gilteritinib
Sources réglementaires consultées
Indications approuvées
- En monothérapie chez l’adulte atteint de leucémie aiguë myéloïde en rechute ou réfractaire avec mutation FLT3 confirmée.
Contre-indications
Absolues
- Hypersensibilité au giltéritinib ou à ses excipients.
Mises en garde cliniques
- Mise en garde encadrée · AVERTISSEMENT ENCADRÉ : peut provoquer un syndrome de différenciation potentiellement mortel ou fatal. En cas de fièvre, dyspnée, prise de poids rapide, œdème, infiltrats pulmonaires, épanchements, hypotension ou atteinte rénale, commencer immédiatement les corticoïdes et la surveillance hémodynamique. — DailyMed, XOSPATA set_id b5ff59aa-9c0d-49a8-9053-1f179b482383
- Mise en garde majeure · Surveiller le QTc et les électrolytes : réaliser un ECG avant le traitement, aux jours 8 et 15 du premier cycle puis avant les trois mois suivants. Corriger l’hypokaliémie et l’hypomagnésémie. — CIMA/AEMPS, ficha técnica XOSPATA 40 mg, registro 1191399001
- Mise en garde majeure · Peut provoquer un syndrome d’encéphalopathie postérieure réversible et une pancréatite. Arrêter définitivement en cas de PRES ; suspendre puis réduire après une pancréatite. — CIMA/AEMPS, ficha técnica XOSPATA 40 mg, registro 1191399001
Interactions médicamenteuses
- SévèreInducteurs puissants du CYP3A, de la P-gp ou de la BCRP
Mécanisme: Ils réduisent fortement l’exposition et peuvent diminuer l’efficacité.
Recommandation: Éviter l’association, y compris le millepertuis.
CIMA/AEMPS, ficha técnica XOSPATA 40 mg, registro 1191399001https://cima.aemps.es/cima/dochtml/ft/1191399001/FT_1191399001.html
- SévèreInhibiteurs puissants du CYP3A, de la P-gp ou de la BCRP
Mécanisme: Ils augmentent l’exposition et peuvent accroître la toxicité.
Recommandation: Préférer une alternative ; si l’association est inévitable, surveiller étroitement les effets indésirables et la prolongation du QT.
CIMA/AEMPS, ficha técnica XOSPATA 40 mg, registro 1191399001https://cima.aemps.es/cima/dochtml/ft/1191399001/FT_1191399001.html
- ModéréeMédicaments sérotoninergiques ciblant 5-HT2B ou les récepteurs sigma
Mécanisme: Le giltéritinib peut réduire leur effet, y compris celui de certains ISRS.
Recommandation: Éviter l’association sauf si elle est indispensable ; surveiller la réponse clinique.
CIMA/AEMPS, ficha técnica XOSPATA 40 mg, registro 1191399001https://cima.aemps.es/cima/dochtml/ft/1191399001/FT_1191399001.html
Effets indésirables
Communs (≥1%)
élévation de l’ALT · élévation de l’AST · élévation de la phosphatase alcaline · élévation de la CPK · diarrhée · fatigue · nausées · constipation · toux · œdème périphérique · dyspnée · vertiges
Rares mais graves
syndrome d’encéphalopathie postérieure réversible
Grossesse et allaitement
Peut provoquer une toxicité embryofœtale. Vérifier la grossesse dans les 7 jours précédant le début. Les femmes doivent utiliser une contraception efficace pendant le traitement et pendant 6 mois après ; ajouter une méthode barrière avec une contraception hormonale. Les hommes doivent utiliser une contraception pendant le traitement et pendant 4 mois après. Ne pas allaiter pendant le traitement ni pendant 2 mois après.
Bibliographie récente (PubMed)
Azacitidine plus venetoclax is a standard of care for patients with newly diagnosed AML who are unfit for intensive chemotherapy. However, FLT3 mutations are a common mechanism of resistance to this regimen. The addition of gilteritinib, an oral FLT3 inhibitor, to azacitidine and venetoclax may improve outcomes in patients with FLT3-mutated AML. This phase I/II study evaluated azacitidine, venetoclax, and gilteritinib in two cohorts: patients with (1) newly diagnosed FLT3-mutated AML who were unfit for intensive chemotherapy or (2) relapsed/refractory FLT3-mutated AML (ClinicalTrials.gov identifier: NCT04140487). The primary end points were the maximum tolerated dose of gilteritinib (phase I) and the combined complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate (phase II). Fifty-two patients were enrolled (frontline [n = 30]; relapsed/refractory [n = 22]). The recommended phase II dose was gilteritinib 80 mg once daily in combination with azacitidine and venetoclax. In the frontline cohort, the median age was 71 years and 73% of patients had an FLT3-internal tandem duplication (ITD) mutation. The CR/CRi rate was 96% (CR, 90%; CRi, 6%). Sixty-five percent of evaluable patients achieved FLT3-ITD measurable residual disease <5 × 10-5 within four cycles. With a median follow-up of 19.3 months, the median relapse-free survival (RFS) and overall survival (OS) have not been reached and the 18-month RFS and OS rates are 71% and 72%, respectively. In the relapsed/refractory cohort, the CR/CRi rate was 27%; nine additional patients (41%) achieved a morphologic leukemia-free state. The most common grade 3 or higher nonhematologic adverse events were infection (62%) and febrile neutropenia (38%), which were more frequent in the relapsed/refractory cohort. The combination of azacitidine, venetoclax, and gilteritinib resulted in high rates of CR/CRi, deep FLT3 molecular responses, and encouraging survival in newly diagnosed FLT3-mutated AML. Myelosuppression
The first 5 decades of research in acute myeloid leukemia (AML) were dominated by the cytarabine plus anthracyclines backbone, with advances in strategies including allogeneic hematopoietic stem cell transplantation, high-dose cytarabine, supportive care measures, and targeted therapies for the subset of patients with acute promyelocytic leukemia. Since 2017, a turning point in AML research, 12 agents have received regulatory approval for AML in the United States: venetoclax (BCL2 inhibitor); gemtuzumab ozogamicin (CD33 antibody-drug conjugate); midostaurin, gilteritinib, and quizartinib (fms-like tyrosine kinase 3 inhibitors); ivosidenib, olutasidenib, and enasidenib (isocitrate dehydrogenase 1 and 2 inhibitors); oral azacitidine (a partially absorbable formulation); CPX351 (liposomal encapsulation of cytarabine:daunorubicin at a molar ratio of 5:1); glasdegib (hedgehog inhibitor); and recently revumenib (menin inhibitor; approved November 2024). Oral decitabine-cedazuridine, which is approved as a bioequivalent alternative to parenteral hypomethylating agents in myelodysplastic syndrome, can be used for the same purpose in AML. Menin inhibitors, CD123 antibody-drug conjugates, and other antibodies targeting CD123, CD33, and other surface markers are showing promising results. Herein, the authors review the frontline and later line therapies in AML and discuss important research directions.
Acute myeloid leukemia (AML) is a clonal hematopoietic cancer that disrupts normal hematopoiesis, ultimately leading to bone marrow failure and death. The annual incidence rate of AML is 4.1 per 100 000 people in the US and is higher in patients older than 65 years. Acute myeloid leukemia includes numerous subgroups with heterogeneous molecular profiles, treatment response, and prognosis. This review discusses the evidence supporting frontline therapies in AML, the major principles that guide therapy, and progress with molecularly targeted therapy. Acute myeloid leukemia is a genetically complex, dynamic disease. The most commonly altered genes include FLT3, NPM1, DNMT3A, IDH1, IDH2, TET2, RUNX1, NRAS, and TP53. The incidence of these alterations varies by patient age, history of antecedent hematologic cancer, and previous exposure to chemotherapy and/or radiotherapy for any cancer. Since 2010, molecular data have been incorporated into AML prognostication, gradually leading to incorporation of targeted therapies into the initial treatment approach of induction chemotherapy and subsequent management. The first molecularly targeted inhibitor, midostaurin, was approved to treat patients with AML with FLT3 variants in 2017. Since then, the understanding of the molecular pathogenesis of AML has expanded, allowing the identification of additional potential targets for drug therapy, treatment incorporation of molecularly targeted therapies (midostaurin, gilteritinib, and quizartinib targeting FLT3 variants; ivosidenib and olutasidenib targeting IDH1 variants, and enasidenib targeting IDH2), and identification of rational combination regimens. The approval of hypomethylating agents combined with venetoclax has revolutionized the therapy of AML in older adults, extending survival over monotherapy. Additionally, patients are now referred for hematopoietic cell transplant on a more rational basis. In the era of genomic medicine, AML treatment is customized to the patient's co
Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 (FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.
The understanding of the molecular pathobiology of acute myeloid leukemia (AML) has spurred the identification of therapeutic targets and the development of corresponding novel targeted therapies. Since 2017, twelve agents have been approved for the treatment of AML subsets: the BCL2 inhibitor venetoclax; the CD33 antibody drug conjugate gemtuzumab ozogamicin; three FLT3 inhibitors (midostaurin, gilteritinib, quizartinib); three IDH inhibitors (ivosidenib and olutasidenib targeting IDH1 mutations; enasidenib targeting IDH2 mutations); two oral hypomethylating agents (oral poorly absorbable azacitidine; fully absorbable decitabine-cedazuridine [latter approved as an alternative to parenteral hypomethylating agents in myelodysplastic syndrome and chronic myelomonocytic leukemia but commonly used in AML]); and CPX-351 (encapsulated liposomal 5:1 molar ratio of cytarabine and daunorubicin), and glasdegib (hedgehog inhibitor). Other targeted therapies (menin inhibitors, CD123 antibody-drug conjugates) are showing promising results. To achieve optimal results in such a rare and heterogeneous entity as AML requires expertise, familiarity with this rare cancer, and the access to, and delivery of disparate therapies under rigorous supportive care conditions. In this review, we update the standard-of-care and investigational therapies and outline promising current and future research directions.