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Promising Targeted Approaches in AML

Panelists: Harry Erba, MD, PhD, University of Alabama at Birmingham; Jorge E. Cortes, MD, MD Anderson Cancer Center; Alexander E. Perl, MD, Perelman School of Medicine; Eunice Wang, MD, Roswell Park Cancer Institute
Published: Wednesday, Mar 14, 2018



Transcript: 

Harry Erba, MD, PhD: Let’s finish up with a few other targeted therapies that I think we’re all excited about. Let me just mention the IDH1 inhibitor ivosidenib, also known as AG-120, in single-agent phase I/phase II data. Remarkably, there are data similar to those we’ve seen with enasidenib in the relapsed/refractory IDH2-mutated setting. These are IDH1-mutated patients, who are a little less frequent, with a 20% CR rate and overall response rate of 40% to 50%. Some deep remissions have been seen, including clearance of the differentiation syndrome being probable.

Eunice Wang, MD: It’s very similar.

Harry Erba, MD, PhD: Very similar. How about venetoclax, Jorge?

Jorge E. Cortes, MD: Venetoclax is a BCL2 inhibitor that, of course, we know in CLL is very effective and well tolerated once we figure out the scheduling at the beginning to eliminate the tumor lysis syndrome issue. There has always been interest in BCL2 in AML because it’s always present and probably overexpressed in many instances. It was many years ago that we had oligonucleotide, and there was high hope for that, but it ended up dying. I remember there was some work—I don’t remember what company was working on it—on apoptosis, and they developed this clever thing that said, “Keep apoptosis alive.” I’m glad we did because eventually we figured out venetoclax. The data that have been generated, particularly in combination with high-methylating agents and also with low-dose Ara-C, have been quite impressive. The response rate—and these are older patients—is in the upper 70% range. Of course, we want control trials and we want more, but it looks pretty impressive.

Harry Erba, MD, PhD: I agree. I think they are very impressive data. The CR rate and the overall response rates are very high, but let’s be cautious. We’ve seen very high overall response rates, for example, with vadastuximab with azacitidine, the anti-CD33 antibody. We need to see that it translates into a survival benefit. We need to make sure it’s tolerable in these patients. I’m going to move on to Eunice. There’s this class of drugs, E-selectin inhibitors, and there is 1 agent that’s moving along in clinical development.

Eunice Wang, MD: This goes back to your original question about the importance of the microenvironment. We know that leukemic stem cells stay within the specific marrow niches, and they have very close relationships with the endothelial and mesenchymal cells that are in the bone marrow microenvironment. Just by taking a leukemic cell and attaching it to endothelial cells or mesenchymal cells, just by having them physically interact, there are ligands that are triggered and factors that are released that allow that to be inherently chemotherapy resistant. When you add chemotherapy, the cells just don’t die.

With this E-selectin agent, it’s going in, and it’s a 1-hour infusion that you give 1 or 2 days prior to chemotherapy, a couple of days after chemotherapy, as well as during the chemotherapy. What it is doing is blocking that very specific therapy-related mediated interaction between the leukemic cell and the microenvironment. By cutting off that E-selectin, which is a key adhesion molecule, those cells cannot adhere, and so they are in suspension. Then, when they’re in suspension, they don’t have the protective mechanisms; they don’t have the activated pathways that promote survival in that setting. When they get exposed to chemotherapy, the hypothesis is that they die.

The exposure to E-selectin inhibition prior to, during, and after chemotherapy has been hypothesized to render those cells inherently more sensitive to baseline chemotherapy. The initial trials, presented here by Daniel DeAngelo at this particular congress, show pretty impressive results both in patients with relapsed/refractory AML getting salvage chemotherapy as well as in a subset of older patients who were fit enough for standard chemotherapy, with impressive or very convincing response rates in those difficult-to-treat patient populations. This is a drug that when the FDA reviewed the data, whether it’s a mechanistic thing or just the lack of toxicity that they saw, they granted this drug Breakthrough approval. The benefit of it is that some of these patients were getting etoposide, which is a mucosal-damaging agent, and there are preclinical data that suggest in addition to allowing the leukemia cells to be more sensitive, it actually can decrease mucositis because it has effects in that region of the microenvironment.

Harry Erba, MD, PhD: Wearing my SWOG leukemia hat, one of the things I’m really excited about is a partnership between the NCI and the sponsor of this drug moving it into a phase III study in older patients who are fit for chemotherapy comparing 7-and-3 chemotherapy versus 7-and-3 chemotherapy with the E-selectin inhibitor GMI-1271. This study has been approved by the Leukemia Steering Committee, so hopefully it’ll be a study that our patients can be registered on next year.

Transcript Edited for Clarity 

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Transcript: 

Harry Erba, MD, PhD: Let’s finish up with a few other targeted therapies that I think we’re all excited about. Let me just mention the IDH1 inhibitor ivosidenib, also known as AG-120, in single-agent phase I/phase II data. Remarkably, there are data similar to those we’ve seen with enasidenib in the relapsed/refractory IDH2-mutated setting. These are IDH1-mutated patients, who are a little less frequent, with a 20% CR rate and overall response rate of 40% to 50%. Some deep remissions have been seen, including clearance of the differentiation syndrome being probable.

Eunice Wang, MD: It’s very similar.

Harry Erba, MD, PhD: Very similar. How about venetoclax, Jorge?

Jorge E. Cortes, MD: Venetoclax is a BCL2 inhibitor that, of course, we know in CLL is very effective and well tolerated once we figure out the scheduling at the beginning to eliminate the tumor lysis syndrome issue. There has always been interest in BCL2 in AML because it’s always present and probably overexpressed in many instances. It was many years ago that we had oligonucleotide, and there was high hope for that, but it ended up dying. I remember there was some work—I don’t remember what company was working on it—on apoptosis, and they developed this clever thing that said, “Keep apoptosis alive.” I’m glad we did because eventually we figured out venetoclax. The data that have been generated, particularly in combination with high-methylating agents and also with low-dose Ara-C, have been quite impressive. The response rate—and these are older patients—is in the upper 70% range. Of course, we want control trials and we want more, but it looks pretty impressive.

Harry Erba, MD, PhD: I agree. I think they are very impressive data. The CR rate and the overall response rates are very high, but let’s be cautious. We’ve seen very high overall response rates, for example, with vadastuximab with azacitidine, the anti-CD33 antibody. We need to see that it translates into a survival benefit. We need to make sure it’s tolerable in these patients. I’m going to move on to Eunice. There’s this class of drugs, E-selectin inhibitors, and there is 1 agent that’s moving along in clinical development.

Eunice Wang, MD: This goes back to your original question about the importance of the microenvironment. We know that leukemic stem cells stay within the specific marrow niches, and they have very close relationships with the endothelial and mesenchymal cells that are in the bone marrow microenvironment. Just by taking a leukemic cell and attaching it to endothelial cells or mesenchymal cells, just by having them physically interact, there are ligands that are triggered and factors that are released that allow that to be inherently chemotherapy resistant. When you add chemotherapy, the cells just don’t die.

With this E-selectin agent, it’s going in, and it’s a 1-hour infusion that you give 1 or 2 days prior to chemotherapy, a couple of days after chemotherapy, as well as during the chemotherapy. What it is doing is blocking that very specific therapy-related mediated interaction between the leukemic cell and the microenvironment. By cutting off that E-selectin, which is a key adhesion molecule, those cells cannot adhere, and so they are in suspension. Then, when they’re in suspension, they don’t have the protective mechanisms; they don’t have the activated pathways that promote survival in that setting. When they get exposed to chemotherapy, the hypothesis is that they die.

The exposure to E-selectin inhibition prior to, during, and after chemotherapy has been hypothesized to render those cells inherently more sensitive to baseline chemotherapy. The initial trials, presented here by Daniel DeAngelo at this particular congress, show pretty impressive results both in patients with relapsed/refractory AML getting salvage chemotherapy as well as in a subset of older patients who were fit enough for standard chemotherapy, with impressive or very convincing response rates in those difficult-to-treat patient populations. This is a drug that when the FDA reviewed the data, whether it’s a mechanistic thing or just the lack of toxicity that they saw, they granted this drug Breakthrough approval. The benefit of it is that some of these patients were getting etoposide, which is a mucosal-damaging agent, and there are preclinical data that suggest in addition to allowing the leukemia cells to be more sensitive, it actually can decrease mucositis because it has effects in that region of the microenvironment.

Harry Erba, MD, PhD: Wearing my SWOG leukemia hat, one of the things I’m really excited about is a partnership between the NCI and the sponsor of this drug moving it into a phase III study in older patients who are fit for chemotherapy comparing 7-and-3 chemotherapy versus 7-and-3 chemotherapy with the E-selectin inhibitor GMI-1271. This study has been approved by the Leukemia Steering Committee, so hopefully it’ll be a study that our patients can be registered on next year.

Transcript Edited for Clarity 
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