midostaurin
Sources réglementaires consultées
Indications approuvées
- Chez l’adulte atteint de leucémie aiguë myéloïde FLT3 positive nouvellement diagnostiquée, avec induction par daunorubicine et cytarabine, consolidation par cytarabine à haute dose puis, en cas de réponse complète, entretien en monothérapie.
- Chez l’adulte atteint de mastocytose systémique agressive, mastocytose systémique associée à une hémopathie ou leucémie à mastocytes.
Contre-indications
Absolues
- Hypersensibilité à la midostaurine ou à ses excipients.
- Utilisation concomitante d’inducteurs puissants du CYP3A4.
Mises en garde cliniques
- Mise en garde majeure · Des pneumopathies interstitielles et pneumonites, parfois mortelles, sont survenues. Surveiller les symptômes pulmonaires et arrêter définitivement en cas de toxicité pulmonaire de grade 3 ou plus non expliquée par une infection. — DailyMed, RYDAPT set_id 11fa3fc9-6776-49a6-b1c1-653f627c3e58
- Mise en garde majeure · Peut prolonger le QT et provoquer cytopénies et infections. Surveiller ECG et électrolytes chez les patients à risque ou avec des médicaments prolongeant le QT, et contrôler régulièrement la numération sanguine. — CIMA/AEMPS, ficha técnica RYDAPT 1171218001
Interactions médicamenteuses
- SévèreInducteurs puissants du CYP3A4
Mécanisme: Ils réduisent fortement l’exposition à la midostaurine et à ses métabolites actifs.
Recommandation: L’association est contre-indiquée.
CIMA/AEMPS, ficha técnica RYDAPT 1171218001https://cima.aemps.es/cima/dochtml/ft/1171218001/FT_1171218001.html
- SévèreInhibiteurs puissants du CYP3A4
Mécanisme: Ils peuvent augmenter l’exposition et la toxicité de la midostaurine.
Recommandation: Préférer une alternative sans forte inhibition du CYP3A4 ; si l’association est inévitable, surveiller étroitement la toxicité, surtout au début.
DailyMed, RYDAPT set_id 11fa3fc9-6776-49a6-b1c1-653f627c3e58https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=11fa3fc9-6776-49a6-b1c1-653f627c3e58
- ModéréeSubstrats du CYP2B6, de la BCRP ou de l’OATP1B1
Mécanisme: La midostaurine peut modifier leur exposition.
Recommandation: Surveiller l’efficacité et la toxicité du substrat et ajuster sa dose si nécessaire.
DailyMed, RYDAPT set_id 11fa3fc9-6776-49a6-b1c1-653f627c3e58https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=11fa3fc9-6776-49a6-b1c1-653f627c3e58
Effets indésirables
Communs (≥1%)
neutropénie fébrile · nausées · dermatite exfoliative · vomissements · céphalées · pétéchies · fièvre
Grossesse et allaitement
Peut provoquer une toxicité embryofœtale. Vérifier la grossesse dans les 7 jours précédant le début et utiliser une contraception efficace pendant le traitement et pendant 4 mois après. Ne pas allaiter pendant le traitement ni pendant les 4 mois suivants.
Bibliographie récente (PubMed)
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
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.
Mastocytosis is a spectrum of clonal myeloid disorders defined by abnormal growth and accumulation of mast cells in various organ systems. The disease is divided into cutaneous mastocytosis, systemic mastocytosis (SM) and mast cell sarcoma. SM is further categorized into several non-advanced and advanced forms. The prognosis of cutaneous mastocytosis and non-advanced SM is mostly favourable, whereas prognosis and survival in advanced SM and mast cell sarcoma are poor. During the past 15 years, major advances have been made in the diagnosis, prognosis and management of patients with mast cell neoplasms. Management of mastocytosis consists of symptomatic therapy, including anti-mast cell mediator drugs, and cytoreductive agents for patients with advanced disease and selected individuals with non-advanced disease, as well as recognition and prevention of comorbidities such as osteoporosis and anaphylaxis. The preclinical and clinical development of KIT-D816V-targeting drugs, such as midostaurin or avapritinib, mark a milestone in improving management, the quality of life and survival in patients with SM. These agents induce major responses or even remission in people with advanced SM and lead to rapid improvement of mediator-related symptoms and quality of life in symptomatic patients.
Since identification of Systemic mastocytosis (SM) as a distinct disease entity by the World Health Organisation (WHO), there has been a wealth of new research in therapeutic targeting of the pathogenic C-KIT D816V mutation. Avapritinib, the first licensed drug in SM capable of disease modification alongside the increasingly potent, oral and highly selective KIT tyrosine kinase inhibitors (TKIs) Bezuclastinib and now Elenestinib have enabled the prospect of long-term remissions. Studies have shown improved survival and symptomatic control in patients with SM. Of great triumph, this has been achieved in an outpatient setting with apparent tolerable and minimal toxicity. The importance of molecular profiling is being demonstrated in administering combination therapies for SM with an associated haematological neoplasm (AHN), allowing more personalised and streamlined treatment regimes. This review focuses on current management strategies of SM, focusing on state-of-the-art directed therapies, the evidence behind their use with presentation of two clinical cases to highlight key messages.