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The Future of AML Therapy: Cause for Optimism

Panelists: Matthew S. Davids, MD, MMSc Dana-Farber Cancer Institute; Naval G. Daver, MD The University of Texas MD Anderson Cancer Center; Daniel A. Pollyea, MD, MS University of Colorado School of Medicine
Published: Thursday, Feb 07, 2019



Transcript: 

Daniel A. Pollyea, MD, MS:
In my view, the most promising therapies for AML [acute myeloid leukemia] are those that affect the leukemic stem cell compartment. Leukemia stem cells are the root cause of the disease, they’re the source of relapse when it occurs. They’re the population that’s typically not killed by chemotherapy. Venetoclax with azacitidine—at least we know that effectively targets the leukemia stem cells, and that at least partially accounts for these really exciting outcomes.

So other therapies that can target leukemic stem cell compartment and specific weaknesses of the leukemic stem population would be really interesting, and there are some. There are some that are in active clinical development, some that got reported at ASH [the American Society of Hematology Annual Meeting and Exposition]. I think we’re really, really excited about, about the potential to target leukemic stem cells.

When you try to think about what the unmet needs of AML are, it really encompasses the entire disease. There are no places that historically have been very successful with this disease. I think an unmet need remains the older unfit patients. I think an unmet need remains the older patients who are deemed fit for chemotherapy. I think an unmet need are younger patients who are candidates for intensive chemotherapy. Historically, we haven’t done well in any of those subsets. So I think that, and then in the relapse setting, of course there’s a huge unmet need. There’s a lot of work to be done here, and I think unmet needs are, you know, in every subset of AML that you look at.

Naval G. Daver, MD: One of the major areas of development that was very heavily represented and presented at ASH this year was immunotherapeutics in acute myeloid leukemia. And this included new antibody drug conjugates [ADCs]. We have 1 antibody drug conjugate, called Mylotarg or gemtuzumab ozogamicin, that’s already approved and has been used. It’s a good drug, but it had some problems with VOD [veno-occlusive disease] myelosuppression. So there are a number of new ADCs. Imunogen has a CD33 and 123 ADC with the chemical payload. That is a next-generation payload that seems to be potent but with less myelosuppression. And we saw some data at this year’s ASH that both of these looked active in relapsed AML with maybe a better tolerability profile than has been seen with gemtuzumab [ozogamicin]. Especially the CD123 seemed to induce about 30% CR complete response rates in relapsed AML without significant myelosuppression, which is quite striking but is very helpful because eventually these drugs will be combined with HMA [a hypomethylating agent], with HMA venetoclax with chemotherapy.

There’s also a big group of T-cell-based therapies in which we use your body’s own T cells to fight against tumors, which is of course becoming the poster child in 1 of the major breakthroughs for solid tumors and lymphoma, but we are seeing similar things with either bispecific antibodies, or with immune checkpoint-based treatments in AML. So we do see that there’s a subset of patients, especially newly diagnosed, early relapsed patients who haven’t had very intensive prolonged chemotherapy who do have a preserved T-cell number and function in their bone marrow and blood. And these T-cells can be harnessed in clinical trials using bispecific antibodies such as AMG330, which is an Amgen CD3, CD33, or an XmAb bispecific, which is a CD3, CD123, or MacroGenics. All 3 of these had oral presentations at ASH.
One of the things we’re seeing with the bispecifics is that even though they’re active, they work best in low-burden disease, people with less than 20% percent blast, because these people have less blast and T cells and more favorable inflammatory immune patterns in their bone marrow, as opposed to those who have lots of blasts in which there are no T cells and nothing to harness.

And the same thing is also being seen with some of the immune checkpoints, especially in salvage 1 and 2 seem to be very effective in people who had no prior azacitidine—the azacitidine, nivolumab is giving us response rates of 52%, which is in the relapse setting very, very encouraging, as well as a survival benefit.

So I think one of the important things with a lot of these immune therapies is that they do have unique toxicities, especially VT-cell therapies. They can cause cytokine release syndromes, organ inflammation, colitis, nephritis, and pneumonitis. So I don’t think these are ready to be used widely in the community setting. They should probably be done more in academic or large community centers that have good expertise with the immunotherapies. And as one gets more familiar and the knowledge spreads, I think eventually these will start going to registrational pathways and be used. So I think this is the space to look out for in the next year or two, how we combine and collaborate immune therapies with molecular and HMA therapies, minimizing and maybe even obviating chemotherapy in some groups of patients.
Daniel A. Pollyea, MD, MS: For community oncologists treating AML, this is a rare disease, and if a person’s practice doesn’t have quite a bit of AML, I think all these approvals and all these gene tests are quite daunting, or would be to me. So I think doing your best to consult with a colleague who may treat more AML, have more experience and can talk through some of these new and exciting options would be a real priority when trying to manage an AML patient.

Naval G. Daver, MD: We’re making progress, there’s no doubt about that. And sometimes when you see the news blasts and e-mails, it seems as if we may have cured AML. That’s not the case. Even with azacitidine and venetoclax, which is wonderful, we went from 10% to 15% survival for our elderly AML, which was sad, to 45% to 50%, which is good, but that’s not enough. We would like to go to 75% to 100% percent like APL [acute promyelocytic leukemia], like CML [chronic myelocytic leukemia], and it could be done in those other tumors. In the last decade, 15 years, we’ve done this.

So I would recommend that if you don’t have a big academic or community center, send these people for trials. I think we’re still looking for patients. In fact, now the real research is beginning as these drugs come out because now we have the tools—how do we combine them, how do we combine them safely because it’s not going to be 1 plus 1 plus 1. You cannot combine azacitidine and venetoclax with quizartinib and gilteritinib without those modifications, sequence, interruptions, count recovery. And so I would say be very cognizant that you have major centers. Considering sending your patients for trials, even 70-, 75-, 80-year-old patients may get many years’ good quality.

Almost no patient today really should be denied treatment. The recent SEER data show almost 50% of patients above 65 are not treated. That’s not acceptable today. I think that’s malpractice. You have the tools, and you have the drugs. If you don’t have the experience and knowledge, call your local doctor, send them to your local academic community center. But no longer can community doctors or academic doctors say, “Oh, you’re 70. There’s nothing I can do. Go home.” I think that’s very inappropriate and should not be done. We need to treat these patients.

And I think the third is, you know we talk a lot about the efficacy, and you see all the knowledge about these drugs. But each one does have some unique toxicities. And if you’re going to use them, you need to learn about them. With venetoclax, you have prolonged neutropenia, so you need to build in dose interruptions. We do a bone marrow at the end of day 28. If the bone marrow is ablated in remission, we actually stop venetoclax for 10, 14, 18, 20 days with close monitoring to allow count recovery. And in the next cycle, we would do only 14 or 21 days of venetoclax.

So there’s a little bit of art…in this. You cannot just give 28 days’ continuous AZA [azacytidine] and venetoclax; 80% of your people who’ve been neutropenic will get infection or die, and then you won’t see the benefit that was seen in the phase III studies. It’s not because the drug doesn’t work; it’s just the technique. And the same is true for gemtuzumab. You need to monitor for VOD very closely. Vyxeos is a very effective drug, but it’s chemotherapy. Quizartinib and gilteritinib cause myelosuppression. They need to be on antibacterial, antifungal prophylaxis close monitoring.

So the point is that before you use these drugs you know, read one of the papers, review a little bit of the data so that you use it in the right setting, so that you do get the same benefits that we would like you to get—that we got in our trials.


Transcript Edited for Clarity 
 
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Transcript: 

Daniel A. Pollyea, MD, MS:
In my view, the most promising therapies for AML [acute myeloid leukemia] are those that affect the leukemic stem cell compartment. Leukemia stem cells are the root cause of the disease, they’re the source of relapse when it occurs. They’re the population that’s typically not killed by chemotherapy. Venetoclax with azacitidine—at least we know that effectively targets the leukemia stem cells, and that at least partially accounts for these really exciting outcomes.

So other therapies that can target leukemic stem cell compartment and specific weaknesses of the leukemic stem population would be really interesting, and there are some. There are some that are in active clinical development, some that got reported at ASH [the American Society of Hematology Annual Meeting and Exposition]. I think we’re really, really excited about, about the potential to target leukemic stem cells.

When you try to think about what the unmet needs of AML are, it really encompasses the entire disease. There are no places that historically have been very successful with this disease. I think an unmet need remains the older unfit patients. I think an unmet need remains the older patients who are deemed fit for chemotherapy. I think an unmet need are younger patients who are candidates for intensive chemotherapy. Historically, we haven’t done well in any of those subsets. So I think that, and then in the relapse setting, of course there’s a huge unmet need. There’s a lot of work to be done here, and I think unmet needs are, you know, in every subset of AML that you look at.

Naval G. Daver, MD: One of the major areas of development that was very heavily represented and presented at ASH this year was immunotherapeutics in acute myeloid leukemia. And this included new antibody drug conjugates [ADCs]. We have 1 antibody drug conjugate, called Mylotarg or gemtuzumab ozogamicin, that’s already approved and has been used. It’s a good drug, but it had some problems with VOD [veno-occlusive disease] myelosuppression. So there are a number of new ADCs. Imunogen has a CD33 and 123 ADC with the chemical payload. That is a next-generation payload that seems to be potent but with less myelosuppression. And we saw some data at this year’s ASH that both of these looked active in relapsed AML with maybe a better tolerability profile than has been seen with gemtuzumab [ozogamicin]. Especially the CD123 seemed to induce about 30% CR complete response rates in relapsed AML without significant myelosuppression, which is quite striking but is very helpful because eventually these drugs will be combined with HMA [a hypomethylating agent], with HMA venetoclax with chemotherapy.

There’s also a big group of T-cell-based therapies in which we use your body’s own T cells to fight against tumors, which is of course becoming the poster child in 1 of the major breakthroughs for solid tumors and lymphoma, but we are seeing similar things with either bispecific antibodies, or with immune checkpoint-based treatments in AML. So we do see that there’s a subset of patients, especially newly diagnosed, early relapsed patients who haven’t had very intensive prolonged chemotherapy who do have a preserved T-cell number and function in their bone marrow and blood. And these T-cells can be harnessed in clinical trials using bispecific antibodies such as AMG330, which is an Amgen CD3, CD33, or an XmAb bispecific, which is a CD3, CD123, or MacroGenics. All 3 of these had oral presentations at ASH.
One of the things we’re seeing with the bispecifics is that even though they’re active, they work best in low-burden disease, people with less than 20% percent blast, because these people have less blast and T cells and more favorable inflammatory immune patterns in their bone marrow, as opposed to those who have lots of blasts in which there are no T cells and nothing to harness.

And the same thing is also being seen with some of the immune checkpoints, especially in salvage 1 and 2 seem to be very effective in people who had no prior azacitidine—the azacitidine, nivolumab is giving us response rates of 52%, which is in the relapse setting very, very encouraging, as well as a survival benefit.

So I think one of the important things with a lot of these immune therapies is that they do have unique toxicities, especially VT-cell therapies. They can cause cytokine release syndromes, organ inflammation, colitis, nephritis, and pneumonitis. So I don’t think these are ready to be used widely in the community setting. They should probably be done more in academic or large community centers that have good expertise with the immunotherapies. And as one gets more familiar and the knowledge spreads, I think eventually these will start going to registrational pathways and be used. So I think this is the space to look out for in the next year or two, how we combine and collaborate immune therapies with molecular and HMA therapies, minimizing and maybe even obviating chemotherapy in some groups of patients.
Daniel A. Pollyea, MD, MS: For community oncologists treating AML, this is a rare disease, and if a person’s practice doesn’t have quite a bit of AML, I think all these approvals and all these gene tests are quite daunting, or would be to me. So I think doing your best to consult with a colleague who may treat more AML, have more experience and can talk through some of these new and exciting options would be a real priority when trying to manage an AML patient.

Naval G. Daver, MD: We’re making progress, there’s no doubt about that. And sometimes when you see the news blasts and e-mails, it seems as if we may have cured AML. That’s not the case. Even with azacitidine and venetoclax, which is wonderful, we went from 10% to 15% survival for our elderly AML, which was sad, to 45% to 50%, which is good, but that’s not enough. We would like to go to 75% to 100% percent like APL [acute promyelocytic leukemia], like CML [chronic myelocytic leukemia], and it could be done in those other tumors. In the last decade, 15 years, we’ve done this.

So I would recommend that if you don’t have a big academic or community center, send these people for trials. I think we’re still looking for patients. In fact, now the real research is beginning as these drugs come out because now we have the tools—how do we combine them, how do we combine them safely because it’s not going to be 1 plus 1 plus 1. You cannot combine azacitidine and venetoclax with quizartinib and gilteritinib without those modifications, sequence, interruptions, count recovery. And so I would say be very cognizant that you have major centers. Considering sending your patients for trials, even 70-, 75-, 80-year-old patients may get many years’ good quality.

Almost no patient today really should be denied treatment. The recent SEER data show almost 50% of patients above 65 are not treated. That’s not acceptable today. I think that’s malpractice. You have the tools, and you have the drugs. If you don’t have the experience and knowledge, call your local doctor, send them to your local academic community center. But no longer can community doctors or academic doctors say, “Oh, you’re 70. There’s nothing I can do. Go home.” I think that’s very inappropriate and should not be done. We need to treat these patients.

And I think the third is, you know we talk a lot about the efficacy, and you see all the knowledge about these drugs. But each one does have some unique toxicities. And if you’re going to use them, you need to learn about them. With venetoclax, you have prolonged neutropenia, so you need to build in dose interruptions. We do a bone marrow at the end of day 28. If the bone marrow is ablated in remission, we actually stop venetoclax for 10, 14, 18, 20 days with close monitoring to allow count recovery. And in the next cycle, we would do only 14 or 21 days of venetoclax.

So there’s a little bit of art…in this. You cannot just give 28 days’ continuous AZA [azacytidine] and venetoclax; 80% of your people who’ve been neutropenic will get infection or die, and then you won’t see the benefit that was seen in the phase III studies. It’s not because the drug doesn’t work; it’s just the technique. And the same is true for gemtuzumab. You need to monitor for VOD very closely. Vyxeos is a very effective drug, but it’s chemotherapy. Quizartinib and gilteritinib cause myelosuppression. They need to be on antibacterial, antifungal prophylaxis close monitoring.

So the point is that before you use these drugs you know, read one of the papers, review a little bit of the data so that you use it in the right setting, so that you do get the same benefits that we would like you to get—that we got in our trials.


Transcript Edited for Clarity 
 
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