KYMRIAH - LDGCB (tisagenlecleucel)

Key points

Favourable opinion for maintenance of reimbursement in the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma after two or more lines of systemic therapy.

What therapeutic improvement?

Maintenance of therapeutic improvement compared to historic management based on various chemotherapies.

Role in the care pathway?

The choice of treatment is based on a systematic assessment of the main prognostic criteria for the disease. The IPI (International Prognostic Index) is used as a prognostic index for aggressive NHL. This takes into account the patient’s age, the ECOG performance score, the lactate dehydrogenase (LDH) level, the disease stage and the extent of extranodal involvement.

The therapeutic options proposed for DLBCL are chemotherapy, immunotherapy with monoclonal antibodies and autologous T lymphocytes with an anti-CD19 chimeric antigen receptor (anti-CD19 CAR-T cells), radiotherapy and haematopoietic stem cell transplantation (primarily used at the time of relapse after salvage therapy).

The first-line treatment of choice is based on R-CHOP induction immunochemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone). Almost 2/3 of patients achieve remission after this treatment.

As second-line therapy in patients not responding to this first-line treatment (primary refractory disease) or who relapse following this treatment, the therapeutic approach depends on the patient’s eligibility for high-dose chemotherapy with the objective of performing allogeneic haematopoietic stem cell transplantation. The major eligibility criteria for high-dose chemotherapy with autologous haematopoietic stem cell transplantation are: chemosensitive disease, adequate performance status (no major organ dysfunction) and age < 65 to 70 years (although there is no consensus concerning this threshold).

In patients in whom high-dose chemotherapy can be envisaged, “salvage” chemotherapy (generally R-DHAP, R-ICE or R-GDP) should be proposed initially, followed by high-dose chemotherapy (intensification) and autologous haematopoietic stem cell transplantation in the event of a response (chemosensitive patients).

In patients who are not candidates for subsequent high-dose chemotherapy, in particular due to their age and/or comorbidities, adapted chemotherapy protocols may be proposed.

Patients who are not eligible for autologous SCT, in particular due to their age or an inadequate response to salvage chemotherapy, may receive platinum and/or gemcitabine-based immunochemotherapy (in particular R-GemOx or R-DHAP regimens) not followed by conditioning for transplant. None of the immunochemotherapies currently recommended have a marketing authorisation.

From the third line of treatment, in patients in whom autologous SCT has failed or having relapsed following two previous treatment lines, two medicinal products based on CAR-T cells, YESCARTA (axicabtagene ciloleucel) and KYMRIAH (tisagenlecleucel), are currently recommended in patients whose life expectancy is compatible with the treatment timeframes (between apheresis and injection). According to the first real-world data, this timeframe, of around 5 to 7 weeks for French patients, is similar for both medicinal products and requires the use of treatments pending injection. In other cases, no chemotherapy (monotherapy or combination therapy) is considered to be a standard of care and the treatment options are limited. Depending on the clinical situation, the following may be envisaged:

• for relapsed patients (excluding refractory patients): additional intensive chemotherapy with the objective of performing allogeneic haematopoietic stem cell transplantation if the patient is eligible; where applicable an autologous transplant. An allogeneic transplant is generally considered in patients under the age of 70, in the absence of major comorbidities, in the presence of a donor (availability of a graft) and in the event of a complete response (or very good partial response) following the chemotherapy regimen;
• other chemotherapies;
• implementation of palliative care.

Role of the medicinal product in the care pathway

The new data available is not of a nature to modify the role of KYMRIAH (tisagenlecleucel) in the care pathway defined in 2018 by the Transparency Committee.

KYMRIAH (tisagenlecleucel) remains a third or later-line treatment for diffuse large B-cell lymphoma (DLBCL) in patients for whom at least 2 lines of systemic treatment have failed, with a history of autologous transplantation for eligible patients.

In view of the available data (numerous limitations of the indirect comparisons provided and immaturity of real-world data), the role of KYMRIAH (tisagenlecleucel) compared to YESCARTA (axicabtagene ciloleucel) in the shared DLBCL indication cannot be robustly established. The Committee nevertheless highlights that, according to the expert opinions and the first follow-up data, it is possible that clinical responses may be more numerous and more rapid under YESCARTA (axicabtagene ciloleucel) than under KYMRIAH (tisagenlecleucel) but with more frequent acute toxicities, particularly neurological, for the former. However, KYMRIAH (tisagenlecleucel) has a logistical advantage compared to YESCARTA (axicabtagene ciloleucel) due to the possibility of freezing the apheresis product.

Therefore both these medicinal products provide an additional response to the identified medical need in relapsed or refractory DLBCL as third or later-line therapy. The choice of one over the other should be made on the basis of the patient’s condition, the availability of production slots, the expected clinical response and the safety profile.

Due to the timeframes for product availability (from determination of patient eligibility for CAR-T cell treatment, leukapheresis, the production of the genetically modified cells and lymphodepleting chemotherapy through to transportation to the patient for reinjection) and the significant short-term toxicity, the general condition and life expectancy of patients eligible for KYMRIAH (tisagenlecleucel) must be compatible with these timeframes.

The Committee also highlights that:

• considering the high frequency of grade ≥ 3 adverse events (90% of patients), with, in particular, cytokine release syndromes, neurological adverse effects and possible hospitalisation in the ICU, as well as the constraints related to the need for a lengthy hospital stay and the potential distance from the patient’s home of a qualified centre, it is essential to inform patients about these constraints and the risks,
• KYMRIAH (tisagenlecleucel) should be administered in a healthcare facility specifically qualified in the use of CAR-Tcells,
• the summary of product characteristics (SPC) and the risk management plan (RMP) must be complied with and special monitoring during and after treatment is required.

Special recommendations

The use of KYMRIAH (tisagenlecleucel) is limited to a small number of centres specifically qualified in the use of CAR-T cells given the complexity of the procedure, as stipulated in the order of 8 August 2019. In this context, the Committee highlights the importance of overall care (in particular including travel and local accommodation near healthcare facilities, where required), as reported by patient and user associations.

The Committee highlights the importance of ensuring patients, and their carers if applicable, having access to appropriate information on the complexity of the CAR-T procedure, the constraints related to prolonged hospitalisation and the risks to patients.

The Committee would like to see all stakeholders mobilised to provide responses to the remaining uncertainties at the next re-evaluation. To this end, the Committee calls for the participation of all qualified centres in the DESCAR-T registry in order to obtain exhaustive, high-quality observational data.