YESCARTA (axicabtagène ciloleucel) - Lymphome folliculaire

Key points

Approval of reimbursement for the treatment of adult patients with refractory or relapsed follicular lymphoma (FL) after at least three lines of systemic treatment.

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 lymphoma4.

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 national5 and international guidelines,4,6 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.7 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.8

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)9,10,11
• 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.3

For third and subsequent lines, treatment with idelalisib (ZYDELIG) may be proposed (in the case of double-refractory disease).12

The proprietary medicinal product KYMRIAH (tisagenlecleucel) may also be proposed after at least two lines of treatment, in the case of refractory or relapsed disease during or within 6 months following the end of their maintenance treatment, or who relapse after autologous haematopoietic stem cell transplantation.13

Role of the medicinal product

YESCARTA (axicabtagene ciloleucel) is a fourth-line or subsequent treatment of refractory or relapsed follicular lymphoma.

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 YESCARTA (axicabtagene ciloleucel) must be compatible with these time frames.

The Committee also points out that:

• considering the high frequency of grade ≥ 3 adverse events (85 % of patients of the ZUMA-5 pivotal study), in particular with cytokine release syndrome, neurological adverse effects 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,
• YESCARTA (axicabtagene ciloleucel) 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 YESCARTA (axicabtagene ciloleucel) 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.