Cost-Effectiveness and Budget Impact Analyses of Tisagenlecleucel in Pediatric and Young Adult Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia from the Singapore Healthcare System Perspective.

Purpose: Children and young adults with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) have poor survival due to ineffective therapy options. The newly approved chimeric antigen receptor T-cell (CAR-T) therapy, tisagenlecleucel, has demonstrated improved survival but at a high up-front cost. The study aims to evaluate the cost-effectiveness and budget impact of tisagenlecleucel versus salvage chemotherapy regimen (SCR) or blinatumomab (BLN) for the treatment of pediatric and young adult patients with relapsed/refractory B-cell ALL from the Singapore healthcare system perspective. Patients and Methods: A three-health state partitioned survival model was constructed to analyze the cost-effectiveness of tisagenlecleucel vs SCR/BLN with/without allogenic hematopoietic stem cell transplantation (allo-HSCT) over a lifetime period. Clinical efficacy for tisagenlecleucel, SCR and BLN were based on pooled data from ELIANA, ENSIGN and B2101J trials, the study by von Stackelberg et al 2011, and MT103-205 respectively. Medical costs from pre-treatment until terminal care, including treatment, side effects, follow-up, subsequent allo-HSCT and relapse, were considered. Incremental cost-effectiveness ratios (ICERs) were estimated as the incremental costs per quality-adjusted life-year (QALY) gain. Additionally, the financial impact of tisagenlecleucel introduction in Singapore was estimated, comparing the present treatment scenario (without tisagenlecleucel) with a future scenario (with tisagenlecleucel), over 5 years. Results: In the base-case analysis, tisagenlecleucel treatment demonstrated cost-effectiveness with an ICER of S$45,840 (US$34,762) per QALY (vs SCR) and S$51,978 (US$39,315) per QALY (vs BLN). The estimated budget ranges from S$477,857 (US$361,438) to S$1.4 million (US$1.05 million) annually for the initial 5 years. Conclusion: Tisagenlecleucel is likely to be a cost-effective treatment option with limited budget implications while treating r/r ALL patients who have failed at least 2 lines of prior therapies.

Cost-effectiveness and budget impact analyses of tisagenlecleucel in adult patients with relapsed or refractory diffuse large B-cell lymphoma from Singapore's private insurance payer's perspective.

BACKGROUND: Patients experiencing relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) have limited treatment options and poor prognosis. Tisagenlecleucel (TIS) has shown improved clinical outcomes, but at a high upfront cost. Singapore has a multi-payer healthcare system where private insurance is one of the major payers. This study evaluated the cost-effectiveness and budget impact of TIS against salvage chemotherapy regimen (SCR) for treating r/r DLBCL patients who have failed ≥2 lines of systemic therapy from Singapore's private insurance payer's perspective. METHODS: Over a life-time horizon, a partitioned survival model with three health-states was developed to evaluate the cost-effectiveness of TIS vs. SCR with or without hematopoietic stem cell transplantation (HSCT). Efficacy inputs for TIS and SCR were based on 43 months of observation data from pooled JULIET and UPenn trials, and CORAL extension studies respectively. Direct costs for pre-treatment, treatment, adverse events, follow-up, subsequent-HSCT, relapse, and terminal care were included. Incremental cost-effectiveness ratios (ICERs) were calculated as the total incremental costs per quality-adjusted life-year (QALY) gained. Additionally, the financial implication of introducing TIS in Singapore from a private payer's perspective was analyzed, comparing the current treatment pathway (without TIS) with a future scenario (with TIS) over 5 years. RESULTS: Compared with SCR, TIS was the dominant option, with cost savings of S$8,477 alongside an additional gain of 2.78 QALYs in privately insured patients who shifted from private to public hospitals for TIS treatment. Scenario analyses for patients starting in public hospitals show ICERs of S$99,623 (no subsidy) and S$133,261 (50% subsidy for SCR treatment, no subsidy for TIS), supporting the base case. The projected annual budget impact ranges from S$850,000 to S$3.4 million during the first 5 years. CONCLUSIONS: TIS for treating r/r DLBCL patients who have failed ≥2 lines of systemic therapies, is likely to be cost effective with limited budget impact.

Rimonabant inhibits TNF-α-induced endothelial IL-6 secretion via CB1 receptor and cAMP-dependent protein kinase pathway.

AIM: To investigate whether rimonabant, a cannabinoid receptor antagonist, had inhibitory effects on inflammatory reactions in human umbilical vein endothelial cells (HUVEC). METHODS: TNF-α-induced IL-6 production was measured by ELISA and effects on related signaling pathways were investigated by immunoblot analysis. Cellular cAMP level was measured using kinase-coupled luciferase reaction. RESULTS: Rimonabant at 1 and 10 µmol/L significantly inhibited TNF-α-induced IL-6 production when added 15, 30 and 60 minutes before TNF-α treatment. Rimonabant also inhibited TNF-α-induced phosphorylation of IκB kinase (IKK) α/ß and IκB-α degradation. ACEA, a cannabinoid receptor subtype 1 (CB1) agonist, added before rimonabant abolished the former effects of rimonabant. H-89, an inhibitor of cAMP-dependent protein kinase (PKA), abolished the inhibitory effects of rimonabant on TNF-α induced IL-6 production. Rimonabant also increased the phosphorylation of PKA regulatory subunit II (PKA-RII), implying the essential role of PKA activation in the inhibitory effects of rimonabant. Treatment with the phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin did not abolish the inhibitory effects of rimonabant on TNF-α induced IL-6 production. CONCLUSION: Rimonabant had anti-inflammatory effects on endothelial cells and inhibited TNF-α-induced IKKα/ß phosphorylation, IκB-α degradation and IL-6 production in HUVEC. This effect was related to CB1 antagonism and PKA activation.