idelalisib
Sources réglementaires consultées
Indications approuvées
- Avec rituximab : leucémie lymphoïde chronique chez l’adulte après au moins un traitement antérieur, ou en première ligne avec délétion 17p ou mutation TP53 si aucun autre traitement ne convient. En monothérapie : lymphome folliculaire chez l’adulte réfractaire à deux lignes antérieures.
Contre-indications
Absolues
- Hypersensibilité à l’idélalisib ou aux excipients.
Mises en garde cliniques
- Ne pas débuter en présence d’une infection systémique active. Assurer une prophylaxie anti-Pneumocystis pendant tout le traitement et 2–6 mois après ; surveiller CMV, LEMP et infections opportunistes. Contrôler la NFS toutes les 2 semaines pendant les 6 premiers mois et chaque semaine si PNN <1 000/mm³. — CIMA/AEMPS, ficha técnica 114938001
- Peut provoquer hépatotoxicité, diarrhée ou colite sévère, pneumopathie ou pneumonie organisée et réactions cutanées graves. Contrôler ALAT, ASAT et bilirubine toutes les 2 semaines pendant les 3 premiers mois et modifier ou arrêter selon la gravité. — CIMA/AEMPS, ficha técnica 114938001
Interactions médicamenteuses
- SévèreInducteurs modérés ou puissants du CYP3A
Mécanisme: Ils réduisent l’exposition à l’idélalisib et peuvent diminuer son efficacité.
Recommandation: Éviter l’association, y compris le millepertuis.
CIMA/AEMPS, ficha técnica 114938001
- SévèreSubstrats sensibles du CYP3A
Mécanisme: Le métabolite de l’idélalisib inhibe fortement le CYP3A et peut fortement augmenter l’exposition au substrat.
Recommandation: Éviter les substrats contre-indiqués ou à marge étroite et appliquer la réduction et la surveillance prévues par le RCP du médicament associé.
CIMA/AEMPS, ficha técnica 114938001
Effets indésirables
Communs (≥1%)
infections · neutropénie · diarrhée ou colite · augmentation des transaminases · éruption cutanée · fièvre · augmentation des triglycérides
Rares mais graves
syndrome de Stevens-Johnson ou nécrolyse épidermique toxique
Grossesse et allaitement
Il n’est pas recommandé pendant la grossesse. Utiliser une contraception très efficace pendant le traitement et pendant 1 mois après ; si elle est hormonale, ajouter une méthode barrière. Interrompre l’allaitement pendant le traitement.
Bibliographie récente (PubMed)
Chronic lymphocytic leukemia (CLL), defined by a minimum of 5 × 109/L monoclonal B cells in the blood, affects more than 200 000 people and is associated with approximately 4410 deaths in the US annually. CLL is associated with an immunocompromised state and an increased rate of complications from infections. At the time of diagnosis, the median age of patients with CLL is 70 years, and an estimated 95% of patients have at least 1 medical comorbidity. Approximately 70% to 80% of patients with CLL are asymptomatic at the time of diagnosis, and one-third will never require treatment for CLL. Prognostic models have been developed to estimate the time to first treatment and the overall survival, but for patients who are asymptomatic, irrespective of disease risk category, clinical observation is the standard of care. Patients with symptomatic disease who have bulky or progressive lymphadenopathy or hepatosplenomegaly and those with a low neutrophil count, anemia, or thrombocytopenia and/or symptoms of fever, drenching night sweats, and weight loss (B symptoms) should be offered treatment. For these patients, first-line treatment consists of a regimen containing either a covalent Bruton tyrosine kinase (BTK) inhibitor (acalabrutinib, zanubrutinib, or ibrutinib) or a B-cell leukemia/lymphoma 2 (BCL2) inhibitor (venetoclax). There is no evidence that starting either class before the other improves outcomes. The covalent BTK inhibitors are typically used indefinitely. Survival rates are approximately 88% at 4 years for acalabrutinib, 94% at 2 years for zanubrutinib, and 78% at 7 years for ibrutinib. Venetoclax is prescribed in combination with obinutuzumab, a monoclonal anti-CD20 antibody, in first-line treatment for 1 year (overall survival, 82% at 5-year follow-up). A noncovalent BTK inhibitor, pitobrutinib, has shown an overall response rate of more than 70% after failure of covalent BTK inhibitors and venetoclax. Phosphoinositide 3'-kinase (PI3K) inhibitors (idelalisib
Pirtobrutinib, a noncovalent, Bruton tyrosine kinase inhibitor (BTKi), has shown clinical efficacy and a favorable safety profile. BRUIN CLL-321 was an open-label, randomized phase III study conducted exclusively in patients with R/R chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) previously treated with cBTKi, and compared pirtobrutinib with investigator's choice (IC) of idelalisib/rituximab (IdelaR) or bendamustine/rituximab (BR). Patients were randomly assigned 1:1 to receive pirtobrutinib (200 mg once daily) or IC of IdelaR or BR, and were stratified by previous use of venetoclax and del(17p). The primary end point was independent review committee-assessed progression-free survival (PFS). Secondary end points included time to next treatment or death (TTNT), overall survival (OS), and safety. The primary PFS end point was met at the time of the primary analysis (August 29, 2023), and updated results are reported from the final OS analysis (August 29, 2024). A total of 238 patients were randomly assigned to receive pirtobrutinib (n = 119) or IC (n = 119; IdelaR [n = 82], BR [n = 37]). The PFS hazard ratio (HR) was 0.54 ([95% CI, 0.39 to 0.75]; P = .0002), with a median PFS of 14 months (95% CI, 11.2 to 16.6) in the pirtobrutinib group and 8.7 months (95% CI, 8.1 to 10.4) with IC. The unadjusted OS HR was 1.09 ([95% CI, 0.68 to 1.75]; P = .7202), and 18-month OS rate was 73.4% (95% CI, 63.9 to 80.7) in the pirtobrutinib group and 70.8% (95% CI, 60.9 to 78.7) with IC. Median TTNT was 24 months (95% CI, 17.8 to 29.7) with pirtobrutinib versus 10.9 months (95% CI, 8.7 to 12.5) with IC (HR, 0.37 [95% CI, 0.25 to 0.52]). At a median follow-up of 17.2 months, grade ≥3 treatment-emergent adverse events (AEs) were lower with pirtobrutinib (57.7%) than IC (73.4%). Treatment discontinuation due to AE occurred in 20 (17.2%) patients receiving pirtobrutinib and 38 (34.9%) patients receiving IC. Pirtobrutinib improved PFS and TTNT, and demonstrated favorable
Autoimmune phenomena, particularly autoimmune cytopenias (AIC), are common complications in patients with chronic lymphocytic leukemia (CLL), arising from the interplay of predisposing genetic and immunologic conditions and extrinsic triggering factors, such as infections and drugs. In this article, we provide insights into the pathogenesis of CLL-associated AIC, discuss diagnostic criteria and treatment recommendations, and present the most recent data on the impact of targeted agents on the management of AIC.
Bruton tyrosine kinase inhibitors (BTKis) have led to changes in the treatment algorithm for patients with high-risk relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), defined based on the presence of genetic mutations. Given the lack of head-to-head trials comparing next-generation BTKis used to treat high-risk R/R disease, a network meta-analysis (NMA) was performed to estimate their relative efficacy. High-risk populations were defined based on the prespecified definitions within each trial, including patients with del(17p) and/or TP53 mutations in the ALPINE (n = 150) and ASCEND (n = 86) trials, and del(17p)/del(11q) in the ELEVATE-RR (n = 533) trial. Bayesian NMAs found zanubrutinib to be the most efficacious treatment for high-risk patients, with significantly reduced risk of progression or death compared with ibrutinib (hazard ratio [HR], 0.49; 95% credible interval [CrI], 0.31-0.78), acalabrutinib (HR, 0.55; 95% CrI, 0.32-0.94), and bendamustine + rituximab or idelalisib + rituximab (BR/IR; HR, 0.12; 95% CrI, 0.05-0.26). Differences in overall survival demonstrated a numerical trend favoring zanubrutinib (probability better than ≥80%) compared with ibrutinib (HR, 0.59; 95% CrI, 0.31-1.11), acalabrutinib (HR, 0.72; 95% CrI, 0.35-1.50), and BR/IR (HR, 0.65; 95% CrI, 0.23-1.75). Rates of response also demonstrated trends favoring zanubrutinib compared with acalabrutinib, with significant results compared with ibrutinib. The NMA suggests that the most efficacious BTKi for patients with high-risk R/R CLL is zanubrutinib.