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

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.481-481
• Main 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.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-210743

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. Thi