duvelisib
Sources réglementaires consultées
Indications approuvées
- Leucémie lymphoïde chronique ou lymphome lymphocytique en rechute ou réfractaire chez l’adulte après au moins deux lignes systémiques. Il n’est ni indiqué ni recommandé en première ou deuxième ligne en raison d’une mortalité liée au traitement accrue.
Contre-indications
Absolues
- L’étiquette FDA n’établit aucune contre-indication formelle.
Mises en garde cliniques
- Avertissement encadré : mortalité liée au traitement 15 % ; infections graves ou mortelles 31 %, diarrhée/colite grave ou mortelle 18 %, réactions cutanées graves ou mortelles 5 % et pneumopathie grave ou mortelle 5 %. Surveiller et suspendre immédiatement en cas de suspicion ; ne reprendre qu’après contrôle de la toxicité et arrêter définitivement en cas de toxicité confirmée menaçant le pronostic vital ou lorsque le RCP l’impose. — OpenFDA, set_id e3c5ac56-e1f6-473a-bc73-687836534780
- Traiter les infections avant le début. Suspendre en cas d’infection de grade ≥3, suspicion de PJP, diarrhée/colite non contrôlée, réaction cutanée grave ou pneumopathie ; arrêter définitivement si PJP, SJS/NET/DRESS ou toxicité menaçant le pronostic vital est confirmée. Surveiller fonction hépatique et NFS. — OpenFDA, set_id e3c5ac56-e1f6-473a-bc73-687836534780
Interactions médicamenteuses
- SévèreInhibiteurs puissants du CYP3A4
Mécanisme: Ils augmentent l’exposition au duvélisib.
Recommandation: Réduire à 15 mg deux fois par jour.
OpenFDA, set_id e3c5ac56-e1f6-473a-bc73-687836534780
- SévèreInducteurs puissants ou modérés du CYP3A4
Mécanisme: Ils réduisent l’exposition au duvélisib et peuvent diminuer son efficacité.
Recommandation: Éviter. Si un inducteur modéré est indispensable, appliquer l’augmentation dès le jour 12 puis revenir à la dose antérieure 14 jours après son arrêt.
OpenFDA, set_id e3c5ac56-e1f6-473a-bc73-687836534780
- SévèreSubstrats sensibles du CYP3A4
Mécanisme: Le duvélisib augmente leur exposition et le risque de toxicité.
Recommandation: Envisager de réduire le substrat et surveiller la toxicité.
OpenFDA, set_id e3c5ac56-e1f6-473a-bc73-687836534780
Effets indésirables
Communs (≥1%)
diarrhée ou colite · neutropénie · éruption cutanée · fatigue · fièvre · toux · nausées · infection respiratoire haute · pneumonie · douleur musculosquelettique · anémie
Grossesse et allaitement
Peut provoquer une atteinte fœtale. Vérifier l’absence de grossesse avant traitement. Les femmes et les hommes ayant une partenaire susceptible de concevoir doivent utiliser une contraception efficace pendant le traitement et pendant 1 mois après. Ne pas allaiter pendant le traitement ni pendant 1 mois après la dernière dose.
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
PI3K-δ inhibitors have shown impressive activity in lymphoid malignancies but have been hampered by autoimmune and infectious toxicities, leading to market withdrawals. We previously demonstrated activity of the PI3K-δγ inhibitor duvelisib in T cell lymphomas (TCLs) that was associated with inflammatory adverse events. As reported here, we conducted a phase 1b/2a study of duvelisib in combination with either romidepsin (n = 66) or bortezomib (n = 32) in patients with relapsed/refractory TCL and found that the addition of romidepsin, but not bortezomib, appeared to increase efficacy while attenuating PI3K inhibitor-driven toxicity. The primary endpoint of the study was to determine the safety and maximum tolerated dose of duvelisib, which was 75 mg twice daily when combined with romidepsin versus 25 mg twice daily when combined with bortezomib. The most common adverse events were neutropenia (42%, 25/59) and fatigue (37%, 22/59) in patients treated with duvelisib and romidepsin and diarrhea (48%, 11/23) and neutropenia (30%, 7/23) in patients treated with duvelisib and bortezomib. Duvelisib and romidepsin resulted in less grade 3/4 hepatotoxicity (14%, 8/59) compared to 40% (14/35) in our previous study with duvelisib monotherapy. This was associated with reductions in circulating inflammatory mediators and myeloid cell inflammatory gene expression. Secondary endpoints of overall and complete response rates were 55% (35/64) and 34% (22/64) for patients treated with duvelisib and romidepsin and 34% (11/32) and 13% (4/32) for patients treated with duvelisib and bortezomib. Among patients with peripheral T cell lymphomas (PTCLs), overall and complete response rates of duvelisib and romidepsin were 56% (27/48) and 44% (21/48), respectively, with exploratory analyses showing increased response rates in patients with a follicular helper T cell subtype. These findings support further development of combined PI3K and histone deacetylase (HDAC) inhibition in TCLs and suggest
The administration of antifungals for therapeutic and, especially, prophylactic purposes is virtually a constant in patients requiring hematology-oncology treatment. Any attempt to prevent or treat Aspergillus or Mucor infections requires the administration of some drugs in the azole group, which include voriconazole, posaconazole and isavuconazole, noted for their activity against these pathogens. One very relevant aspect is the potential risk of interaction when associated with one of the antineoplastic drugs used to treat hematologic tumors, with serious complications. In this regard, acalabrutinib, bortezomib, bosutinib, carfilzomib, cyclophosphamide, cyclosporine A, dasatinib, duvelisib, gilteritinib, glasdegib, ibrutinib, imatinib, nilotinib, ponatinib, prednisone, ruxolitinib, tacrolimus, all-transretinoic acid, arsenic trioxide, venetoclax, or any of the vinca alkaloids, are very clear examples of risk, in some cases because their clearance is reduced and in others because of increased risk of QTc prolongation, which is particularly evident when the drug of choice is voriconazole or posaconazole. La administración de antifúngicos con fines terapéuticos y especialmente, profilácticos es casi un constante en el paciente que precisa tratamiento oncohematológico. El intento de evitar o de tratar infecciones por Aspergillus o por Mucor exige la administración de algunos fármacos pertenecientes al grupo de los azoles, entre los que destacan por su actividad frente a estos patógenos, voriconazol, posaconazol e isavuconazol. Un aspecto de gran importancia es el riesgo potencial de interacciones cuando se asocian a alguno de los fármacos antineoplásico utilizados en el tratamiento de los tumores hematológicos, dando lugar a graves complicaciones. En este sentido, acalabrutinib, bortezomid, bosutinib, carfizolid, ciclofosfamida, ciscloporina A, dasatinib, duvelisib, gilteritinib, glasdegib, ibrutinib, imatinib, nilotinib, ponatinib, prednisona, ruxolitinib, tacrolimus