A phase 2 study of fedratinib in patients with MDS/MPN and chronic neutrophilic leukemia.

Abstract

6509 Background: MDS/MPNs are complex diseases that exhibit proliferative symptoms and aggressive clinical courses. Treatment options are limited. Ruxolitinib, a JAK1/JAK2 inhibitor, showed clinical benefit in pts with chronic neutrophilic leukemia (CNL) and atypical CML (aCML); yet survival remained poor (mOS 18.8 mo). Fedratinib (Fed) is a JAK2 inhibitor approved for MF that, compared to ruxolitinib, has a broader kinase inhibition profile which may provide enhanced efficacy in molecularly complex disease. Fed potently inhibits FLT3 and BRD4 and potently suppresses c-Myc, a critical upregulated pathway in MDS/MPN. Here, we present the primary results of NCT05177211 assessing the efficacy of Fed in pts with MDS/MPNs. Methods: NCT05177211 is a phase 2, multi-institutional study that enrolled pts with aCML, CNL, MDS/MPN-unclassifiable (MDS/MPN-U), and MDS/MPN-ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) who have splenomegaly (spleen volume > 450cc) and/or significant symptom burden (MPN TSS ≥ 10). The primary endpoint is overall response defined as complete/partial response or clinical benefit at 24 weeks per MDS/MPN IWG response criteria. Exploratory endpoints include progression-free survival (PFS), overall survival (OS), and duration of response (DOR). Fed was given at a dose of 400 mg daily on day 1-28 of 28-day cycles. Results: The data cutoff was 1/1/2026. Among 25 pts, 6 had aCML, 5 had CNL, 6 had MDS/MPN-RS-T, and 8 had MDS/MPN-U. Median age was 68.8 y. ≥3 mutations were present in 19 (76%) pts. Three (12%) pts remain on study. Median duration of treatment was 7.4 months. Eleven (44%) pts responded at week 24: 6 (30%) spleen responses (SVR35) and 9 (47%) symptom responses (TSS50). Four (25%) pts had both spleen and symptom response. Among 16 pts with splenomegaly treated for ≥ 24 weeks, spleen volume decreased by an average of 30% (+9% to -61%). Among 16 pts with symptomatic disease treated for ≥ 24 weeks, TSS improved by an average of -41% (range +35% to -80%). CSF3R mutations were enriched among pts with SVR35 (n = 4; 67%). Median PFS and OS were 36.9 mo (95% CI 19.3-NR) and 36.9 mo (95% CI 18.4-NR), respectively. Among responders, the duration of response was 7.6 mo (95% CI: 3.72-not reached). When stratified by diagnosis, OS for aCML, CNL, MDS/MPN-RS-T, and MDS/MPN-U was 19.8, 36.9, NR and NR, respectively. SAEs occurred in 13 (52%) pts. SAEs possibly related to Fed included acute kidney injury (n = 2), low thiamine (n = 1), colitis (n = 1), diarrhea (n = 1), arthralgias (n = 1), and edema (n = 1). Any grade nausea, vomiting, diarrhea, and constipation were seen in 52%, 16%, 44%, and 48% of pts, respectively. Conclusions: Fed demonstrates promising clinical efficacy in MDS/MPN and CNL pts with proliferative features. The safety profile is consistent with prior experience. Fed’s unique kinase inhibition profile may provide a mechanism for enhanced effectiveness in this pt population. Clinical trial information: NCT05177211 .