P997: FEDRATINIB IS EFFECTIVE IN RUXOLITINIB-RESISTANT CELLS: CLINICAL AND PRECLINICAL CORRELATIONS
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".