Evaluating Fedratinib in Rare Myeloproliferative Diseases

Andrew Kuykendall, MD, an assistant member at the H. Lee Moffitt Cancer Center of University of South Florida in Tampa, FL, discusses the rationale behind choosing to evaluate fedratinib (Inrebic) in a phase 2, multi-institutional, investigator-initiated study (NCT05177211) for patients with atypical chronic myeloid leukemia, chronic neutrophilic leukemia, myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN)-unclassifiable, and MDS/MPN-ring sideroblasts and thrombocytosis.

He then discusses how fedratinib’s broader kinase inhibition profile differs from ruxolitinib (Jakafi) in this space.

Transcription:

0:10 | 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.

1:00 | 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.

1:30 | 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.

1:56 | 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.