AML Research Continues to Explore Precision Medicine Options

Decision-making among oncologists who treat acute myeloid leukemia (AML) has become easier in the past 6 to 7 years, according to Brian A. Jonas, MD. This progress is due to the knowledge of biomarkers like genetic lesions, mutations, and chromosome abnormalities and how they affect a patient’s disease.

Research shows that alterations like FLT3 mutations, minimal residual disease status, IDH1/IDH2 mutations, CD33, and TP53 mutations are treatable with targeted therapies. Other alterations like NMP1 mutations, RUNX1 mutations, and mutations associated with the e-selectin ligand are being investigated. According to Jonas, associate professor of medicine at UC Davis Health in Sacramento, California, e-selectin is one of the most interesting novel biomarkers in AML.¹

“There's been a drug developed to target the e-selectin ligand interaction, it’s a so-called e-selectin 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,” Jonas told Targeted Oncology™, in an interview.

In the phase 1/2 trial of uproleselan in combination with mitoxantrone etoposide, and cytarabine (MEC;NCT02306291), the median overall survival (OS) among in the relapsed or refractory AML population was 8.8 months, according to data presented at the American Society of Hematology (ASH) Annual Meeting. In the newly diagnosed population, the OS was 12.6 months. Overall, treatment with the e-selectin inhibitor was associated with higher rates of response and improved survival in patients with relapsed/refractory disease. Treatment in the study was also well-tolerated.²

For other biomarker like NPM1 and MLL1, Jonas explained that Menin inhibitors are showing promise for the treatment of AML. A presentation of the phase 1/2 KOMET-001 study (NCT04067336) at the ASH Annual Meeting showed that ziftomenib (KO-539) has preliminary efficacy and a manageable safety profile. The agent achieved complete response (CR) rate or CR with partial hematologic recovery rate of 33%.³

Jonas stated the multiple studies are ongoing to further investigate uproleselan and other targeted therapies for AML treatment.

In the interview, Jonas took a close look at the precision medicine landscape for AML and discussed key biomarker and research needs for the future.

TARGETED ONCOLOGY: What are the most relevant biomarkers in AML at present?

Jonas: When we think about the bottom records with the most data right now, I would think of things like the genetic lesions and the mutations, the chromosome abnormalities, as being the principal driving force in a lot of our decision-making in AML. This is true whether it's a decision about transplant, or a decision about therapy. But there are emerging market biomarkers out there, and one of them is e-selectin.

E-selectin is involved in the bone marrow microenvironment where the hematopoietic stem cells, and the leukemia stem cells are located. It's a molecule, it's kind of like a sticky molecule that binds the selected ligand on the cell, and then it causes them to be retained or stay in that microenvironment. It’s involved in a lot of the interactions involved in a lot of intracellular pathways as well. It can be a potential target for AML treatment.

Can you discuss any research supporting e-selectin as a biomarker in AML?

There's 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.

What important updates in AML came out of the ASH Annual Meeting?

There's so much going on right now. I think the drugs that are very exciting to everyone are things like the drugs that target CD47. For examples, CD47-targeting antibodies like magrolimab are exciting. Then there's a whole new class of drugs that are being explored, and the early returns are very promising. Those are the Menin inhibitors, which will allow us to target NPM1 mutations and MLL1 rearrangements, which are alterations that we've historically not been able to target. There's more data coming out with those drugs, and I think that they are very promising.

There was an interesting plenary at ASH, talked about the potential to take patients to transplant without giving them salvage chemotherapy. I think that's something that's going to be potentially something that needs to be verified. It's also in a practice pattern that's not totally consistent with how we do things in the United States. But nevertheless, it was a very intriguing and very thought-provoking study and could ultimately affect practice.

There are multiple interesting studies that came out of ASH with regards to maintenance approaches in AML. For example, maintenance with targeted agents after transplant, or HMA after transplant. I think all those presentations were interesting. Of course, we had our own investigator-initiated trial results with the uproleselan combination, which I think was intriguing, but of course, those were very early results.

What will be important research topics for AML going forward?

I know that I just talked amount my excitement with all the progress, but there is still a long way to go. Those of us who take care of patients with AML, unfortunately, see issues on a day-to-day basis in our practices. I think treatment for the relapse patients is still a huge unmet need. They unfortunately, don't have great outcomes still, and there's a lot of progress that needs to be made with them. On that subject, at the Tandem meetings there was a presentation on a new drug. I apamistamab [Iomab-B] that very interesting for patients with active disease and destined to go to transplant. That's hopefully something that might be important for that space. Obviously, we need a lot of new combinations and new targeted agents to help us with these relapsed/refractory patients.

On the other hand, we've made tons of progress in the frontline setting, but I wouldn't say that we've, won the game there because, of course, I just got through talking about how much trouble there is with relapse. We still have a long way to go with even our frontline therapies. More targeted agents may be moving into the frontline and different combinations and maintenance strategies to try to prevent relapse. I think those are still areas of need.

Additional approaches to enhance the efficacy and safety of transplant and to maybe expand the number of people that would be able to get by marrow transplant, I think would be a research topic that I would welcome. I think getting more immunotherapy approaches into AML realm, like more chimeric antigen receptor T approaches, which are having huge success with our colleagues that treat and lymphoma, would be beneficial as well. I'm sure there are many other unmet needs that I haven't addressed.

I think my overall message would be we've made huge strides in the last 6 or 7, but we started at a kind of a low bar. We still have a long way to go, and I think we're starting to get the tools that we need to have in order to make huge strides. I think that's why I'm so excited about these new molecules that are being tested. I think it’s a result of all this effort we put into understanding the biology and the mutational spectrum of the disease now.

_REFERENCES:

_{1. Small S, Oh TS, Platanias LC, et al. Role of biomarkers in the management of acute myeloid leukemia. Int J Mol Sci. 2022; 23(23): 14543. doi: 10.3390/ijms232314543}

_{2. 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. 2022;139 (8): 1135–1146. doi: 10.1182/blood.2021010721}

_{3. Erba HP, FAthi AT, Issa GC, et al. 64 Update on a Phase 1/2 first-in-human study of the Menin-KMT2A (MLL) inhibitor ziftomenib (KO-539) in patients with relapsed or refractory acute myeloid leukemia. Blood. 2022; 140 (suppl 1): 153–156. doi: 10.1182/blood-2022-167412}