Lisocabtagene maraleucel (liso-cel; Breyanzi®; Bristol-Myers Squibb), a CD19-directed genetically modified autologous T-cell immunotherapy, also known as chimeric antigen receptor (CAR) T-cell therapy, is a cost effective second line treatment for relapsed and refractory diffuse large B-cell lymphoma (r/r DLBCL).

This conclusion is based on results from a study published in Blood Advances, an online only, open access journal of the American Society of Hematology (ASH).[1]

The study is the first of its kind to incorporate healthcare expenses, societal productivity losses, and patient quality of life in assessing the drug’s cost-effectiveness.

Overlooked societal costs
“In our study, we incorporated the often-overlooked societal costs associated with cancer treatment, which are typically neglected in cost-effectiveness analyses that focus solely on the healthcare sector related-expenses,” noted Mohamed Abou-el-Enein, MD, PhD, MSPH, an associate professor of medicine at the Keck School of Medicine at the University of Southern California and the senior author of the study.

“Cancer treatments can diminish quality of life, causing work absences and challenges in managing everyday activities, especially among the elderly. Treatments that improve quality of life not only benefit the patient but also reduce these broader societal costs, which is an important aspect of our cost-effectiveness evaluation,” Abou-el-Enein added,

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Non-Hodgkin lymphoma
Diffuse large B-cell lymphoma or DLBCL, the most prevalent form of non-Hodgkin lymphoma, is a cancer that affects lymphocytes, a type of white blood cell. In cases where DLBCL does not respond to initial treatment or recurs within 12 months after treatment completion, the standard care protocol typically includes platinum-based chemotherapy, followed by high-dose chemotherapy and autologous stem cell transplantation.* /**

In 2022, the U.S. Food and Drug Administration (FDA) granted approval to liso-cel as a second-line treatment for DLBCL. However, the cost-effectiveness of liso-cel is currently a topic of debate among many oncologists, especially considering the drug’s steep price tag which increased from US $ 410,300 to US $ 447,227 between 2022 and 2023.

Cost-effectiveness analysis
In this study, researchers performed a cost-effectiveness analysis of liso-cel for treating r/r DLBCL using a partitioned survival model, a common economic tool for assessing medical treatments across various stages of disease progression.[2]

The researchers found that patients treated with liso-cel had an average life expectancy of 5.34 years and gained 3.64 quality-adjusted life years (QALYs), compared to the 2.47 years and 1.62 QALYs with the standard of care. The cost-effectiveness of liso-cel, measured by the incremental cost-effectiveness ratio (ICER), was US$ 99,669 per QALY from a healthcare sector perspective and US $ 68,212 per QALY from a societal perspective.

The ICER evaluates the additional cost required for each QALY gained, assuming a societal willingness to pay up to US $ 100,000 per QALY. These figures indicate that liso-cel is a cost-effective treatment, staying below the US $ 100,000 per QALY threshold.

Second-line treatment
An important aspect of the study is its modeling based on outcomes from the TRANSFORM trial, the pivotal study assessing the cost-effectiveness of liso-cel in second-line treatment. This approach closely mirrors the patient population from the TRANSFORM trial ( NCT03575351), thereby reducing bias in the results. The patient demographic typically involving patients aged 60, with a majority (57%) being male, and all having r/r DLBCL with a relapse occurring within 12 months of initial treatment. The treatment regimens were consistent with those used in the TRANSFORM trial.[3] **

Direct medical costs included in the analysis were comprehensive, covering CAR T-cell therapy procedures, chemotherapy, stem cell transplant, hospital admissions, ongoing monitoring, management of disease progression, and end-of-life care. This also encompassed the costs associated with treating adverse events. These costs were derived from published literature and public datasets. Societal costs considered lost productivity, including lost labor market earnings, the value of unpaid productivity and household activities, and out-of-pocket travel expenses. Notably, in terms of mortality-related lost labor earnings, liso-cel was associated with a loss of US $ 110,608, which is lower than the US $ 156,362 for the Standard of Care. Additionally, both unpaid productivity loss and uncompensated household production costs were comparatively lower for liso-cel. These findings indicate that liso-cel offers economic benefits by reducing losses in both paid and unpaid labor sectors, compared to treatment with the current Standard of Care.

Study limitation
The authors’ strict adherence to data from the TRANSFORM trial brings about a limitation in their study due to the lack of long-term follow-up data to be incorporated in their cost-effectiveness analysis. Moreover, the scenario analyses conducted, which looked at various time horizons, utility values, and list prices, reveal that maintaining liso-cel cost-effective at the US $ 100,000 per QALY threshold might pose a challenge. This underlines the critical need to manage liso-cel’s costs effectively to ensure its affordability and economic sustainability.

Looking ahead, Abou-el-Enein explains that their objective is to continue evaluating the cost-effectiveness of various CAR-T therapies. This information is crucial for making informed decisions about reimbursements and their integration into the healthcare system. He also stresses the significance of ongoing dialogue among clinicians, researchers, pharmaceutical manufacturers, and patients concerning the escalating costs of CAR-T cell therapy.

“This study demonstrates that CAR T-cell therapy is worth considering as a second line treatment for r/r/ DLBCL,” Abou-el-Enein said.

“When deciding on what therapies to use in clinical practice, I think it is important that we do not shy away from these therapies solely because of their list price. We must keep our patients front and center in these decisions and continue to have conversations about how we can lower the price of CAR T cells and increase patient access to this life-saving treatment,” Abou-el-Enein concluded.

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Note: * Autologous stem cell transplants are generally used in patients who need to undergo high doses of chemotherapy and radiation. Because these treatments are most likely damaging the bone marrow, autologous stem cell transplant can are used helps to replace this damaged bone marrow. This approach is used in the treatment of patients diagnosed with Hodgkin lymphoma, Non-Hodgkin lymphoma, Myeloma and Plasma cell disorders.

**  The TRANSFORM trial is a global, phase 3 clinical study, conducted in 47 sites in the United States, Europe, and Japan, comparing lisocabtagene maraleucel (liso-cel) with the current Standard of Care as second-line therapy in patients with primary refractory or early (≤12 months) relapsed large B-cell lymphoma. In this study, adult patients aged 18-75 years, Eastern Cooperative Oncology Group (ECOG) performance status score of 1 or less, adequate organ function, PET-positive disease per Lugano 2014 criteria, and candidates for autologous hematopoietic stem cell transplant (HSCT) were randomly assigned (1:1), by use of interactive response technology, to liso-cel or the current Standard of Care.

Patients in the liso-cel cohort received lymphodepleting chemotherapy which consisted of fludarabine and cyclophosphamide, followed by an infusion of liso-cel (100 × 106 CAR+ T cells intravenously). In the study, liso-cel was administered as separate infusions of CD8+ and CD4+ CAR+ T cells to achieve a target dose of 100 million CAR+ T cells. During the the manufacturing period of liso-cel, a ‘so-called’ bridging cycle of chemoimmunotherapy, which was similar to the one given to patients in the Standard of Care group, was permitted at the discretion of the treating physician. The effectiveness of this interim treatment was assessed by PET scan before commencing the lymphodepletion

In the TRANSFORM trial, the Standard of Care consisted of three cycles of salvage immunochemotherapy delivered intravenously-R-DHAP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1-4, two infusions of cytarabine 2000 mg/m2 on day 2, and cisplatin 100 mg/m2 on day 1), R-ICE (rituximab 375 mg/m2 on day 1, ifosfamide 5000 mg/m2 on day 2, etoposide 100 mg/m2 on days 1-3, and carboplatin area under the curve 5 [maximum dose of 800 mg] on day 2), or R-GDP (rituximab 375 mg/m2 on day 1, dexamethasone 40 mg on days 1-4, gemcitabine 1000 mg/m2 on days 1 and 8, and cisplatin 75 mg/m2 on day 1)-followed by high-dose chemotherapy and autologous hematopoietic stem cell transplant (HSCT) in responders. The Primary endpoint of the was event-free survival, with response assessments by an independent review committee per Lugano 2014 criteria. Efficacy was assessed per intention-to-treat (i.e, all randomly assigned patients) and safety in patients who received any treatment.

Clinical trials
A Study to Compare the Efficacy and Safety of JCAR017 to Standard of Care in Adult Subjects With High-risk, Transplant-eligible Relapsed or Refractory Aggressive B-cell Non-Hodgkin Lymphomas (TRANSFORM) – ClinicalTrials.gov ID NCT03575351

Highlights of Prescribing Information
Lisocabtagene maraleucel (liso-cel; Breyanzi®; Bristol-Myers Squibb)[Prescribing Information]

References
[1] Choe JH, Yu T, Abramson JS, Abou-El-Enein M. Cost-Effectiveness of second-line lisocabtagene maraleucel in relapsed or refractory diffuse large B-cell lymphoma. Blood Adv. 2023 Dec 28:bloodadvances.2023011793. doi: 10.1182/bloodadvances.2023011793. Epub ahead of print. PMID: 38153350.
[2] Sanders GD, Neumann PJ, Basu A, Brock DW, Feeny D, Krahn M, Kuntz KM, Meltzer DO, Owens DK, Prosser LA, Salomon JA, Sculpher MJ, Trikalinos TA, Russell LB, Siegel JE, Ganiats TG. Recommendations for Conduct, Methodological Practices, and Reporting of Cost-effectiveness Analyses: Second Panel on Cost-Effectiveness in Health and Medicine. JAMA. 2016 Sep 13;316(10):1093-103. doi: 10.1001/jama.2016.12195. Erratum in: JAMA. 2016 Nov 8;316(18):1924. PMID: 27623463.
[3] Kamdar M, Solomon SR, Arnason J, Johnston PB, Glass B, Bachanova V, Ibrahimi S, Mielke S, Mutsaers P, Hernandez-Ilizaliturri F, Izutsu K, Morschhauser F, Lunning M, Maloney DG, Crotta A, Montheard S, Previtali A, Stepan L, Ogasawara K, Mack T, Abramson JS; TRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022 Jun 18;399(10343):2294-2308. doi: 10.1016/S0140-6736(22)00662-6. Erratum in: Lancet. 2022 Jul 16;400(10347):160. PMID: 35717989.

Featured image: Cost of Healthcare. Photo courtesy: © 2016 – 2023 Fotolia/Adobe.  Used with permission.

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