A phase 2 trial (NCT05177211) investigating fedratinib, a JAK2-selective kinase inhibitor, has shown promising results in patients with rare myeloid neoplasms, including atypical chronic myeloid leukemia (aCML), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN)-unclassifiable, and MDS/MPN with ring sideroblasts and thrombocytosis. The multi-institutional, investigator-initiated study, presented at the 2024 American Society of Hematology (ASH) Annual Meeting, suggests that fedratinib could offer a valuable treatment option for these underserved patient populations.
The study enrolled patients with splenomegaly and/or significant disease-related symptoms. The primary endpoint was the overall response rate, defined as complete or partial response or clinical benefit at 24 weeks. At the data cutoff, 24 patients were enrolled, with 19 evaluable for response. The results showed that 53% of evaluable patients responded at week 24, including 50% symptom responses and 37.5% spleen responses. Four patients experienced both symptom and spleen responses. Among the 13 patients with splenomegaly treated for at least 24 weeks, spleen volume decreased in all (100%) by an average of 32% (ranging from -2% to -61%).
Efficacy and Molecular Correlates
The study revealed that responses were enriched in patients with CSF3R mutations (83%) and JAK-STAT pathway mutations (70%). The median overall survival (OS) was estimated at 19.7 months. These findings suggest that specific molecular features may predict the likelihood of response to fedratinib in these rare myeloid neoplasms.
Safety and Tolerability
Fedratinib was generally well-tolerated, with most adverse events (AEs) being grade 1 or 2. Common AEs included diarrhea (37.5%), constipation (37.5%), and anemia (29%). A single grade 4 neutropenia event was reported but resolved with dose adjustments. According to Andrew Kuykendall, MD, an assistant member at the H. Lee Moffitt Cancer Center of University of South Florida, a proactive approach to mitigate gastrointestinal adverse events, including the use of antiemetics during the first 8 weeks, was implemented.
Implications for Clinical Practice
Dr. Kuykendall noted that fedratinib is already approved for myelofibrosis and expressed hope that these findings could support its use in these rare conditions. He emphasized the unmet need for effective treatments in this patient population and suggested that the study could provide proof-of-concept for fedratinib's efficacy. "My hope is that once we get final results and get this published, that this could support the use of the fedratinib in these rare conditions where we often are trying to draw on small studies to give proof-of-concept as far as the efficacy. So really, my hope is this can support what is already being done in practice," he stated.
Study Design and Rationale
The phase 2 trial was designed to address the lack of effective treatments for patients with MDS/MPN overlap syndromes and chronic neutrophilic leukemia. Patients with chronic myelomonocytic leukemia were excluded, as individual trials can often be conducted for that specific diagnosis. The study included patients with MDS/MPN-unclassifiable, atypical CML, MDS/MPN with ring sideroblasts and thrombocytosis, and chronic neutrophilic leukemia, recognizing that these diseases may represent a spectrum rather than distinct entities.
The researchers used a Simon two-stage design, planning to enroll around 25 patients. An interim analysis was conducted after the first nine patients to ensure the treatment showed benefit. With the help of three additional partner sites—University of Michigan, Cleveland Clinic, and Johns Hopkins—the trial successfully enrolled all 25 patients.
