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Dr Garcia-Manero on Dual IRAK4/FLT3 Inhibition With Emavusertib in MDS and AML

Guillermo Garcia-Manero, MD, discusses the rationale for investigating the dual inhibition of IRAK4 and FLT3 with emavusertib in MDS and AML

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    "We have developed a number of clinical trials for [emavusertib in] high-risk MDS and AML targeting different splice forms. In AML, [this research specifically] focused on FLT3 mutational status. What we [have seen], both in MDS and AML, is that there is significant clinical activity with this oral compound as a single agent.

    Guillermo Garcia-Manero, MD, professor, chief, Section of Myelodysplastic Syndromes, deputy chair, Translational Research, fellowship program director, Department of Leukemia, Division of Cancer Medicine, chair, faculty senate, The University of Texas MD Anderson Cancer Center, discusses the rationale for investigating the dual inhibition of IRAK4 and FLT3 with emavusertib (CA-4948) in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

    IRAK4 is a key mediator of interleukin and toll-like receptor (TLR) signaling in innate immune responses, facilitating downstream activation of NF-κB and cytokine production, Garcia-Manero begins. Although these processes are part of normal host defense mechanisms, TLRs and their associated signaling components are frequently overexpressed or activated in patients with lower-risk MDS, AML, and certain B-cell malignancies, Garcia-Manero details. This overactivation suggests that IRAK4 could serve as a potential therapeutic target across various hematologic malignancies, he states.

    Research into this pathway has led to the development of multikinase FLT3/IRAK inhibitors, such as emavusertib, Garcia-Manero continues. Although emavusertib is not highly specific to IRAK4, its ability to inhibit FLT3 broadens its potential applications, he notes. Furthermore, studies of alternative IRAK4 splicing have indicated that distinct isoforms may influence sensitivity to IRAK inhibitors, potentially guiding patient selection and treatment strategies, Garcia-Manero adds.

    Building on these findings, multiple clinical trials have been initiated to evaluate IRAK inhibitors in high-risk MDS and AML, focusing on targeting different IRAK4 splice forms and FLT3 mutations, he says, including the ongoing phase 1/2 TakeAim Leukemia trial (NCT04278768). Early clinical data demonstrate significant activity with oral emavusertib as a single agent in patients with AML and MDS, suggesting its potential to modulate key pathogenic pathways in these diseases, Garcia-Manero reports. Further research will clarify the role of IRAK inhibitors in broader therapeutic contexts and refine strategies for their use in these malignancies, he concludes.