P997: FEDRATINIB IS EFFECTIVE IN RUXOLITINIB-RESISTANT CELLS: CLINICAL AND PRECLINICAL CORRELATIONS
Notice bibliographique
Résumé
Topic: 15. Myeloproliferative neoplasms - Biology & Translational Research Background: Myelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by a hyperactive JAK-STAT pathway, bone marrow fibrosis, extramedullary hematopoiesis, and splenomegaly. Ruxolitinib (RUX) and fedratinib (FEDR) are JAK inhibitors used for the treatment of patients (pts) with higher-risk MF. Furthermore, FEDR is clinically efficacious in pts previously exposed to RUX (Gupta, et al., Blood 2022: abstract 1711). The cellular and molecular mechanisms of FEDR efficacy in RUX-exposed/resistant pts are not fully understood. Aims: To explore potential mechanisms of FEDR efficacy after RUX exposure using clinical and preclinical data. Methods: In the FREEDOM study (NCT03755518), pts with MF (N=38) received FEDR 400 mg once daily in continuous 28-day cycles until lack of efficacy, intolerance, disease progression, or consent withdrawal. The primary endpoint was the percentage of pts with ≥35% spleen volume reduction at the end of cycle 6 (SVR35 at EOC6). In the FREEDOM biomarker cohort (pts with paired samples at cycle 1 day 1 (C1D1) and EOC6 [n=19]), levels of 85 serum cytokine levels were measured using the RBM HumanMAP v2.0 panel. BaF3 cell lines overexpressing JAK2 V617F were incrementally exposed to RUX over 3 weeks (up to IC90) to induce RUX-resistance. Cell proliferation and phosphorylation of STAT5 in FEDR- and RUX-treated cells was measured using CellTiter-Glo and immunoblotting, respectively. Kinome screening was performed using the ThermoFisher LanthaScreen Eu kinase binding assay and the reaction biology kinome assay. Results: Paired analysis between C1D1 and EOC6 revealed increases in cytokines including adiponectin, carcinoembryonic antigen (CEA), erythropoietin (EPO), and ferritin and decreases in pro-inflammatory EN-RAGE, IL-16, IL-18, IL1-RA, TIMP-1, TNFR2, MPO, VCAM1, and VEGF (P<0.001). Increases in adiponectin, CEA, ferritin, haptoglobin, EPO, and CCL18 also significantly correlated with SVR (P<0.05) (Jeyaraju, et al., Blood 2022: abstract 1682). The cytokine profile of RUX-exposed pts in FREEDOM was similar to cytokine changes previously measured in RUX-naive pts (Pardanani et al., Blood Cancer J 2015), suggesting that prior RUX exposure/resistance does not interfere with FEDR efficacy or mechanism of action. RUX-resistant JAK2 V617F BaF3 cell lines showed <10% loss of proliferation when treated with 4mM RUX for 24 hours, while control cells remained sensitive to RUX (IC50 120nM). In contrast, both RUX-resistant and control cells showed loss of proliferation when treated with FEDR (IC50 650nM vs 1552nM, respectively) (Figure). Immunoblotting showed that RUX-resistant cells treated with 2uM RUX maintained high levels of STAT5 phosphorylation, while in RUX-resistant cells treated with 2uM FEDR, STAT5 phosphorylation was inhibited. FEDR also had a 2–3-fold higher kinase inhibitory profile compared with RUX in an in-vitro kinome screen. Summary/Conclusion: In the FREEDOM study, FEDR treatment resulted in cytokine changes, some of which suggest an anti-inflammatory and anti-fibrotic effect. Changes to cytokine profile, specifically anti-inflammatory effects, are a potential disease-modifying effect in MF therapies. Preclinical studies at clinically relevant exposures further demonstrated that FEDR inhibited proliferation and STAT phosphorylation in RUX-resistant cell lines, and had a broader kinase inhibition profile compared with RUX. These results indicate additional effects of FEDR which allow efficacy in previously RUX-exposed pts.Keywords: Myeloproliferative disorder, Janus Kinase inhibitor
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,004 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».