Cost-effectiveness of chimeric antigen receptor T-cell therapy in multiply relapsed or refractory adult large B-cell lymphoma.

7561 Background: Two anti-CD19 chimeric antigen receptor T-cell therapies are approved for large B-cell lymphoma (DLBCL): axicabtagene ciloleucel (axi-cel) and tisagenlecleucel. Each costs $373,000 (wholesale acquisition). We evaluated each therapy’s cost-effectiveness. Methods: A decision analytic Markov model evaluated axi-cel and tisagenlecleucel in multiply relapsed/refractory adult DLBCL from a US health-payer perspective over a lifetime horizon. The model was informed by recent multi-center, single-arm clinical trials. Under a range of plausible long-term effectiveness assumptions, axi-cel and tisagenlecleucel were each compared with salvage chemoimmunotherapy regimens and stem-cell transplantation. Main outcomes were un-discounted life-years, discounted lifetime costs, discounted quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (3% discount rate). Sensitivity analyses explored uncertainty. Results: In an optimistic scenario, assuming 40% five-year progression-free survival (PFS), axi-cel increased life-expectancy by 8.15 years at $129,000/QALY (95% UI: $90,000-215,000/QALY) gained. At 30% five-year PFS, improvements in life-expectancy were more modest (6.4 years) and expensive ($159,000/QALY [$107,000-281,000/QALY] gained). In an optimistic scenario, assuming 35% five-year PFS, tisagenlecleucel increased life-expectancy by 4.6 years at $168,000/QALY ($104,000-453,000/QALY) gained. At 25% five-year PFS, improvements in life-expectancies were more modest (3.4 years) and expensive ($224,000/QALY [$124,000-1,190,000/QALY] gained). Administering CAR-T to all indicated patients would increase US healthcare costs by $10 billion over 5 years. Price reductions to $250,000 or payment only for initial CR or 90-day CR/PR (at current prices) would allow both therapies to cost < $150,000/QALY down to 25% PFS. Conclusions: At current prices, it is possible that each CAR-T therapy may meet a < $150,000/QALY threshold; this is dependent on long-term benefit compared with chemoimmunotherapy and SCT, which is uncertain. Widespread adoption would increase non-Hodgkin lymphoma healthcare costs substantially. Price reductions or payment for initial CR or 90-day CR/PR would favorably influence cost-effectiveness even if long-term outcomes are modest.

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Cost Effectiveness of Chimeric Antigen Receptor T-Cell Therapy in Multiply Relapsed or Refractory Adult Large B-Cell Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.18.02079 ◽

2019 ◽

Vol 37 (24) ◽

pp. 2105-2119 ◽

Cited By ~ 38

Author(s):

John K. Lin ◽

Lori S. Muffly ◽

Michael A. Spinner ◽

James I. Barnes ◽

Douglas K. Owens ◽

...

Keyword(s):

Cost Effectiveness ◽

Life Expectancy ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Uncertainty Interval ◽

Large B Cell Lymphoma ◽

Car T ◽

Large B Cell

PURPOSE Two anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapies are approved for diffuse large B-cell lymphoma, axicabtagene ciloleucel (axi-cel) and tisagenlecleucel; each costs $373,000. We evaluated their cost effectiveness. METHODS We used a decision analytic Markov model informed by recent multicenter, single-arm trials to evaluate axi-cel and tisagenlecleucel in multiply relapsed/refractory, adult, diffuse large B-cell lymphoma from a US health payer perspective over a lifetime horizon. Under a range of plausible long-term effectiveness assumptions, each therapy was compared with salvage chemoimmunotherapy regimens and stem-cell transplantation. Main outcomes were undiscounted life years, discounted lifetime costs, discounted quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (3% annual discount rate). Sensitivity analyses explored uncertainty. RESULTS In an optimistic scenario, assuming a 40% 5-year progression-free survival (PFS), axi-cel increased life expectancy by 8.2 years at $129,000/QALY gained (95% uncertainty interval, $90,000 to $219,000). At a 30% 5-year PFS, improvements in life expectancy were more modest (6.4 years) and expensive ($159,000/QALY gained [95% uncertainty interval, $105,000 to $284,000]). In an optimistic scenario, assuming a 35% 5-year PFS, tisagenlecleucel increased life expectancy by 4.6 years at $168,000/QALY gained (95% uncertainty interval, $105,000 to $414,000/QALY). At a 25% 5-year PFS, improvements in life expectancy were smaller (3.4 years) and more expensive ($223,000/QALY gained [95% uncertainty interval, $123,000 to $1,170,000/QALY]). Administering CAR-T to all indicated patients would increase US health care costs by approximately $10 billion over 5 years. Price reductions to $250,000 and $200,000, respectively, or payment only for initial complete response (at current prices) would allow axi-cel and tisagenlecleucel to cost less than $150,000/QALY, even at 25% PFS. CONCLUSION At 2018 prices, it is possible that both CAR-T therapies meet a less than $150,000/QALY threshold. This depends on long-term outcomes compared with chemoimmunotherapy and stem-cell transplantation, which are uncertain. Widespread adoption would substantially increase non-Hodgkin lymphoma health care costs. Price reductions or payment for initial response would improve cost effectiveness, even with modest long-term outcomes.

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Cost-Effectiveness of Axicabtagene Ciloleucel for Relapsed or Refractory Dffuse Large B-Cell Lymphoma in Italy

Blood ◽

10.1182/blood-2018-99-113838 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4779-4779 ◽

Cited By ~ 1

Author(s):

Monia Marchetti ◽

Elisa Martelli ◽

Pier Luigi Zinzani

Keyword(s):

Board Of Directors ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Cost Effective ◽

Advisory Committees ◽

Large B Cell Lymphoma ◽

Life Years ◽

Large B Cell

Abstract BACKGROUND: Axicabtagene ciloleucel (axi-cel) is a CD19-directed chimeric antigenic receptor (CAR) T-cell therapy which has been approved by FDA for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (RR-LBCL) after two or more lines of systemic therapy based on the results of the pivotal ZUMA-1 trial: the study demonstrated an objective response rate of 82% and a median overall survival has not been reached after at least 12 months of follow-up (Neelapu et al. 2017), while, historically, median survival of RR-LBCL is 6.3 months (Crump et al. 2017). AIMS & METHODS: To better understand the economic and health outcome implications of axi-cel in the perspective of the Italian National Healthcare Service, we adapted an earlier US model (Roth et al. 2018) to a Markov decision model assessing lifetime costs and outcomes of RR-LBCL patients treated with axi-cel or best supportive chemotherapy (BSC). Transition probabilities were derived from ZUMA-1 and SCHOLAR-1 studies. Long-term survival of axi-cel treated patients was derived from a mixture cure model (Bansal et al.2018) and Italian life tables. Health utility data were based on published literature (Lin et al. 2018, Chen et al. 2017). Unit costs for chemo-immunotherapy, leukapheresis, adverse events (including ICU stay and tocilizumab use for cytokine releasing syndrome) and stem cell transplant were based on Italian national charges. Costs of palliative care for progressing patients were from a country-specific study (Caroni et al. 2007). Since Axi-cel is not available in Italy yet, the US list price was used and converted in Euros (€327,000). Life years, quality-adjusted life years (QALYs) and costs were generated both with and without discount (3% per year). Uncertainty analysis included one-way and probabilistic sensitivity analysis of all model inputs. RESULTS: Over a lifetime horizon, treatment with axi-cel increased life expectancy of RR-LBCL by 6.64 QALYs (9.45 undiscounted) at an additional cost of €297,114 (€291,245 undiscounted): the corresponding cost per QALY gained was €44,746 (undiscounted €30,819). Details are reported in the table below. The cost-effectiveness of axi-cel was most sensitive to the axi-cel price, the proportion of long-term remission after axi-cel and the time horizon. Probabilistic sensitivity analysis showed 67% (95% undiscounted) likelihood of axi-cel being cost-effective at a willingness to pay threshold of €50,000/QALY. DISCUSSION: Axi-cel may be considered a cost-effective alternative to salvage chemotherapy for adults with RR-DLBCL from an Italian third-party payer perspective. This analysis confirms the good value for money of axi-cel, which has been previously reported in a US-specific analysis (Roth et al. 2018). Since follow-up data are limited for patients treated with axi-cel, continued evaluation of outcomes and costs are necessary to better understand the value of this novel therapy over years of patient experience. Disclosures Marchetti: Gilead: Consultancy; takeda: Speakers Bureau; amgen: Speakers Bureau; janssen: Speakers Bureau. Martelli:Gilead: Employment. Zinzani:Bayer: Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau.

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Safety and Efficacy of CD19 CAR-T Cells Co-Expressing IL-7 and CCL19 in Combination with Anti-PD-1 Antibody for Refractory/Relapsed DLBCL: Preliminary Data from the Phase Ⅰb Trial (NCT04381741)

Blood ◽

10.1182/blood-2021-144523 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3843-3843

Author(s):

Wenbin Qian ◽

Aiqi Zhao ◽

Hui Liu ◽

Wen Lei ◽

Yun Liang ◽

...

Keyword(s):

T Cells ◽

Response Rate ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Car T Cells ◽

Large B Cell Lymphoma ◽

Car T ◽

Large B Cell

Abstract Keywords CD19, fourth-generation CAR-T cell therapy, diffuse large B cell lymphoma, anti-PD-1 antibody Background With the advance in CD19 CAR-T therapy, there have been improvements in the treatment of refractory/relapsed diffuse large B cell lymphoma (R/R DLBCL). Still, many genetic modifications on this CAR-T product or combination agents are being explored to improve the immunosuppressive tumor microenvironment, CAR-T cell exhaustion or overcome other limitations. Using a series of in vitro studies, we demonstrated that IL-7 and CCL19 prominently promoted the cytotoxicity and the expansion of CAR-T cells. On the other hand, the existence of different immunosuppressive pathways such as PD-1/PD-L1 pathway can restrict the full potential of CAR-T therapy. Thus, it is reasonable to postulate that CD19-specific CAR-T cells that express both IL-7 and CCL19 (CD19-7×19 CAR-T cells) in combination with anti-PD-1 antibody may constitute a potential option for R/R DLBCL. Here, we present the preliminary results from a groundbreaking clinical trial of CD19-7×19 CAR-T cells plus anti-PD-1 antibody which evaluates the safety and efficacy of this new strategy. Methods This phase Ib, single-arm, open-label, single-center trial enrolled 8 patients (18-75 years) with R/R DLBCL. Lymphoma biopsies were immunostained for various target antigens including CD19. PD-L1 expression was confirmed by immunohistochemistry using an anti-PD-L1 mAb. Autologous T cells were apheresis collected and transduced with a safety-engineered lentiviral CAR with the following intracellular signaling domains: CD8/4-1BB/CD3ζ/IL-7/T2A/CCL19 (4SCAR). CD19-7×19 CAR-T cells were administrated at dose of 1 to 3×10 6 CAR-T cells/kg following lymphodepleting chemotherapies using fludarabine (30 mg/m 2) and cyclophosphamide (500 mg/m 2). At 30th day after modified T-cells infusion, patients received 6 cycles of anti-PD-1 antibody Tislelizumab (200mg) for every 3 weeks. The primary endpoints were safety and objective response rate (ORR). The key second endpoints included 2 years PFS, 2 years OS, DOR, blood CAR copies, and cytokine profiles. Adverse events (AEs) were defined according to CTCAE 5.0. Efficacy of the treatment was assessed by F-FDG PET/CT at 3 months after CAR-T infusion. Results At the data cutoff, 8 patients had received CD19-7×19 CAR-T cells, including 7 males and 1 female. The median age was 45.5 years old (range, 38-65). The performance status of the 8 patients was Eastern Co-operative Oncology Group score 0 to 3 at the time of infusion. Patient characteristics include 4 with stage IV disease (50%), 1 after autologous stem cell transplantation (12.5%), 2 with bone marrow involvement (25%), and none of them received prior PD-1 antibody treatment. The average transduction efficiency of CAR was 30.625%. Among the 8 pts, 3 received infusion dose of 1 × 10 6/kg, 3 received the dose of 2 × 10 6/kg and 2 received the dose of 3 × 10 6/kg. 2 patients (25%) developed greater than grade 2 cytokine release syndrome and 2 (25%) developed neurotoxicity (grade 3). These adverse effects resolved quickly after intervention. Total 7 patients were evaluated at three months follow-up time, resulting in 4 complete response (CR), 1 partial response (PR), and 2 disease progression (PD). The overall response rate was 5/7 and CR rate was 4/7. Moreover, another R/R DLBCL patient with stage Ⅳ disease and a bulky mass in the liver (＞12 cm) receiving compassionate CAR-T therapy, who wasn't enrolled because of hepatitis B virus infection, achieved and still remained in continuous CR over 6 months. Conclusion These results showed the feasibility, controllable toxicities, and marked response rate with this potential approach for R/R DLBCL. However, it remains unclear whether long term remission rate can be achieved. Long term follow-up and additionally enrolled patients would be necessary. Disclosures The authors declare that they have no competing interests. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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