IMBRUVICA - Leucemie lymphoïde chronique (LLC)

Key points

Favourable opinion for reimbursement in combination with rituximab for the first-line treatment of chronic lymphocytic leukaemia (CLL), only in patients eligible for full-dose fludarabine treatment and not presenting a del17p deletion or a TP53 mutation.

Unfavourable opinion for reimbursement in combination with rituximab for the first-line treatment of chronic lymphocytic leukaemia (CLL) in patients ineligible for full-dose fludarabine treatment and/or presenting a del17p deletion and/or a TP53 mutation.

What therapeutic improvement?

Therapeutic improvement compared to the FCR (fludarabine, cyclophosphamide, rituximab) immunochemotherapy protocol in the therapeutic strategy.

Role in the care pathway?

In patients requiring treatment, the choice depends on several parameters: the patient’s age and general condition, the presence or otherwise of comorbidities and the cytogenetic status (presence of the del17p deletion and/or the TP53 mutation, IgVH mutation status):

• In the presence of a TP53 mutation or a del17p deletion, IMBRUVICA (ibrutinib) as monotherapy is currently the reference treatment.
• In the absence of a TP53 mutation or del17p deletion, in patients without significant comorbidities, immunochemotherapy with rituximab + fludarabine + cyclophosphamide (FCR protocol) is the reference treatment. In these patients, in the event of a non-mutated IgVH status (currently recognised as being a factor for a poor response to immunochemotherapy), ibrutinib is recommended internationally, with the FCR protocol remaining an available alternative. It should be noted, however, that in France, IMBRUVICA (ibrutinib) as monotherapy does not currently have a reimbursed indication for the first-line treatment of patients eligible for the FCR protocol and not presenting a TP53 mutation or del17p deletion. In elderly patients and/or those with comorbidities making them ineligible for the FCR protocol, the options are as follows: GAZYVARO (obinutuzumab) + chlorambucil (G-Clb protocol), MABTHERA (rituximab) + bendamustine (BR), VENCLYXTO (venetoclax) + GAZYVARO (obinutuzumab) (G-VEN) or IMBRUVICA (ibrutinib) as monotherapy.

Role of the medicinal product in the care pathway

IMBRUVICA (ibrutinib) in combination with rituximab is a first-line treatment for chronic lymphocytic leukaemia (CLL) in patients eligible for full-dose fludarabine treatment and not presenting a del17p deletion or a TP53 mutation.

Considering the distinct medical need, the latest international guidelines and the exploratory subgroup analyses of the E1912 study suggesting a benefit of the ibrutinib + rituximab combination compared to the FCR protocol only in patients with a non-mutated IgVH status, it is necessary to adapt the care pathway based on the patient’s IgVH status:

• In patients with a non-mutated IgVH status, the ibrutinib (administered continuously) + rituximab (administered over 6 months) combination is the first-line treatment.
• In patients with a mutated IgVH status, the choice between targeted therapy (ibrutinib administered continuously + rituximab over 6 months) and immunochemotherapy (FCR protocol administered over 6 months) must be discussed, taking into account the safety, the extent of the response expected, the administration conditions (duration and administration routes), and the patient’s preferences.

As a reminder, in the E1912 study, exploratory results suggested a response to treatment that was rarely extensive in the ibrutinib + rituximab group (8% negative MRD versus 59% in the FCR group).

As regards toxicity, the ibrutinib + rituximab combination presents a cardiovascular and haemorrhagic safety profile while the FCR protocol is associated with a risk of myelodysplasia and acute leukaemia.

In patients ineligible for full-dose fludarabine treatment and/or presenting a del17p deletion and/or a TP53 mutation, the role of the ibrutinib + rituximab combination is not established, in the absence of data. In these patients, it is highlighted that IMBRUVICA (ibrutinib) as monotherapy is a first-line treatment (Committee’s opinions of 17 June 2015 and 20 March 2020).