fedratinib
Sources réglementaires consultées
Indications approuvées
- Myélofibrose primitive ou secondaire de risque intermédiaire-2 ou élevé chez l’adulte.
- Splénomégalie ou symptômes liés à une myélofibrose primitive, post-polyglobulie de Vaquez ou post-thrombocytémie essentielle chez l’adulte naïf d’inhibiteur de JAK ou déjà traité par ruxolitinib.
Contre-indications
Absolues
- CIMA : hypersensibilité au fédratinib ou aux excipients et grossesse ; l’étiquette FDA n’établit aucune contre-indication formelle.
Mises en garde cliniques
- Peut provoquer une encéphalopathie grave ou mortelle, notamment de Wernicke. Contrôler et corriger la thiamine avant le traitement, administrer 100 mg/jour et, en cas de suspicion, arrêter immédiatement et donner de la thiamine parentérale. — OpenFDA, set_id f0f55a2a-4e0c-4cba-8571-03e1424486d7
- Surveiller NFS, fonction hépatique, amylase et lipase. Traiter précocement la toxicité digestive et modifier la dose en cas d’anémie, thrombopénie, hépatotoxicité ou élévation des enzymes pancréatiques. — OpenFDA, set_id f0f55a2a-4e0c-4cba-8571-03e1424486d7
Interactions médicamenteuses
- SévèreInhibiteurs puissants du CYP3A4
Mécanisme: Ils augmentent l’exposition au fédratinib.
Recommandation: Réduire à 200 mg/jour et appliquer le schéma de remontée du RCP après arrêt de l’inhibiteur.
OpenFDA, set_id f0f55a2a-4e0c-4cba-8571-03e1424486d7
- SévèreInducteurs puissants ou modérés du CYP3A4
Mécanisme: Ils peuvent réduire l’exposition et l’efficacité du fédratinib.
Recommandation: Éviter l’association.
OpenFDA, set_id f0f55a2a-4e0c-4cba-8571-03e1424486d7
Effets indésirables
Communs (≥1%)
diarrhée · nausées · anémie · vomissements
Grossesse et allaitement
Le RCP CIMA contre-indique l’utilisation pendant la grossesse. Utiliser une contraception efficace pendant le traitement et pendant au moins 1 mois après la dernière dose. Ne pas allaiter pendant le traitement ni pendant au moins 1 mois après la dernière dose.
Bibliographie récente (PubMed)
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell-derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR, or MPL mutations; additional features include bone marrow reticulin/collagen fibrosis, aberrant inflammatory cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, risk of leukemic progression, and shortened survival. Bone marrow examination with cytogenetic and mutation studies provides integrated diagnostic information; presence of JAK2, CALR or MPL mutation is expected but not required. The International Consensus Classification distinguishes "prefibrotic" from "overtly fibrotic" PMF; the former might mimic essential thrombocythemia (ET) in its presentation. Approximately 15% of patients with ET or polycythemia vera (PV) might progress into post-ET/PV MF. SRSF2, ASXL1, and U2AF1-Q157 mutations predict inferior survival in PMF; RAS/CBL mutations predict resistance to ruxolitinib therapy. Type 1/like CALR mutation is associated with superior survival. Very high-risk abnormalities include -7, inv (3), i(17q), +21, +19, 12p- and 11q-. Favorable risk abnormalities include normal karyotype or isolated +9, 13q-, 20q-, 1q abnormalities and loss of Y chromosome. Contemporary prognostic systems include GIPSS (genetically-inspired prognostic scoring system) and MIPSS70+ version 2.0 (MIPSSv2; mutation-and karyotype-enhanced international prognostic scoring system). GIPSS is based exclusively on mutations and karyotype; MIPSSv2 includes, in addition, clinical risk factors. Observation alone is advised for MIPSSv2 "low" and "very low" risk disease (estimated 10-year survival 56%-92%); allogeneic hematopoietic stem cell transplant (AHSCT) is the preferred treatment of choice for "very high" and "high" risk disease (estimated 10-year survival 0-13%), as well as in carefully selected patients with intermediate-risk disease (estimated 1
The clinical phenotype of primary and post-polycythemia vera and postessential thrombocythemia myelofibrosis (MF) is dominated by splenomegaly, symptomatology, a variety of blood cell alterations, and a tendency to develop vascular complications and blast phase. Diagnosis requires assessing complete cell blood counts, bone marrow morphology, deep genetic evaluations, and disease history. Driver molecular events consist of JAK2V617F, CALR, and MPL mutations, whereas about 8% to 10% of MF are "triple-negative." Additional myeloid-gene variants are described in roughly 80% of patients. Currently available clinical-based and integrated clinical/molecular-based scoring systems predict the survival of patients with MF and are applied for conventional treatment decision-making, indication to stem cell transplant (SCT) and allocation in clinical trials. Standard treatment consists of anemia-oriented therapies, hydroxyurea, and JAK inhibitors such as ruxolitinib, fedratinib, and pacritinib. Overall, spleen volume reduction of 35% or greater at week 24 can be achieved by 42% of ruxolitinib-, 47% of fedratinib-, 19% of pacritinib-, and 27% of momelotinib-treated patients. Now, it is time to move towards new paradigms for evaluating efficacy like disease modification, that we intend as a robust and unequivocal effect on disease biology and/or on patient survival. The growing number of clinical trials potentially pave the way for new strategies in patients with MF. Translational studies of some molecules showed an early effect on bone marrow fibrosis and on variant allele frequencies of myeloid genes. SCT is still the only curative option, however, it is associated with relevant challenges. This review focuses on the diagnosis, prognostication, and treatment of MF. Fedratinib is an oral selective inhibitor of Janus associated kinase 2 (JAK-2) and FMS-like tyrosine kinase 3 (FLT3) that is used in the therapy of intermediate or high-risk, primary or secondary myelofibrosis. Fedrat
While allogeneic hematopoietic stem cell transplantation remains the only curative therapy for patients with myelofibrosis, its applicability is limited both by the high morbidity and mortality associated with the procedure and by the fact that only a minority of patients are eligible due to age or comorbidities. Ruxolitinib, a JAK1/JAK2 inhibitor, is the standard first-line therapy for intermediate- and high-risk MF, offering symptom relief and splenic volume reduction but lacking a clear survival benefit. Its use may be limited by hematologic toxicities, increased infection risk, and an inability to prevent disease progression. Ruxolitinib failure remains a significant clinical challenge, with resistance mechanisms not fully elucidated. The approval of other JAK inhibitors-fedratinib, pacritinib, and momelotinib-has expanded treatment options, particularly for patients with cytopenias or transfusion dependence. Moreover, many other targeted agents are in development in clinical trials, as monotherapy or in combination with ruxolitinib. This review provides an update on the use of JAK inhibitors and novel agents, with a focus on treatment options for ruxolitinib-resistant or refractory patients. As therapeutic strategies evolve, optimizing treatment sequencing and incorporating next-generation sequencing will be critical for improving patient outcomes.
Chronic neutrophilic leukemia (CNL) is a rare BCR::ABL1-negative myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis and bone marrow granulocyte hyperplasia. Atypical chronic myeloid leukemia (aCML) (myelodysplastic "[MDS]/MPN with neutrophilia" per World Health Organization [WHO]) is a MDS/MPN overlap disorder featuring dysplastic neutrophilia and circulating myeloid precursors. Both manifest with frequent hepatosplenomegaly and less commonly, bleeding, with high rates of leukemic transformation and death. The 2022 revised WHO classification conserved CNL diagnostic criteria of leukocytosis ≥25 × 109/L, neutrophils ≥80% with <10% circulating precursors, absence of dysplasia, and presence of an activating CSF3R mutation. ICC criteria are harmonized with those of other myeloid entities, with a key distinction being lower leukocytosis threshold (≥13 × 109/L) for cases CSF3R-mutated. Criteria for aCML include leukocytosis ≥13 × 109/L, dysgranulopoiesis, circulating myeloid precursors ≥10%, and at least one cytopenia for MDS-thresholds (ICC). In both classifications ASXL1 and SETBP1 (ICC), or SETBP1 ± ETNK1 (WHO) mutations can be used to support the diagnosis. Both diseases show hypercellular bone marrow due to a granulocytic proliferation, aCML distinguished by dysplasia in granulocytes ± other lineages. Absence of monocytosis, rare/no basophilia, or eosinophilia, <20% blasts, and exclusion of other MPN, MDS/MPN, and tyrosine kinase fusions, are mandated. Cytogenetic abnormalities are identified in ~1/3 of CNL and ~15-40% of aCML patients. The molecular signature of CNL is a driver mutation in colony-stimulating factor 3 receptor-classically T618I, documented in >80% of cases. Atypical CML harbors a complex genomic backdrop with high rates of recurrent somatic mutations in ASXL1, SETBP1, TET2, SRSF2, EZH2, and less frequently in ETNK1. Leukemic transformation rates are ~10-25% and 30-40% for CNL and aCML, respectively. Overall survi