Uproleselan Plus Chemotherapy Continues to Show Promise in AML

Geoffrey L. Uy, MD

The addition of uproleselan to standard chemotherapy improved improve response rates and reduced chemotherapy-induced mucositis in patients with newly diagnosed and relapsed/refractory acute myeloid leukemia (AML) in a phase 1/2 trial (NCT02306291),¹ said Geoffrey L. Uy, MD.

Based on findings from the phase 1/2 trial, further research of the E-selectin antagonist’s effect on this patient population is being conducted, including a phase 2/3 study (NCT03701308) that will examine the agent in older adult patients with newly diagnosed disease, Uy added.

“We think that the addition of uproleselan to chemotherapy increases the sensitivity of leukemic blasts to chemotherapy and potentially may improve response rates,” Uy said. “There is also a second potential mechanism of action in which E-selectin is important for trafficking inflammatory macrophages to areas of tissue damage.”

In an interview with OncLive^®, Uy, a professor in the Department of Medicine, Oncology Division, Bone Marrow Transplantation & Leukemia at Washington University School of Medicine in St Louis and a bone marrow transplant specialist and medical oncologist at Siteman Cancer Center, discussed accumulating research with uproleselan plus standard chemotherapy and explained how this combination could shift the treatment paradigm in AML.

OncLive^®: Could you discuss the role of E-selectin in the tumor microenvironment? What is the rationale for targeting this molecule in AML?

Uy: Normal hematopoietic stem cells reside in the bone marrow in these specialized microenvironments, which refer to the stem cell niche. We know that the microenvironment interacts with normal hematopoietic cells and is important for critical stem cell functions, such as self-renewal pluripotency. A lot of evidence suggests that malignant stem cells, leukemia stem cells, occupy specific niches within the bone marrow. This interaction confers protection against genotoxic stresses, such as chemotherapy.

This phenomenon has been known for many years and has been termed cell adhesion–mediated drug resistance. Plenty of ligands and receptors are involved in this process. One of these ligand–receptor pairs involves E-selectin [and the] E-selectin ligand pathway.

E-selectin is a cell adhesion molecule. It’s normally expressed on endothelial cells and is upregulated in response to inflammation, which includes IL-1, tumor necrosis factor, and lipopolysaccharide. When E-selectin is upregulated, it binds to E-selectin ligands present on leukocytes and is an important mechanism for these leukocytes to traffic to areas of inflammation.

In the bone marrow microenvironment, we know that E-selectin is present in the bone marrow sinusoids. It is expressed at high levels, and the E-selectin ligands are expressed on tumor cells. We think that this interaction confers specific protective effects to these AML blasts, and plenty of data have shown that specific pathways are activated, such as PI3K, AKT, and NFKB that can be important for leukemia cell survival.

What is known about uproleselan, and what is the mechanism of action of this agent?

Uproleselan is an E-selectin antagonist. It blocks the interaction between E-selectin present on endothelial and bone marrow microenvironments with the leukemic blasts. In preclinical and mouse models, genetic deletion of E-selectin or antagonism with uproleselan sensitizes these tumor cells to chemotherapy.

In xenograft models, chemotherapy appears more effective if you block the E-selectin pathway. This has been translated into early preclinical studies. There was a phase 1/2 study published in Blood, led by Daniel J. D’Angelo, MD, PhD, of Dana-Farber Cancer Institute, in which the investigators tested uproleselan in combination with chemotherapy. [The trial] demonstrated promising results, both in the up-front setting and in the relapsed/refractory setting, showing higher rates of remission and a low incidence of toxicity when uproleselan was added to standard chemotherapy.

What was the rationale of adding uproleselan to standard chemotherapy?

There are data to suggest that blockade of this E-selectin pathway with uproleselan may protect against chemotherapy-induced mucositis. This was a finding that was seen in the initial phase 1/2 study in patients receiving a chemotherapy regimen of mitoxantrone, etoposide, and cytarabine, which is classically associated with mucositis [and] diarrhea. These patients had low rates of mucositis compared with what we typically expect for that regimen.

Could you speak to the rationale for the ongoing phase 2/3 trial in patients with newly diagnosed disease? What are the key objectives of the study?

Two pivotal studies are currently being conducted. The study that I am leading is the Alliance A041701 study, which is a randomized phase 2/3 study of uproleselan added to standard chemotherapy in older adults with leukemia. This study is for patients aged 60 years or older who are considered appropriate candidates for intensive chemotherapy. In the experimental arm, uproleselan will be added to standard 7+3 induction chemotherapy, consisting of cytarabine and daunorubicin. Furthermore, patients will receive consolidation with a combination of uproleselan and intermediate-dose cytarabine. [That regimen] is being compared with standard 7+3 [induction] chemotherapy plus [consolidation] cytarabine alone.

In this study, the phase 2 end point is event-free survival [EFS]. The study has completed enrollment for the phase 2 cohort, and we are waiting for the readout of the phase 2 portion to determine whether to proceed with the phase 3 portion of the study, which will use overall survival as the primary end point.

When are the phase 2 results expected?

The phase 2 study completed enrollment in November 2021. It was estimated that it could take approximately 12 months from the completion of the phase 2 portion [until we] have the conditional [results for the] EFS end point.

What is the significance of this study?

The study is important for 2 reasons. One is that this study is being done in the up-front setting. There is also a concurrent, randomized phase 3 study being done in the relapsed/refractory setting with a similar design in which uproleselan will be added to standard chemotherapy. These 2 studies collectively will define the role of uproleselan in this disease. Both studies are expected to read out approximately at the same time. They are relatively large studies with straightforward end points. Collectively, they will define whether uproleselan has a role in the treatment of patients with AML.

Regarding the safety profile of this agent, what are the known toxicities and how do they affect the toxicities associated with chemotherapy?

In general, this agent was well tolerated in the initial phase 1/2 study. There were no clear additive toxicities of uproleselan. There are no significant drug interactions [with chemotherapy], such as QT prolongation or CYP3A4 interactions. [Uproleselan] is easy to add to different chemotherapy backbones.

One of the potential benefits of this drug is that it may protect patients against chemotherapy-induced mucositis. Gastrointestinal toxicity can be quite significant in patients receiving induction chemotherapy for leukemia, [and uproleselan] may protect against [this] important cause of morbidity in this population.

What is unique about this agent that you’d like to explore further?

The mucositis aspect of this agent is interesting. This is based on nice work done in Australia by an investigator named Ingrid Winkler. We are testing the mucositis aspect in an investigator-initiated study in patients with multiple myeloma. We are using uproleselan as a mucositis-protecting agent in combination with high-dose melphalan. This study is being done as a randomized study, so we will have a good cohort of control patients who did not receive uproleselan to see whether there is a clear signal of benefit [with this agent].

Reference

1. DeAngelo DJ, Jonas BA, Liesveld JL, et al. Phase 1/2 study of uproleselan added to chemotherapy in patients with relapsed or refractory acute myeloid leukemia. Blood. doi:10.1182/blood.2021010721