ibrutinib
Sources réglementaires consultées
Indications approuvées
- Leucémie lymphoïde chronique ou lymphome lymphocytique, y compris avec délétion 17p, et macroglobulinémie de Waldenström chez l’adulte ; maladie chronique du greffon contre l’hôte après échec d’au moins une ligne systémique chez l’adulte et l’enfant dès 1 an.
- Lymphome à cellules du manteau non traité chez l’adulte éligible à la greffe selon le schéma combiné spécifié, ou maladie en rechute/réfractaire en monothérapie ; leucémie lymphoïde chronique et macroglobulinémie de Waldenström selon les schémas et lignes autorisés par le RCP CIMA.
Contre-indications
Absolues
- CIMA : hypersensibilité à l’ibrutinib ou aux excipients et préparations à base de millepertuis ; l’étiquette FDA n’établit aucune contre-indication formelle.
Mises en garde cliniques
- Peut provoquer une hémorragie grave ou mortelle. Évaluer le risque avec anticoagulants ou antiagrégants et suspendre au moins 3–7 jours avant et après une chirurgie selon le risque de l’intervention. — OpenFDA, set_id 0dfd0279-ff17-4ea9-89be-9803c71bab44
- Surveiller infections, arythmies, insuffisance cardiaque, mort subite, hypertension, cytopénies, hépatotoxicité et syndrome de lyse tumorale. Réaliser une NFS mensuelle, surveiller la fonction hépatique et évaluer immédiatement les symptômes cardiaques ou infectieux. — OpenFDA, set_id 0dfd0279-ff17-4ea9-89be-9803c71bab44
Interactions médicamenteuses
- SévèreWarfarine ou autres antivitamines K
Mécanisme: L’association majore un risque hémorragique déjà accru avec l’ibrutinib.
Recommandation: Ne pas administrer concomitamment.
CIMA/AEMPS, ficha técnica 114945001
- SévèreInhibiteurs puissants ou modérés du CYP3A
Mécanisme: Ils augmentent l’exposition à l’ibrutinib et le risque de toxicité.
Recommandation: Éviter si possible les inhibiteurs puissants ; appliquer l’adaptation propre à l’indication. Si l’inhibiteur puissant est utilisé ≤7 jours, interrompre temporairement l’ibrutinib.
OpenFDA, set_id 0dfd0279-ff17-4ea9-89be-9803c71bab44
- SévèreInducteurs puissants ou modérés du CYP3A4, pamplemousse ou orange amère
Mécanisme: Les inducteurs diminuent l’exposition ; le pamplemousse et l’orange amère peuvent l’augmenter.
Recommandation: Éviter les inducteurs puissants ou modérés, le pamplemousse et l’orange amère ; le millepertuis est contre-indiqué selon le RCP CIMA.
CIMA/AEMPS, ficha técnica 114945001
Effets indésirables
Communs (≥1%)
diarrhée · neutropénie · douleur musculosquelettique · saignement ou ecchymoses · éruption cutanée · nausées · thrombopénie · infection des voies respiratoires supérieures
Grossesse et allaitement
Peut provoquer une atteinte fœtale et ne doit pas être utilisé pendant la grossesse. Le RCP CIMA exige une contraception très efficace chez la femme pendant le traitement et pendant 3 mois après ; la FDA exige une contraception chez les femmes et les hommes pendant le traitement et pendant 1 mois après. Ne pas allaiter pendant le traitement ni pendant 1 semaine après la dernière dose.
Bibliographie récente (PubMed)
The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m2 once daily; days 1 and 2) and rituximab (375 mg/m2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.
Among Bruton's tyrosine kinase inhibitors, acalabrutinib has greater selectivity than ibrutinib, which we hypothesized would improve continuous therapy tolerability. We conducted an open-label, randomized, noninferiority, phase III trial comparing acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia (CLL). Patients with previously treated CLL with centrally confirmed del(17)(p13.1) or del(11)(q22.3) were randomly assigned to oral acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until progression or unacceptable toxicity. The primary end point was independent review committee-assessed noninferiority of progression-free survival (PFS). Overall, 533 patients (acalabrutinib, n = 268; ibrutinib, n = 265) were randomly assigned. At the data cutoff, 124 (46.3%) acalabrutinib patients and 109 (41.1%) ibrutinib patients remained on treatment. After a median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib with a median PFS of 38.4 months in both arms (95% CI acalabrutinib, 33.0 to 38.6 and ibrutinib, 33.0 to 41.6; hazard ratio: 1.00; 95% CI, 0.79 to 1.27). All-grade atrial fibrillation/atrial flutter incidence was significantly lower with acalabrutinib versus ibrutinib (9.4% v 16.0%; P = .02); among other selected secondary end points, grade 3 or higher infections (30.8% v 30.0%) and Richter transformations (3.8% v 4.9%) were comparable between groups and median overall survival was not reached in either arm (hazard ratio, 0.82; 95% CI, 0.59 to 1.15), with 63 (23.5%) deaths with acalabrutinib and 73 (27.5%) with ibrutinib. Treatment discontinuations because of adverse events occurred in 14.7% of acalabrutinib-treated patients and 21.3% of ibrutinib-treated patients. In this first direct comparison of less versus more selective Bruton's tyrosine kinase inhibitors in CLL, acalabrutinib demonstrated noninferior PFS with fewer cardiovascular adverse events.
Treatment of chronic lymphocytic leukemia (CLL) currently consists of two main approaches - continuous therapy with Bruton's tyrosine kinase inhibitors and fixed-duration regimens combining venetoclax with either CD20 antibodies or Bruton's tyrosine kinase inhibitors. Comparisons of these two therapeutic approaches are lacking. We conducted an investigator-initiated, phase 3, randomized trial involving patients with previously untreated CLL. Patients were randomly assigned to receive continuous ibrutinib or fixed-duration venetoclax-obinutuzumab or venetoclax-ibrutinib. The primary end point was investigator-assessed progression-free survival (noninferiority margin for the hazard ratio, 1.608, corresponding to a noninferiority margin of 8 percentage points at 3 years). Secondary end points included minimal residual disease (MRD), response, overall survival, and safety. A total of 909 patients were assigned to venetoclax-obinutuzumab (303 patients), venetoclax-ibrutinib (305 patients), or ibrutinib (301 patients). The median follow-up was 34.2 months. In this prespecified interim analysis, 3-year progression-free survival was 81.1% in the venetoclax-obinutuzumab group, 79.4% in the venetoclax-ibrutinib group, and 81.0% in the ibrutinib group (hazard ratio for venetoclax-obinutuzumab vs. ibrutinib, 0.87 [98.3% confidence interval {CI}, 0.54 to 1.41]; hazard ratio for venetoclax-ibrutinib vs. ibrutinib, 0.84 [98.0% CI, 0.53 to 1.32]); the results for each comparison met the criterion for noninferiority. After the end of treatment, MRD in peripheral blood was undetectable in 73.3% of the patients in the venetoclax-obinutuzumab group, 47.2% in the venetoclax-ibrutinib group, and 0% in the ibrutinib group. Three-year overall survival was 91.5%, 96.0%, and 95.7%, respectively. The most common adverse events were infections, gastrointestinal disorders, and cytopenias. In patients with previously untreated CLL, fixed-duration treatment with venetoclax-obinutuzumab or venetoc
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
Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment landscape for B cell lymphomas such as chronic lymphocytic leukemia (CLL). The first-in-class BTK inhibitor ibrutinib has recently been succeeded by covalent BTK inhibitors that are safer but still face challenges of resistance mutations. The noncovalent BTK inhibitor pirtobrutinib was recently approved for relapsed and refractory CLL, and whether noncovalent BTK inhibitors will supplant covalent BTK inhibitors as upfront treatment options either alone or in combination will be determined. Meanwhile, newer BTK inhibitors and BTK degraders are vying for their place in the potential future landscape of B cell cancers as well as autoimmune diseases. This review will cover the latest progress in BTK inhibitor development and where the field is moving in light of these recent discoveries.