E-selectin Inhibitor Uproleselan May Bolster SOC Efficacy in AML

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Richard M. Stone, MD, highlights how uproleselan disrupts E-selectin in the AML tumor microenvironment, the variety of AML regimens that uproleselan may amplify in efficacy, including chemotherapies and venetoclax combinations, and the need for further research to determine whether minimal residual disease negativity rates will improve patient prognoses.

Richard M. Stone, MD

Richard M. Stone, MD

Novel agents such as uproleselan (GMI-1271), which inhibits the potential acute myeloid leukemia (AML) target E-selectin, may enhance the efficacy of standard-of-care (SOC) chemotherapies like MEC (mitoxantrone, etoposide, and cytarabine) and 7+3, particularly in patients with relapsed/refractory AML, according to Richard M. Stone, MD.

An ongoing phase 3 trial (NCT03616470) is investigating uproleselan plus MEC or FAI (fludarabine, cytarabine, and idarubicin) vs placebo plus the chemotherapy regimens in patients with relapsed/refractory AML. Additionally, a phase 2/3 trial (NCT03701308) is evaluating 7+3 chemotherapy with cytarabine and daunorubicin with or without uproleselan in older patients with AML receiving intensive induction chemotherapy.

“[This E-selectin research introduces] a novel mechanism of potentially disrupting leukemia resistance,” Stone said.

In an interview with OncLive®, Stone highlighted how uproleselan disrupts E-selectin in the AML tumor microenvironment, the variety of AML regimens that uproleselan may amplify in efficacy, including chemotherapies and venetoclax (Venclexta) combinations, and the need for further research to determine whether minimal residual disease (MRD) negativity rates will improve patient prognoses.

Stone is the chief of staff, the director of Translational Research in the Adult Leukemia Program, and the Lunder Family Chair in Leukemia at Dana-Farber Cancer Institute in Boston, Massachusetts. He is also a professor of medicine at Harvard Medical School in Boston, Massachusetts.

OncLive®: Could you highlight some of the updates regarding diagnostic tools and treatment in AML?

Stone: Important updates regarding diagnosis come from the updated World Health Organization classification system and the new International Consensus Classification system. An updated publication from the European LeukemiaNet describes a slightly altered risk classification system.

We also continue to have new drugs at our disposal in AML, and we’re trying to understand how to use those individually and in combinations. Finally, the issue of [how to use] MRD is a major, new, and vexing issue in AML.

E-selectin has become a potential target in patients with this disease. What role does E-selectin play in the tumor microenvironment, and what is the rationale behind targeting it in these patients?

The question about E-selectin targeting in AML therapy is contemporaneously important. The biggest problem in AML therapy [has to do with] issues that promote AML resistance.

AML cells exist in a protected stem cell niche in the bone marrow, where they’re surrounded by immune cells and vascular endothelial cells. They’re happy in that niche; they may be protected by a different use of oxygen and the cells that I mentioned. If they can be liberated from this happy niche, they may be more susceptible to death by more traditional chemotherapy or even targeted therapy.

There are numerous leukemia cell and host cell interaction points, 1 of which is the E-selectin ligand system. Liberating the cells from that network using an E-selectin inhibitor might be good. Numerous such ligand and receptor pairs use the E-selectin inhibitor uproleselan, which is being tested now. Whether it’s going to be the answer remains to be seen.

My colleague, [Daniel J. DeAngelo, MD, PhD, of Dana-Farber Cancer Institute,] published some important results in older adults with AML and relapsed AML in uncontrolled studies that suggest it might be beneficial. Results are pending for the randomized studies.

What is the mechanism of action of uproleselan that may make it effective in combination with chemotherapy?

We don’t know how effective it’s going to be yet, but the mechanism is that the E-selectin inhibitor will disrupt the bond between the leukemic cell and the niche. That disruption may allow the cell to go into cell cycle, thereby being more susceptible to cell cycle–specific chemotherapy agents that we use all the time, like cytarabine. That’s the idea, making the cell more susceptible to chemotherapy-induced death.

What has been seen so far with the combination of uproleselan and chemotherapy?

Several ongoing trials have been using uproleselan and chemotherapy, and they fall into 2 main categories. One is in relapsed patients, [who typically receive] a commonly used relapsed regimen, such as MEC. Will the antileukemic effects of this regimen be enhanced safely by the addition of uproleselan?

The second group of trials are patients who historically don’t do well from the get-go with standard chemotherapy, such as 3 days of daunorubicin and 7 days of cytarabine. These will be older adults who have a more unfavorable disease biology compared with younger patients with AML, and who may be a bit more susceptible to the adverse effects [AEs] of chemotherapy, thereby preventing dose increases. It’d be nice to make 7+3 chemotherapy more effective in that group.

Initial results combining uproleselan with 7+3 chemotherapy and uproleselan with MEC in relapsed patients showed encouraging remission rates. We have been down this road before with encouraging early results, where they have been able to [translate] into benefits in the phase 3 trials, so hopefully these will be [as well].

In particular, 2 important trials are going to answer these questions. One has been completed and accrued, the [phase 3] company-sponsored trial of MEC plus or minus uproleselan in relapsed AML. We’ll see if the response rate is increased. If the survival is increased, we need to also be cognizant of the fact that in relapsed AML, a high response rate doesn’t always translate into better survival because of the brevity of the duration of the responses at times.

[The phase 2/3] US Intergroup trial includes a phase 2 randomized portion of 7+3 chemotherapy plus or minus uproleselan in adults greater than 60 years of age with AML who are candidates for chemotherapy. [The phase 2 portion of that trial has been completed.] We’re awaiting the results to see if the event-free survival is great enough in the experimental arm compared with the control arm to justify moving that [combination] to a full phase 3 trial.

Could uproleselan be further investigated in combination with venetoclax and other AML regimens?

You could combine uproleselan with any AML regimen because presumptively, if the theory turns out to be true, it will enhance the efficacy of virtually any antineoplastic regimen in AML by virtue of getting rid of the cells from a place where they either don’t see the chemotherapy or can’t be killed by the chemotherapy. It can be combined with azacitidine [Onureg] plus venetoclax, which is the go-to regimen for older adults with AML. Theoretically, it can be combined with the more intensive venetoclax regimens that are being developed, like 7+3 chemotherapy plus venetoclax or FLAG-IDA [fludarabine, cytarabine, idarubicin, and granulocyte-colony stimulating factor] plus venetoclax, [a combination] which has been published by [Courtney D. DiNardo, MD, MSCE, of The University of Texas MD Anderson Cancer Center in Houston, Texas].

Regarding safety with uproleselan, earlier trials have shown lower rates of mucositis, a common AE of chemotherapy. How could uproleselan potentially affect these rates of mucositis in these patients?

It would be great to enhance the safety of the chemotherapy by lessening mucositis, which can be quite devastating. [Mucositis can impair] quality of life for our patients undergoing chemotherapy, and it could also lead to bad AEs like bacteremia if the mucosal barrier is overly disrupted. [The mucosal barrier] is important, as are the neutrophils, in preventing infections after chemotherapy.

The mechanism, frankly, of the mucositis protection is a little unclear, but uproleselan does seem to prevent normal cell injury from chemotherapy, and it’s good to see that, although I’m not sure we know why, exactly.

Beyond E-selectin and uproleselan, what other research and potential agents in AML are you particularly intrigued by?

There’s many. If you ask most AML experts, the top 2 agents that come to mind are the CD47 antagonists and the menin inhibitors. Both therapies have had some promising uncontrolled trials that suggest that they, in their own ways, may be able to deal with resistance.

CD47 is an epitope that’s expressed on the surface of many neoplastic cells, including AML cells, the expression of which is an adverse prognostic factor. CD47 helps the leukemic cell by being a “don’t eat me” signal on the surface of the cell. It impairs the ability of the macrophages to destroy the leukemic cell. Using drugs that cover up this “don’t eat me” signal lets macrophages kill the leukemic cell. That is the most prominent mechanism assigned to these antibodies that cover up the “don’t eat me” signal.

The CD47 inhibitor magrolimab is 1 of many CD47 inhibitors in development. It’s certainly the furthest along. The studies with azacitidine and, more recently, azacitidine and venetoclax and azacitidine plus magrolimab, have led to considerably high response rates in AML, particularly in TP53-mutated disease, which is the most noxious AML subtype and does not respond well to chemotherapy at all. It’d be wonderful if we had an agent that enhances responses, prolongs responses, and improves survival [in this population].

Those things are going to be progressively difficult to achieve. However, the randomized trial of azacitidine plus venetoclax vs azacitidine plus magrolimab in TP53-mutant AML, the [phase 3] ENHANCE-2 trial [NCT04778397], sponsored by the company that owns magrolimab, is ongoing. There’ll also be a trial of azacitidine plus venetoclax plus or minus magrolimab in the general older adult AML population that will be important.

There’s also a host of other CD47 inhibitors. We hope that the early encouraging high response rates, particularly in the TP53 context with azacitidine plus magrolimab, will translate into better survival.

We’ve seen, for example, 10-day decitabine be touted as a regimen with a high response rate in TP53-mutant AML. Those data, which were published in the New England Journal of Medicine by [John S. Welch, MD, PhD, of Washington University School of Medicine in St. Louis, Missouri, and colleagues, in 2016], didn’t pan out to improving survival. Hopefully results will be different for magrolimab plus azacitidine or magrolimab plus azacitidine and venetoclax.

Moving on to the menin inhibitors, thanks to work done by [Scott A. Armstrong, MD, PhD, of Dana-Farber Cancer Institute] and [Margaret A. Goodell, PhD, of Baylor College of Medicine in Houston, Texas], we know that menin is an important component of the protein complex that is operative in turning on a bank of genes called the HOX MEIS1 cluster, which are pro-leukemic. This multiprotein complex is highly dependent on this protein, menin, which interacts with many other proteins.

Several agents are in development that disrupt this protein-protein interaction, which, historically, has been hard to do. The 1 that’s farthest along is made by Syndax [Pharmaceuticals Inc.], and another 1 is made by Kira [Pharmaceuticals].

[At least] 2 types of leukemias have a pathophysiology that requires the menin to interact with this protein complex: MLL-rearranged leukemias, generally involving abnormalities in chromosome 11q23, which is highly resistant to most forms of chemotherapy, and the more sensitive, but still often vexing, NPM1-mutant leukemias, which are more common. Those 2 subtypes depend on this protein complex. In both of those subtypes of AML, responses have been seen with those inhibitors.

As single agents, those inhibitors will be combined with azacitidine and venetoclax, and they’ll be combined with standard chemotherapy, and we’ll see if they fit into the FLT3 or IDH inhibitor bandwagon of targeted agents that may enhance chemotherapy in specific subtypes of AML.

What main message would you impart to colleagues based on this research with E-selectin inhibitors?

The phase 3 trials that have either been done or will be completed will be critical in determining whether uproleselan will be added to the armamentarium of our anti-leukemic approaches. Because of its mechanism, it could potentially enhance any anti-leukemic therapy, including FLT3 inhibitors, IDH inhibitors, menin inhibitors, or magrolimab. It’s another way to get rid of the leukemic cell.

As we know from the early days of chemotherapy combinations in Hodgkin lymphoma and many other cancers, it’s important to combine agents that have different mechanisms of action. Uproleselan has a totally different mechanism of action than [treatments like] chemotherapy and venetoclax. Hopefully it’ll be useful.

What are the potential benefits of testing for MRD in AML?

MRD monitoring is now commonly used in AML. The European LeukemiaNet published a paper by Michael Heuser, [of Hannover Medical School in Hannover, Germany,] et al [in 2021], which provided guidelines for the monitoring and actual clinical decision making involving certain MRD results. That remains an area of active investigation and high controversy.

For example, if a patient with AML is being treated with standard chemotherapy or some variant, and they’re still in remission after a couple of cycles of chemotherapy, but they still have evidence of disease based on flow cytometry, or polymerase chain reaction detection if they have a relevant mutation, what [should we] do with that situation, which we know is not good? It’s not good if we need to give them more chemotherapy. It’s not good if we need to do a transplant.

We don’t know if MRD erasure is going to change that negative prognostic effect of having MRD persistence. That, to me, is 1 of the key areas of research in AML that we need to figure out.

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