Fedratinib Shows Promise in Chronic Neutrophilic Leukemia and MDS/MPN

Andrew Kuykendall, MD

Fedratinib (Inrebic), a JAK2-selective kinase inhibitor, demonstrated promising efficacy and a manageable safety profile in a phase 2 trial (NCT05177211) for patients with atypical chronic myeloid leukemia (aCML), chronic neutrophilic leukemia (CNL), myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN)-unclassifiable, and MDS/MPN-ring sideroblasts and thrombocytosis per the 2016 WHO classification.¹ 

Data from this phase 2, multi-institutional, investigator-initiated study were presented at the 2024 American Society of Hematology (ASH) Annual Meeting. Patients were required to have splenomegaly and/or significant disease-related symptoms, and the primary end point being evaluated in the study is overall response rate defined as complete or partial response or clinical benefit at 24 weeks.

At the time of data cutoff, 24 patients were enrolled; 6 with aCML, 5 with CNL, 6 with MDS/MPN-ring sideroblasts and thrombocytosis, and 7 with MDS/MPN-unclassifiable. Ten (53%) of 19 evaluable patients responded at week 24, including 8 (50%) symptom responses and 6 (37.5%) spleen responses. Four patients 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%).

At the data cutoff, 19 patients were evaluable, with 53% achieving a response at 24 weeks. This included 50% symptom responses and 37.5% spleen responses. Among those treated for ≥24 weeks, spleen volume decreased by an average of 32%, and 85% showed symptomatic improvement. 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.

For safety, the treatment was 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 resolved with dose adjustments.

“[M]y hope is this can support what is already being done in practice. We certainly have access to fedratinib as it is already approved for myelofibrosis, and I think that very quickly this can translate to being utilized in clinical practice,” explained Andrew Kuykendall, MD, in an interview with Targeted Oncology^TM.

In the interview, Kuykendall, an assistant member at the H. Lee Moffitt Cancer Center of University of South Florida in Tampa, FL, discussed fedratinib’s potential as an effective option for patients with MDS/MPN and CNL.

Targeted Oncology: What was the rationale for choosing the fedratinib in this trial, and how does its broader kinase inhibition profile differentiate from ruxolitinib in this space?

Kuykendall: Overall, the rationale is kind of multipronged. Initially, as someone who focuses a lot on myelofibrosis, fedratinib as an agent is a JAK2 inhibitor that is quite potent, and probably the most potent of the JAK inhibitors that we have in terms of achieving spleen volume reduction and symptom improvement. Unfortunately, it really does not have a clear space in myelofibrosis, given the fact that it is competing with agents that were approved nearly a decade before it. It still has some of the anemia and thrombocytopenia adverse events that may make it not as attractive as an option for some of our patients with more profound cytopenias, where we have other JAK inhibitors. But fedratinib is kind of this potent agent. We wanted to see if maybe there was a place for it in more aggressive diseases that have overlapped phenotypically with myelofibrosis.

That was the initial kind of thought process. Maybe this is just a natural fit. But when you look at fedratinib, it also has kind of a distinct kinase inhibition profile, where, in addition to JAK2, it is a weaker JAK1 inhibitor, so may avoid some of the [adverse events] that come from that. Also, it inhibits BRD4, which is part of this BET protein complex. That is something that we have been evaluating in myeloproliferative neoplasms and may play a role in NF-κB inflammatory signaling. It also hits FLT3, which has unclear benefits, but maybe something that is helpful and then also potently down regulates MYC, which we often think about in lymphomas.

Microscopic examination revealing red blood cells, white blood cells, neutrophils, eosinophils: ©AkuAku - stock.adobe.com

Recently, work from some physician-scientists in our group has suggested that MYC can be a potent proliferative driver, particularly overrepresented in triple-negative myelofibrosis or possibly in MDS/MPN overlap syndromes that harbor mutations activating MYC pathways. The rationale for this approach is multi-pronged. First, MYC represents a potent target, potentially better suited for more aggressive diseases. Additionally, the kinase inhibition profile of the agent may uniquely position it for use in these MDS/MPN overlap syndromes.

Who was included in the study, and what were the methods and design utilized?

When we designed the study, we wanted to serve an underserved population of patients that often get excluded from clinical trials, and so we were in a bit of a unique situation as a standalone cancer center where we see a lot of these rare diseases more frequently than they are seen out in the community. We feel like we can offer something to these patients that often get excluded and not enrolled in trials because people think it would be hard to accrue.

We designed this study specifically for patients with MDS/MPN overlap syndromes and chronic neutrophilic leukemia. We excluded patients with chronic myelomonocytic leukemia, as those are more common, and individual trials can often be conducted for that specific diagnosis. This trial included patients with MDS/MPN-unclassifiable, atypical CML, MDS/MPN with ring sideroblasts and thrombocytosis, and chronic neutrophilic leukemia. These diseases fall under the category of MDS/MPN overlap syndromes.

Prior studies have suggested that these are not as distinct as we would like them to be; instead, they should be viewed more as a spectrum of diseases. This perspective was the rationale for including them together in this study.

[For this] phase 2 trial, we enrolled patients with these diagnoses based on specific criteria. Patients needed to have either disease-related symptoms or an enlarged spleen, as we believe this is where JAK inhibitors could offer a benefit. We used a Simon two-stage design for this study. Our goal was to enroll around 25 patients, but after the first 9, we conducted an interim analysis to ensure the treatment showed some benefit. If we observed benefit in the initial group, we would proceed with enrolling the remaining patients.

What from the trial was presented at the 2024 American Society of Hematology Annual Meeting?

We were able to present that this trial has now fully enrolled. With the help of 3 additional partner sites—University of Michigan, Cleveland Clinic, and Johns Hopkins, all of which are specialty centers for these rare diagnoses—we successfully enrolled all 25 patients. Currently, we do not yet have efficacy data for all patients, as the last patient was enrolled in October 2024. However, we do have efficacy data for 21 out of the 25 patients, and the results so far are quite striking.

This was a very high-risk population, as these diagnoses are associated with poor prognosis. Despite that, we observed spleen responses in approximately 35% of patients, symptom responses in 50%, and some durable responses, with the median time on treatment nearing a year. These outcomes were particularly exciting given the molecular features of this patient population, which typically predict lower response rates.

Regarding the safety profile, it was consistent with prior studies of fedratinib. There were some manageable low-grade gastrointestinal [adverse events]. We implemented a more proactive approach to mitigate these, including the use of antiemetics during the first 8 weeks. Overall, the [adverse event] profile remained manageable, and the efficacy outcomes likely exceeded our initial expectations.

What are the next steps for this study?

We will have final results of this study, at least the 24-week results, sometime in April or May of this year. One challenge with these rare diseases is the difficulty in conducting large phase 3 trials required for traditional labeled approvals. However, oftentimes, given the lack of standard-of-care [options], we can use small studies like this to guide treatment.

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. We certainly have access to fedratinib as it is already approved for myelofibrosis, and I think that very quickly this can translate to being utilized in clinical practice.

REFERENCE:

Kuykendall AT, Jain T, Singh A, et al. A phase 2 study of fedratinib in patients with MDS/MPN and chronic neutrophilic leukemia. Blood. 2024;144(suppl 1):481. doi:10.1182/blood-2024-210743