Type: Oral
Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: JAK Inhibitors in MPDs, Novel Insights and Next-Gen Agents
Hematology Disease Topics & Pathways:
Research, MDS, Clinical trials, MPN, Clinical Research, Chronic Myeloid Malignancies, Diseases, Myeloid Malignancies
MDS/MPNs are clinically and molecularly complex diseases that exhibit proliferative symptoms and aggressive clinical courses. Evaluation of mutational patterns and gene expression profiles suggest these diseases should be viewed as a spectrum rather than distinct disease entities. Treatment options are limited and poorly defined as patients (pts) are often excluded from clinical trials.
The JAK1/JAK2 inhibitor, ruxolitinib, has shown clinical benefit in pts with MDS/MPN and pts harboring CSF3R mutations. The experience of JAK2 inhibitors in myelofibrosis (MF) has shown that non-JAK2 kinase targets of JAK inhibitors may result in unique profiles of clinical benefit.
Fedratinib is a JAK2 inhibitor approved for higher-risk MF. Compared to ruxolitinib, it has a broader kinase inhibition profile which may convey enhanced efficacy in high-risk, molecularly complex disease. Fedratinib potently inhibits FLT3 and BRD4 and potently suppresses c-Myc expression which may have biologic relevance in MDS/MPN.
Study Design
This is a phase 2, multi-institutional, investigator-initiated clinical trial (NCT05177211) assessing the efficacy of fedratinib in pts with atypical chronic myeloid leukemia (aCML), chronic neutrophilic leukemia (CNL), MDS/MPN-unclassifiable (MDS/MPN-U), and MDS/MPN-ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) per 2016 WHO classification.
Pts were required to have splenomegaly and/or significant disease-related symptoms (MPN TSS ≥ 10). Pts with a platelet count < 35 x 109/L or peripheral/marrow blasts > 10% were excluded.
The primary endpoint is overall response rate defined as complete or partial response or clinical benefit at 24 weeks per proposed MDS/MPN IWG response criteria. C-Myc (a potential biomarker for response) was stained in the bone marrow collected at baseline and week 24. C-Myc expression product was scored by multiplying % positive cells by intensity (0 = none, 1 = mild, 2 = moderate, 3 = marked).
Fedratinib was given at a dose of 400 mg daily. Planned enrollment is 25 pts.
Results
At time of data cut-off, 24 pts have been enrolled; 6 with aCML, 5 with CNL, 6 with MDS/MPN-RS-T, and 7 with MDS/MPN-U. Median age was 69.0 y. ≥3 mutations were present in 18 (75%) pts. Median time from diagnosis to treatment was 10.0 mo. Twelve pts remain on treatment. The most common reasons for treatment discontinuation include disease progression (n = 3) and patient decision (n = 3).
10/19 (53%) evaluable pts responded at week 24. This included 8 (50%) symptom responses (≥50% reduction in TSS from baseline) and 6 (37.5%) spleen responses (≥35% reduction of spleen volume from baseline). Four pts had both. Among 13 pts with splenomegaly treated for ≥ 24 weeks, spleen volume decreased in 13 (100%) by an average of 32% (-2% to -61%). Among 13 pts with symptomatic disease at baseline who were treated for ≥ 24 weeks, 11 (85%) experienced an improvement in TSS by an average of -41% (range +35% to -80%). Responses were enriched in patients harboring CSF3R mutations (83% vs. 42%, p = 0.15) and patients with JAK-STAT activating mutations (inclusive of CSF3R, JAK2, MPL, or CALR) (70% vs. 43%, p = 0.35). With a median follow-up of 8.5 months, median OS is estimated at 19.7 mo.
At baseline, C-Myc expression was demonstrated by IHC staining in a median of 10% of cells (2.5-15%). Average baseline c-Myc expression product (% positive cells * staining intensity) was 22.3 (range 5-37.5). In pts with paired samples (n = 9), c-Myc expression product decreased in 7 (78%) by an average of 30%. Expression product did not correlate with degree of spleen volume reduction or symptom improvement; however, it weakly correlated with duration of treatment (R2 = 0.24; p = 0.18).
Twenty-four pts were evaluable for safety. Treatment-emergent AEs occurring in >20% of pts were anemia (29%), diarrhea (37.5%), nausea (25%), constipation (37.5%), serum amylase (29%) and lipase (37.5%) increase, AST increase (25%), and creatinine increase (21%). The vast majority of TEAEs were grade 1 or 2. Grade 4 neutropenia occurred in 1 patient with baseline grade 2 neutropenia and resolved with treatment interruption and dose reduction.
Conclusion:
Fedratinib demonstrates promising clinical efficacy in MDS/MPN and CNL pts with proliferative features. The safety profile is consistent with prior experience. Fedratinib’s unique kinase inhibition profile may provide a mechanism for enhanced effectiveness in this pt population.
Disclosures: Kuykendall: Protagonist Therapeutics: Honoraria, Research Funding; PharmaEssentia: Honoraria; Novartis: Research Funding; Incyte: Honoraria. Jain: Bristol Myers Squibb, Incyte, Abbvie, CTI, Kite, Cogent Biosciences, Blueprint Medicine, Telios pharma, Protagonist therapeutics, Galapagos, Tscan therapeutics, Karyopharm, Morphosys: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma, Kartos therapeutics, Incyte, Bristol Myers Squibb: Research Funding. Pettit: Imago: Research Funding; Kura Oncology: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; BMS: Research Funding; Merck: Research Funding; PharmaEssentia: Consultancy; AbbVie: Consultancy, Research Funding; Blueprint Medicines: Research Funding; Sierra Oncology: Consultancy; Incyte: Consultancy. Sallman: Abbvie: Consultancy; Agios: Consultancy; Axiom: Consultancy; Gilead: Consultancy; Celyad: Consultancy; Froghorn: Consultancy; Incyte: Consultancy; Intellisphere, LLC: Consultancy; Johnson & Johnson: Consultancy; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; NextTech: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; AvenCell: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; BlueBird Bio: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Dark Blue Therapeutics: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Jasper Therapeutics: Membership on an entity's Board of Directors or advisory committees; NKARTA: Membership on an entity's Board of Directors or advisory committees; Orbital Therapeutics: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Apera: Research Funding; Jazz: Research Funding. Chan: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Research Funding; AbbVie: Honoraria, Research Funding; Syndax: Membership on an entity's Board of Directors or advisory committees; Aptitude Health: Honoraria. Lancet: Tradewell Therapeutics: Consultancy, Other: Consultant/Advisory Board; Prelude Therapeutics: Consultancy, Other: Bristol Myers Squibb; Bristol Myers Squibb: Consultancy, Other: Consultant/Advisory Board. Komrokji: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; DSI: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sumitomo Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Rigel: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy; Keros: Membership on an entity's Board of Directors or advisory committees; Servio: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Servio: Honoraria; DSI: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Consultancy, Membership on an entity's Board of Directors or advisory committees; Taiho: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; CTI biopharma: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding.
OffLabel Disclosure: Fedratinib is approved for high-risk myelofibrosis. This abstract discusses its use within the context of a clinical trial for patients with MDS/MPN overlap syndromes.
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