Lower Dose Mitoxantrone for Venetoclax Resistant Acute Myeloid Leukemia
Daniel Pollyea
MDUniversity of Colorado Denver, Anschutz Medical Campus
Project Term: July 1, 2024 - June 30, 2027
Venetoclax-based regimens are the standard of care for many patients with acute myeloid leukemia (AML) and are highly active therapeutic strategies for this challenging disease. However, some patients do not respond, and most patients who do respond will relapse. We have discovered that resistance to venetoclax may be mediated by the movement patterns of calcium throughout a cell. Furthermore, we have found that mitoxantrone, a conventional chemotherapy agent, can interrupt these calcium fluctuations at very low doses. Therefore we have proposed a clinical trial using lower-dose mitoxantrone for AML patients whose disease has resistance to venetoclax-based regimens.
Venetoclax-based regimens have been very effective for patients with acute myeloid leukemia (AML) and for many patients represent the standard of care. While venetoclax has been transformational for the field, not all patients respond, and most responders ultimately relapse. It is important to search for therapies that might work to overcome resistance to venetoclax. Our recent work has shown that fluctuations in calcium in a cell can mediate resistance to venetoclax; this represents a potential target that could be exploited to allow for better clinical outcomes. Indeed, we have discovered that the conventional chemotherapy drug mitoxantrone, given at very low doses, can target these calcium fluctuations and eradicate AML that venetoclax cannot treat. We propose to use lower-dose mitoxantrone in combination with venetoclax-based regimens in situations in which patiente are resistant to venetoclax. We have designed a pilot clinical trial to evaluate this question and will measure results by investigating the ability of this intervention to eradicate low level residual disease when present after initial treatment with venetoclax-based regimens. If successful, we will have identified a well-tolerated and widely accessible therapy that can extend venetoclax remissions, delaying or even preventing relapse, and prove that it is possible to specifically target AML populations that are resistant to venetoclax.