Active Research on Uproleselan in Acute Myeloid Leukemia

Brian A. Jonas, MD, associate professor of medicine at UC Davis Health in Sacramento, California, discusses studies investigating the use of uproleselan for the treatment of patients with acute myeloid leukemia (AML).

Transcript:

0:08 | been a drug developed to target the e-selectin ligand interaction, it’s a so-called e-selecting antagonist and it's called uproleselan. In terms of like the disease setting in AML, the e-selectin ligand is upregulated on the AML cells and interacts with the selected and again, it causes them to be sequestered in this receptive microenvironment in the bone marrow that allows them to grow and activates pathways like NF-κB signaling and so on. These pathways are involved in cancer survival and growth.

Uproleselan one was developed to disrupt this interaction, and this causes the leukemia cells to be released from this vascular protective environment, that unwraps it disrupts their chemoresistance pathways. What's kind of interesting is it doesn't seem to matter which features the disease expresses, so this drug could potentially affect that biology.

With that in mind, a phase 1 clinical trial was started with the combination of this e-selectin inhibitor uproleselan combination with high intensity salvage chemotherapy called MEC, for patients with relapsed/refractory AML. There was also a parallel arm on that study looking at older patients, in which uproleselan was combined with the 7 + 3 induction chemotherapy. That study was published in 2022 in Blood, and that study showed that the compound was safe and tolerable. It also showed that you could combine it with intense chemotherapy. It seemed to do what we had hoped it would do, which is aimed to improve the response that you'd expect to see at least with that chemotherapy, in the relapsed/refractory patients.

One thing it was kind of interesting was it was again, well-tolerated, there were no dose-limiting toxicities and there seems to be a very low rate of mucositis and the MEC arm, which was something that's challenging with MEC. Something that preclinical models suggested is that it would also be protective of the colon environment too, which I thought was interesting. As a result of this very promising phase 1 study, additional phase 3 studies were launched, both in the relapsed/refractory setting with combinations of MEC, and derivative of the regimen FLAG [fludarabine, cytarabine and filgrastim]. And there was another study that was launched with a combination with 7 + 3, and neither of those studies have results yet. We eagerly await the results of those studies. In addition, there's been some smaller investigator-initiated studies that are looking at uproleselan in another combinations.