G­DRG coding principles were used to evaluate the reimbursement and remuneration system in Germany. Practical experiences of medical sites were integrated in the analysis. RESULTS: The findings demonstrate great economic challenges especially from the perspective of a CAR T site. Increasing certification and qualification efforts lead to financial pressure. Insufficient reimbursement and inadequate cost-covering for CAR T treatment result in budget restrictions for hospitals. CONCLUSION: High drug costs as well as enormous personnel and infrastructural requirements demand transparent and sufficient reimbursement for hospitals. Interaction between hospital and pharmaceutical manufacturer in the CAR T process might enable new means of cooperation.

Non-transplantable cord blood units as a source for adoptive immunotherapy of leukaemia and a paradigm of circular economy in medicine.

Advances in immunotherapy with T cells armed with chimeric antigen receptors (CAR-Ts), opened up new horizons for the treatment of B-cell lymphoid malignancies. However, the lack of appropriate targetable antigens on the malignant myeloid cell deprives patients with refractory acute myeloid leukaemia of effective CAR-T therapies. Although non-engineered T cells targeting multiple leukaemia-associated antigens [i.e. leukaemia-specific T cells (Leuk-STs)] represent an alternative approach, the prerequisite challenge to obtain high numbers of dendritic cells (DCs) for large-scale Leuk-ST generation, limits their clinical implementation. We explored the feasibility of generating bivalent-Leuk-STs directed against Wilms tumour 1 (WT1) and preferentially expressed antigen in melanoma (PRAME) from umbilical cord blood units (UCBUs) disqualified for allogeneic haematopoietic stem cell transplantation. By repurposing non-transplantable UCBUs and optimising culture conditions, we consistently produced at clinical scale, both cluster of differentiation (CD)34+ cell-derived myeloid DCs and subsequently polyclonal bivalent-Leuk-STs. Those bivalent-Leuk-STs contained CD8+ and CD4+ T cell subsets predominantly of effector memory phenotype and presented high specificity and cytotoxicity against both WT1 and PRAME. In the present study, we provide a paradigm of circular economy by repurposing unusable UCBUs and a platform for future banking of Leuk-STs, as a 'third-party', 'off-the-shelf' T-cell product for the treatment of acute leukaemias.

Perspectives on outpatient administration of CAR-T cell therapy in aggressive B-cell lymphoma and acute lymphoblastic leukemia.

Chimeric antigen receptor (CAR) T-cell therapies that specifically target the CD19 antigen have emerged as a highly effective treatment option in patients with refractory B-cell hematological malignancies. Safety and efficacy outcomes from the pivotal prospective clinical trials of axicabtagene ciloleucel, tisagenlecleucel and lisocabtagene maraleucel and the retrospective, postmarketing, real-world analyses have confirmed high response rates and durable remissions in patients who had failed multiple lines of therapy and had no meaningful treatment options. Although initially administered in the inpatient setting, there has been a growing interest in delivering CAR-T cell therapy in the outpatient setting; however, this has not been adopted as standard clinical practice for multiple reasons, including logistic and reimbursement issues. CAR-T cell therapy requires a multidisciplinary approach and coordination, particularly if given in an outpatient setting. The ability to monitor patients closely is necessary and proper protocols must be established to respond to clinical changes to ensure efficient, effective and rapid evaluation either in the clinic or emergency department for management decisions regarding fever, sepsis, cytokine release syndrome and neurological events, specifically immune effector cell-associated neurotoxicity syndrome. This review presents the authors' institutional experience with the preparation and delivery of outpatient CD19-directed CAR-T cell therapy.

Next-generation CAR T cells to overcome current drawbacks.

As a rapidly emerging treatment in the oncology field, adoptive transfer of autologous, genetically modified chimeric antigen receptor (CAR) T cells has shown striking efficacy and is curative in certain relapsed/refractory patients with hematologic malignancy. This treatment modality of using a "living drug" offers many tantalizing and novel therapeutic strategies for cancer patients whose remaining treatment options may have otherwise been limited. Despite the early success of CAR T cells in hematologic malignancies, many barriers remain for widespread adoption. General barriers include cellular manufacturing limitations, baseline quality of the T cells, adverse events post-infusion such as cytokine release syndrome (CRS) and neurotoxicity, and host rejection of non-human CARs. Additionally, each hematologic disease presents unique mechanisms of relapse which have to be addressed in future clinical trials if we are to augment the efficacy of CAR T treatment. In this review, we will describe current barriers to hindering efficacy of CAR T-cell treatment for hematologic malignancies in a disease-specific manner and review recent innovations aimed at enhancing the potency and applicability of CAR T cells, with the overall goal of building a framework to begin incorporating this form of therapy into the standard medical management of blood cancers.

Chimeric antigen receptor (CAR) natural killer (NK)-cell therapy: leveraging the power of innate immunity.

Chimeric antigen receptor (CAR) T cells are a rapidly emerging form of cancer treatment, and have resulted in remarkable responses in refractory lymphoid malignancies. However, their widespread clinical use is limited by toxicity related to cytokine release syndrome and neurotoxicity, the logistic complexity of their manufacturing, cost and time-to-treatment for autologous CAR-T cells, and the risk of graft-versus-host disease (GvHD) associated with allogeneic CAR-T cells. Natural killer (NK) cells have emerged as a promising source of cells for CAR-based therapies due to their ready availability and safety profile. NK cells are part of the innate immune system, providing the first line of defence against pathogens and cancer cells. They produce cytokines and mediate cytotoxicity without the need for prior sensitisation and have the ability to interact with, and activate other immune cells. NK cells for immunotherapy can be generated from multiple sources, such as expanded autologous or allogeneic peripheral blood, umbilical cord blood, haematopoietic stem cells, induced pluripotent stem cells, as well as cell lines. Genetic engineering of NK cells to express a CAR has shown impressive preclinical results and is currently being explored in multiple clinical trials. In the present review, we discuss both the preclinical and clinical trial progress made in the field of CAR NK-cell therapy, and the strategies to overcome the challenges encountered.

Concepts in immuno-oncology: tackling B cell malignancies with CD19-directed bispecific T cell engager therapies.

The B cell surface antigen CD19 is a target for treating B cell malignancies, such as B cell precursor acute lymphoblastic leukemia and B cell non-Hodgkin lymphoma. The BiTE® immuno-oncology platform includes blinatumomab, which is approved for relapsed/refractory B cell precursor acute lymphoblastic leukemia and B cell precursor acute lymphoblastic leukemia with minimal residual disease. Blinatumomab is also being evaluated in combination with other agents (tyrosine kinase inhibitors, checkpoint inhibitors, and chemotherapy) in various treatment settings, including frontline protocols. An extended half-life BiTE molecule is also under investigation. Patients receiving blinatumomab may experience cytokine release syndrome and neurotoxicity; however, these events may be less frequent and severe than in patients receiving other CD19-targeted immunotherapies, such as chimeric antigen receptor T cell therapy. We review BiTE technology for treating malignancies that express CD19, analyzing the benefits and limitations of this bispecific T cell engager platform from clinical experience with blinatumomab.