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Relevant comparators
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| There was no direct comparator in the phase II information submitted by the sponsor. PAG notes that current treatments for relapsed or refractory FL after 2 lines of systemic therapy vary and can include a CD20-targeted medication (e.g., rituximab, obinutuzumab) plus various chemotherapy backbones if they were not used previously (e.g., GDP, ICE), lenalidomide plus rituximab, and SCT. | Comment from the drug programs to inform pERC deliberations. |
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Considerations for initiation of therapy
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| The Health Canada indication for tisagenlecleucel is specific to relapsed or refractory grade 1, 2, 3a FL after 2 or more prior lines of systemic therapy. The ELARA trial excluded those with grade 3b FL. Are patients with relapsed or refractory grade 3b FL eligible for treatment with tisagenlecleucel? | The clinical experts noted that grade 3b FL accounts for a small proportion of all FL and behaves more like DLBCL. Patients with grade 3b FL have an unmet need and a poor prognosis. These patients are usually excluded from the clinical trials. Although there is insufficient evidence to inform this decision, the clinical experts agreed that it might be reasonable to generalize the ELARA trial’s results to patients with grade 3b FL. The clinical experts noted that another CAR T-cell therapy has been approved for use in patients with grade 3b FL and DLBCL. pERC noted that the approved Health Canada indication does not include grade 3b FL; therefore, pERC cannot provide guidance on this population. |
PAG noted that patients with the following characteristics were excluded from the ELARA trial. If recommended for reimbursement, will these patients be excluded from treatment with tisagenlecleucel? Those with:an ECOG PS > 1 prior CD19-targeted therapy (e.g., tafasitamab) prior allogeneic SCT prior CAR T-cell therapy active CNS involvement other types of low-grade lymphomas (e.g., marginal zone, Waldenström macroglobulinemia, MALT lymphoma).
| pERC agreed with the clinical experts that it would be reasonable to generalize the ELARA trial’s results to patients with good performance status. The clinical experts noted that patients with an ECOG PS of 0, 1, or 2 are eligible for treatment with tisagenlecleucel in many centres, while those with an ECOG PS of 3 or 4 are not. The clinical experts noted that it may be reasonable to generalize the ELARA trial’s results to patients who had received prior CD19-targeted therapy and in whom CD19 positivity was confirmed. pERC noted that there is no evidence to support using tisagenlecleucel in patients who received prior CD19-targeted therapy. pERC agreed with the clinical experts that it may be reasonable to generalize the ELARA trial’s results to patients who had prior allogeneic SCT. These patients represent a small proportion of the population in practice and are generally excluded from clinical trials. pERC agreed with the clinical experts that the ELARA trial’s results should not be generalized to patients with prior CAR T-cell therapy, patients with active CNS disease, and patients with other types of low-grade lymphomas. pERC agreed with the clinical experts consulted by CADTH that as long as the CNS disease is being treated and the patient is neurologically stable, they should not be excluded from consideration for tisagenlecleucel. |
| What bridging therapies can be considered for tisagenlecleucel in patients with relapsed or refractory FL? | The clinical experts noted that in practice, radiation would be used as bridging therapy for localized FL. Steroids, rituximab, R2, and chemotherapies are also used in clinical practice. pERC agreed with the clinical experts that selection of bridging therapies should be at the discretion of the treating physicians. |
| Is there sufficient evidence to support re-treatment with tisagenlecleucel in cases of disease relapse in the future? | Re-treatment was not permitted in the ELARA trial. The clinical experts and pERC agreed that there is currently a lack of data to support re-treatment with tisagenlecleucel in patients with disease relapse. |
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Considerations for prescribing of therapy
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| The manufacturer indicates that tisagenlecleucel can be given in either the inpatient or outpatient setting, provided that it is a CAR T-cell therapy certified centre. | Comment from the drug programs to inform pERC deliberations. |
| Delivery of tisagenlecleucel must take place at specialized treatment centres that are accredited and certified by the manufacturer. There continues to be limited access to CAR T-cell services in Canada. While access is expanding, interprovincial travel or out-of-country funding remains necessary in many parts of Canada. Due to geographical site limitations, patients may need to travel for treatment, which requires interprovincial agreements to ensure equitable access. | Comment from the drug programs to inform pERC deliberations. |
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Generalizability
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| Should patients who recently started their third-line systemic therapy be allowed to switch to CAR T-cell therapy provided all other criteria are met? | pERC agreed with the clinical experts that if patients respond to their current third-line systemic therapy and do not have progressive disease, there is no need to switch them to CAR T-cell therapy. However, if progressive disease is a concern, the patients would be allowed to switch to CAR T-cell therapy, provided all other criteria are met. |
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Funding algorithm
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| This is a complex therapeutic space with multiple lines of therapy, subpopulations, or competing products. | Comment from the drug programs to inform pERC deliberations. |
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Care provision issues
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| CRS is sometimes managed with tocilizumab. The product monograph of tisagenlecleucel indicates that 2 doses of tocilizumab should be onsite before the tisagenlecleucel infusion is started and that additional doses can be obtained within 8 hours, if needed. In the event of a tocilizumab shortage, is there another treatment that can be used to manage CRS? | The clinical experts noted that when tocilizumab is not available, other treatments used to manage CRS can include steroids, siltuximab, or anakinra (an interleukin-1 receptor inhibitor). pERC agreed with the clinical experts. |
| Acetaminophen and diphenhydramine, as premedication, within 30 to 60 minutes before tisagenlecleucel infusion are recommended. Systemic corticosteroids should be avoided. | Comment from the drug programs to inform pERC deliberations. |
| Other care provision issues include that patients need to stay within 2 hours of travel of a qualified clinical facility for at least 4 weeks following infusion. | Comment from the drug programs to inform pERC deliberations. |
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System and economic issues
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| The feasibility of adoption (including budget impact) must be addressed. Given the anticipated patient volumes, PAG is concerned that existing capacity may not be able to meet demand. | Comment from the drug programs to inform pERC deliberations. |
| There have been significant manufacturing delays for tisagenlecleucel. How does the delayed turnaround time impact the clinical effectiveness of tisagenlecleucel? | The clinical experts indicated that manufacturing delays are a significant clinical problem, especially for the patients who progress quickly and have more disease burden. In these cases, tisagenlecleucel may not be as effective as for other patients who do not have disease progression. In addition, some patients may not be able to receive tisagenlecleucel after leukapheresis and bridging therapies. pERC acknowledged the response by the clinical experts. |
