A Phase 2 Study of Fedratinib in Patients with MDS/MPN and Chronic Neutrophilic Leukemia
Authors: Kuykendall Andrew T. , Jain Tania , Singh Abhay , Pettit Kristen M. , Lovette Quan , McFadden Cain Joan , Cinalli Tracy Ann , Gallagher Mary , Sallman David , Mo Qianxing , Zhang Ling , Chan Onyee , Walker Alison R. , Xie Zhuoer , Lancet Jeffrey E , Balasis Maria , Yun Seongseok , Padron Eric , Komrokji Rami S. 
Published: December 2024

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 &lt; 35 x 109/L or peripheral/marrow blasts &gt; 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 &gt;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.