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481 A Phase 2 Study of Fedratinib in Patients with MDS/MPN and Chronic Neutrophilic Leukemia

Program: Oral and Poster Abstracts
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
Sunday, December 8, 2024: 9:30 AM

Andrew T. Kuykendall, MD1, Tania Jain, MD2, Abhay Singh, MD, MPH3, Kristen M. Pettit, MD4, Quan Lovette5*, Joan McFadden Cain, BSN, RN6*, Tracy Ann Cinalli, RN7*, Mary Gallagher, RN8*, David Sallman, MD1, Qianxing Mo, PhD5*, Ling Zhang, MD9*, Onyee Chan, MD10, Alison R. Walker, MD, MBA, MPH1, Zhuoer Xie, MD, MS1, Jeffrey E Lancet, MD1, Maria Balasis5*, Seongseok Yun, MD, PhD1, Eric Padron, MD11 and Rami S. Komrokji, MD1

1Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL
2Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD
3Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
4Rogel Cancer Center, University of Michigan, Ann Arbor, MI
5Moffitt Cancer Center, Tampa, FL
6Johns Hopkins, Baltimore, MD
7Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
8University of Michigan, Ann Arbor, MI
9Hematopathology and Laboratory Medicine, Moffitt Cancer Center & Research Institute, Tampa, FL
10Department of Malignant Hematology, University of Arizona, Banner University Medical Center-Tucson, Tampa, FL
11Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL

Introduction

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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