Momelotinib Inhibits FLT3-Mutant AML Without Major Side Effects

Published February 2022 | Blood Advances

An estimated one third of patients with acute myeloid leukemia (AML) have mutations in the FLT3 gene that often results in poor survival rates even when patients receive stem cell transplants. Yet two generations of FLT3 inhibitors have failed to help people achieve lasting disease remission.

Now, another emerging drug called momelotinib appears to avoid problems encountered by other drugs such as gilteritinib (approved in 2018 for treating adults with FLT3-positive AML), according to a pre-clinical study led by first author Mohammad Azhar, PhD, and senior author Mohammad Azam, PhD.

This JAK2 inhibitor potently inhibits FLT3, including preventing activation loop mutations that make AML resistant to quizartinib and a compound mutant form of FLT3 that is fully resistant to gilteritinib.

“Because momelotinib showed equipotent inhibition of JAK2 and FLT3 and suppressed ACVR1 to alleviate anemic response, we reasoned that it will be more effective in suppressing AML progression and may alleviate chemothera-py induced anemia,” Azam says.

In addition, unlike gilteritinib, the drug does not inhibit c-KIT, an off-target side effect that can lead to heart damage, poor bone marrow function, and weak blood cell production.

“Its ability to impede the resistance conferred by growth factor signaling and activation loop mutants suggests that momelotinib treatment could provide a deeper and durable response and, thus, warrants clinical evaluation,” the study concludes.

Cincinnati Children’s and University of Cincinnati co-authors on this study included Zachary Kincaid, BS, Meenu Kesarwani, PhD, Arhama Ahmed, BS, Mark Wunder-lich, Tahir Latif, MD, and Daniel Starczynowski, PhD.