The Singapore Ministry of Health’s (MoH) Drug Advisory Committee has recommended Tisagenlecleucel cells dispersion for infusion for treating patients 18 years of age and above with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) after two or more lines of systemic therapy. Tisagenlecleucel cells dispersion for infusion is recommended for inclusion on the MoH Cell, Tissue, and Gene Therapy Product (CTGTP) List for the specified indication starting 1 August 2024.
The MoH Drug Advisory Committee reviewed the evidence for the technology evaluation of tisagenlecleucel for treating relapsed or refractory diffuse large B-cell lymphoma after two or more lines of systemic therapy. The Agency for Care Effectiveness (ACE) conducted the evaluation based on evidence submitted by the company, with input from clinical experts from public healthcare institutions and patient experts from local patient and voluntary organizations.
The evidence was used to inform the Committee’s deliberations around four core decision-making criteria: clinical need of patients and the nature of the condition; clinical effectiveness and safety of the technology; cost-effectiveness (value for money) – the incremental benefit and cost of the technology compared to existing alternatives; and the estimated annual technology cost and the number of patients likely to benefit from the technology. Additional factors, including social and value judgments, also inform the Committee’s funding considerations.
Clinical Need and Patient Experiences with Lymphoma Treatments
Large B-cell lymphoma (LBCL) is an aggressive subtype of non-Hodgkin lymphoma, with DLBCL being the most common. Approximately 300 patients are diagnosed with diffuse large B-cell lymphoma each year in Singapore. Although many patients can be cured with first-line multi-agent immunochemotherapy, 30-40% experience relapse or have primary refractory disease and require further treatment.
In local practice, patients with relapsed or refractory diffuse large B-cell lymphoma are typically treated with salvage chemotherapy at the third-line setting, using treatments such as R-DHAP (rituximab, dexamethasone, cisplatin, cytarabine), R-GDP (rituximab, gemcitabine, dexamethasone, cisplatin or carboplatin), and R-ICE (rituximab, ifosfomide, carboplatin, etoposide). Tisagenlecleucel is a one-time, chimeric antigen receptor T-cell (CAR-T) therapy. The Committee acknowledged the clinical need to consider tisagenlecleucel for funding to improve affordability and ensure appropriate patient care.
The Committee considered five testimonials from local patients and carers about their experiences with diffuse large B-cell lymphoma and the treatments they received. Patients highlighted the significant negative impact of the condition on their physical, mental, and emotional well-being, with the fear of relapse being their greatest concern. One patient who received tisagenlecleucel reported that it worked well with more manageable side effects compared to a stem cell transplant. Patients expected tisagenlecleucel to lead to better outcomes, achieve remission, improve quality of life, prevent relapse, enable them to return to work, be more affordable, and have fewer side effects.
Clinical Effectiveness and Safety
The Committee reviewed indirect comparisons based on two single-arm trials for tisagenlecleucel (JULIET and U-PEN) and three observational studies (CORAL extension and SCHOLAR-1) for salvage chemotherapy. Tisagenlecleucel was associated with improved overall response rate and overall survival compared to salvage chemotherapy.
The Committee noted that results from the intention-to-treat population would be more appropriate for assessing comparative efficacy, as the full analysis set (FAS) excluded patients assigned to the tisagenlecleucel arm who did not receive it. The Committee acknowledged bias in naïve comparisons due to differences in study design and patient populations, and uncertainty in matching-adjusted indirect comparisons.
In terms of safety, tisagenlecleucel was associated with a higher proportion of grade ≥3 adverse events compared to salvage chemotherapy. Common adverse events included cytokine release syndrome and anaemia. The Committee concluded that tisagenlecleucel was superior in terms of effectiveness compared to salvage chemotherapy, but the magnitude of the treatment effect was uncertain. Safety concerns and long-term survival benefit uncertainties were noted.
Economic Evaluation and Funding Decision for Lymphoma Treatment
The Committee reviewed a cost-utility analysis comparing tisagenlecleucel with salvage chemotherapy in adult patients with relapsed or refractory diffuse large B-cell lymphoma. Key components of the company’s base-case economic evaluation were considered. The incremental cost-effectiveness ratio (ICER) of SG$75,000 to SG$105,000 per quality-adjusted life-year (QALY) gained was deemed uncertain and likely underestimated due to overly optimistic assumptions and inappropriate estimations.
The ICER increased further in the revised base case, accounting for changes such as reducing the time horizon and revising cure assumptions. The major limitation was the indirect comparisons between tisagenlecleucel and salvage chemotherapy. Following pricing negotiations, the Committee agreed that tisagenlecleucel likely represents an acceptable use of healthcare resources considering the improved ICER and prices in overseas reference jurisdictions. The annual cost impact to the public healthcare system was estimated to be between SG$3 million and SG$5 million in the first year, increasing to between SG$5 million and SG$10 million by the fifth year following inclusion on the MoH CTGTP List.
Given the clinical need, acceptable clinical effectiveness compared with current treatment options, and the acceptable use of healthcare resources, the Committee recommended including tisagenlecleucel cells dispersion for infusion on the MoH CTGTP List for treating patients 18 years and above with relapsed or refractory diffuse large B-cell lymphoma after two or more lines of systemic therapy. Tisagenlecleucel should be used in line with additional clinical criteria listed in the Annex to govern appropriate use in local practice, consistent with the pivotal trial population and overseas reimbursement criteria.
The Agency for Care Effectiveness (ACE) drives better decision-making in healthcare through health technology assessment (HTA), clinical guidance, and education. ACE conducts evaluations to inform government funding decisions for treatments, diagnostic tests, and vaccines, and provides guidance for public hospitals and institutions in Singapore.
Resource: Agency for Care Effectivenes, August 01, 2024

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