KYMRIAH (tisagenlecleucel) - Lymphome folliculaire

Key points

Approval of reimbursement for the treatment of adult patients presenting with follicular lymphoma after at least two lines of treatment:

• whose disease is refractory;
• or who relapse during or within 6 months following the end of their maintenance treatment;
• or who relapse after autologous haematopoietic stem cell transplantation.

Disapproval of reimbursement for other marketing authorisation contexts.

Therapeutic improvement?

No therapeutic improvement.

Role in therapeutic strategy?

The histological grading of follicular lymphoma is defined by WHO according to the centroblast count observed with a microscope.  Grade 1-2 FL, and generally grade 3a, are indolent forms, whereas grade 3b FL cases are considered as aggressive forms of FL and treated as diffuse large B-cell lymphoma.5

The treatment initiation criteria are signs of clinical progression (inflammatory syndrome, LDH, beta 2 microglobulin or impact on general state of health assessed by the ECOG performance score) and the presence of a large or compressive tumour mass.

Currently, no treatments, including intensifications with stem cell transplantation, can be expected to achieve recovery.

As a first-line treatment, according to national8 and international guidelines5,

dent on the first-line treatment received, the type and duration of remission from the previous line and the spread of the disease. The treatments available from the second line are:

• a new immuno-chemotherapy regimen (R-CHOP, R-CVP, R-bendamustine, Obinutuzumab-bendamustine)12,13,14
• or radio-immunotherapy if permitted by the degree of medullary invasion,
• or autologous stem cell transplantation if permitted by age and particularly in the case of early relapse,
• or autologous stem cell transplantation which may also be proposed for some high-risk younger patients in the event of subsequent relapse or also for patients failing to respond to autologous transplantation,

For patients non-refractory to rituximab, in contexts where CHOP, bendamustine or CVP type chemotherapy is not feasible, lenalidomide (REVLIMID) may be used in association with rituximab.6

For third and subsequent lines, treatment with idelalisib (ZYDELIG) may be proposed (in the case of double-refractory disease).15

From the fourth line, the proprietary medicinal product YESCARTA (axicabtagene ciloleucel) which has been granted an early-access authorisation for this indication, may be proposed.16

Role of the medicinal product

KYMRIAH (tisagenlecleucel) is a third-line or subsequent treatment for relapsed follicular lymphoma (during or within 6 months following the end of their maintenance treatment, or relapsing after autologous haematopoietic stem cell transplantation) or refractory follicular lymphoma after the second or subsequent line of systemic treatment.

the therapeutic options are based on immuno-chemotherapy, i.e. an association of rituximab + chemotherapy (such as R-CHOP, R-CVP or R-bendamustine mostly) followed by maintenance treatment based on rituximab.10 In some cases, rituximab monotherapy treatment may be recommended (off-label). As an alternative to rituximab, obinutuzumab (GAZYVARO) may also be used in induction in association with chemotherapy (such as CHOP, CVP or bendamustine mostly), followed by maintenance treatment based on Obinutuzumab.11

In the event of failure to respond or progression, a second-line regimen is proposed. A further tumour sample biopsy optionally guided by PET-scan is recommended to rule out conversion to diffuse large B-cell lymphoma. The second-line treatment is dependent on the first-line treatment received, the type and duration of remission from the previous line and the spread of the disease. The treatments available from the second line are:

• a new immuno-chemotherapy regimen (R-CHOP, R-CVP, R-bendamustine, Obinutuzumab-bendamustine)12,13,14
• or radio-immunotherapy if permitted by the degree of medullary invasion,
• or autologous stem cell transplantation if permitted by age and particularly in the case of early relapse,
• or autologous stem cell transplantation which may also be proposed for some high-risk younger patients in the event of subsequent relapse or also for patients failing to respond to autologous transplantation,

For patients non-refractory to rituximab, in contexts where CHOP, bendamustine or CVP type chemotherapy is not feasible, lenalidomide (REVLIMID) may be used in association with rituximab.6

For third and subsequent lines, treatment with idelalisib (ZYDELIG) may be proposed (in the case of double-refractory disease).15

From the fourth line, the proprietary medicinal product YESCARTA (axicabtagene ciloleucel) which has been granted an early-access authorisation for this indication, may be proposed.16

Role of the medicinal product

KYMRIAH (tisagenlecleucel) is a third-line or subsequent treatment for relapsed follicular lymphoma (during or within 6 months following the end of their maintenance treatment, or relapsing after autologous haematopoietic stem cell transplantation) or refractory follicular lymphoma after the second or subsequent line of systemic treatment.

Given the lack of methodologically robust comparative data, it is not possible to specify the role of KYMRIAH (tisagenlecleucel) in relation to the other therapeutic alternatives available.

Due to the time needed to make the product available (including the time to determine whether the patient is eligible for CAR-T cell treatment, leukapheresis, genetically-modified cell production, lymphodepleting chemotherapy until the patient is presented for reinjection) and the significant short-term toxicity, the general state of health and life expectancy of patients eligible for KYMRIAH (tisagenlecleucel) must be compatible with these time-frames. 

The Committee also points out that:

• considering the high frequency of grade ≥ 3 adverse events (81.4% of patients of the ELARA pivotal study) and potential admissions to intensive care, and the constraints associated with the need for long hospital stays and the possible distance from the qualified centre, it is crucial that patients receive information on these constraints and the risks involved,
• KYMRIAH (tisagenlecleucel) must be administered in a healthcare organisation specifically qualified for the use of CAR-T cells,

the summary of product characteristics (SPC) and the risk management plan (RMP) must be adhered to, and special monitoring during and after treatment is required.

Special recommendations

The use of KYMRIAH (tisagenlecleucel) is limited to a restricted number of centres qualified for the use of CAR-T cells, given the complexity of the procedure, as set out in the order of 19 May 2021. In this context, the Committee points out the importance of comprehensive care (particularly including travel and accommodation close to qualified healthcare organisations, where necessary) as reported by patient and user associations.

The Committee points out the importance, for patients and their caregivers where applicable, of having information tailored to the complexity of the CAR-T procedure, the constraints associated with long hospital stays, and the risks involved for the patient.

The Committee calls for commitment from all stakeholders to ensure that the uncertainties in this dossier are addressed by the time of its reassessment. In this aim, the Committee calls for the participation of all qualified centres of the required category in order to obtain high-quality and exhaustive observational data.

Avis économique

Ce produit a fait l'objet d'un avis économique rendu par la Commission d'évaluation économique et de santé publique le 13 décembre 2022. L’avis économique porte sur la demande de remboursement concerne KYMRIAH (tisagenlecleucel) dans le traitement des patients adultes atteints de lymphome folliculaire (LF) en rechute ou réfractaire après la deuxième ligne ou plus d’un traitement systémique :

• qui présentent une maladie réfractaire ;
• ou en rechute pendant ou dans les 6 mois qui suivent la fin de leur traitement d’entretien ;
• ou en rechute après une greffe de cellules souches hématopoïétiques autologues.

La demande de remboursement est plus restreinte que l’indication de l’AMM obtenue le 29 avril 2022 en procédure centralisée. L’AMM de KYMRIAH a été octroyée dans le traitement des adultes atteints de lymphome folliculaire (LF) en rechute ou réfractaire après la deuxième ligne ou plus d’un traitement systémique.

La CEESP a été en mesure de conclure sur le niveau d’efficience du produit, avec RDCR de tisagenlecleucel versus les traitements usuels sur un horizon temporel de 15 ans de 295 406 €/QALY (232 907 €/AVG), ratio très probablement sous-estimé compte-tenu des choix favorables retenus sur l’horizon temporel et l’extrapolation des courbes de survie sans traitement ultérieur (SSTU) du bras prise en charge usuelle, au prix revendiqué.

L’impact budgétaire associé à l’introduction du pembrolizumab en association représente une augmentation des dépenses de l’assurance maladie dans l’indication de 50%.

KYMRIAH - Avis économique (pdf)