ONCAlert | Upfront Therapy for mRCC

AML: Optimizing Selection and Use of Venetoclax + Azacitidine

Targeted Oncology
Published Online:12:00 PM, Thu August 22, 2019

Harry Erba, MD, PhD: Quickly, the other study that’s been posted by Andrew Wei, MBBS, PhD, now in Journal of Clinical Oncology just this year was the phase Ib experience with low-dose AraC [cytarabine] and venetoclax. Again, the venetoclax ramped up to 600 mg very quickly. In that regimen the response rate was a little lower, just above 50%, and it’s probably because they did accept patients who had received prior HMAs [hypomethylating agents]. If you look at the prior-HMA-exposure patients, the responses were only about 35%, and only 5% of those were complete remission. So that’s a little signal that prior HMA exposure may predict for more resistance, but unfortunately this is what we see in patients who have failed prior HMA exposure, and treatment is that they have a very poor outcome because of resistance to therapies.

This is a very, very promising regimen. What makes it so exciting is that we now really do have a regimen with a very high response rate in these older infirm patients. But I still think we need to be cautious about how we use it and give it safely to patients with AML [acute myeloid leukemia].

Matthew Davids, MD, MMSc: When you have an AML patient who would qualify for 1 of these studies, and you’re going to choose 1 of these 2, how do you choose hypomethylating versus low-dose AraC?

Harry Erba, MD, PhD: It’s a great question. I tend not to use a lot of low-dose AraC. The benefit of low-dose AraC is that it’s a subcutaneous injection. It’s a tiny dose, 20 mg, a flat dose you could give. There are many different regimens, but that’s 1 of them. And so you could give it at home, but you can’t give it at home; that’s the problem. Home med companies often do not give this chemotherapy at home. So that’s been the biggest challenge. If we can make that easier, I think that would be a very attractive way of treating patients, because they wouldn’t have to come in for that first week.

Having said that, at least for that first cycle I’m happy that they’re coming in for that first week, because I want to monitor them closely during the ramp-up for tumor lysis syndrome anyways. And quite frankly, during that first cycle, they’re coming in at least twice a week, maybe three times a week for transfusion support, because it’s a marrow failure syndrome.

I generally use an HMA. I think the response is about the same, taking into account that the low-dose AraC had some HMA failures, and that’s why it might be a little lower, but it’s really that I’m accustomed to using an HMA in that setting.

Matthew Davids, MD, MMSc: You mentioned that the durability of the response is generally good when you look at the overall population, but do you see differences in terms of molecular subtypes with that?

Harry Erba, MD, PhD: Yes. Unfortunately, the TP53 patients still have a very short duration of response. I have used it in that situation because chemotherapy leaves a lot to be desired as well, and my own experience has been that you can get a response, but the response is quite short. If you’re thinking about curative options for a patient, you need to get them quickly to a transplant.

Matthew Davids, MD, MMSc: As you’ve mentioned, the data that have been presented so far have been mainly in an older, frailer population. Have you extrapolated that to a younger AML population yet?

Harry Erba, MD, PhD: This is going to be a very important issue. I’m sure it’ll work there. Honestly, I will use that regimen in a younger patient with comorbidities who might not completely preclude chemotherapy, but especially in patients with high-risk disease, with P53, with complex karyotypes. The duration is short, but let’s face it, the goal in those patients is going to be to get them to a transplant. What I don’t know is treating them with intensive chemotherapy, getting them into remission, and then a transplant, is that outcome going to be as good as an HMA venetoclax-based regimen, achieving a remission and then transplant. We don’t know the answer to that yet. But in a patient who’s a little younger and infirm in some way, I do think it’s an option for them.

What I am concerned about, though, is that this is a regimen that will be more easily given outside major academic centers. You don’t need to admit these patients for therapy. I think we still need to remember, or at least think about, what is the goal of treatment right from the start? Is the goal of the treatment cure, or is the goal palliation? If the goal is cure, then we really have no data to support using HMA venetoclax in that setting, and we have to think about the most appropriate chemotherapy regimens to use to get a patient to a transplant.

Transcript edited for clarity.

Harry Erba, MD, PhD: Quickly, the other study that’s been posted by Andrew Wei, MBBS, PhD, now in Journal of Clinical Oncology just this year was the phase Ib experience with low-dose AraC [cytarabine] and venetoclax. Again, the venetoclax ramped up to 600 mg very quickly. In that regimen the response rate was a little lower, just above 50%, and it’s probably because they did accept patients who had received prior HMAs [hypomethylating agents]. If you look at the prior-HMA-exposure patients, the responses were only about 35%, and only 5% of those were complete remission. So that’s a little signal that prior HMA exposure may predict for more resistance, but unfortunately this is what we see in patients who have failed prior HMA exposure, and treatment is that they have a very poor outcome because of resistance to therapies.

This is a very, very promising regimen. What makes it so exciting is that we now really do have a regimen with a very high response rate in these older infirm patients. But I still think we need to be cautious about how we use it and give it safely to patients with AML [acute myeloid leukemia].

Matthew Davids, MD, MMSc: When you have an AML patient who would qualify for 1 of these studies, and you’re going to choose 1 of these 2, how do you choose hypomethylating versus low-dose AraC?

Harry Erba, MD, PhD: It’s a great question. I tend not to use a lot of low-dose AraC. The benefit of low-dose AraC is that it’s a subcutaneous injection. It’s a tiny dose, 20 mg, a flat dose you could give. There are many different regimens, but that’s 1 of them. And so you could give it at home, but you can’t give it at home; that’s the problem. Home med companies often do not give this chemotherapy at home. So that’s been the biggest challenge. If we can make that easier, I think that would be a very attractive way of treating patients, because they wouldn’t have to come in for that first week.

Having said that, at least for that first cycle I’m happy that they’re coming in for that first week, because I want to monitor them closely during the ramp-up for tumor lysis syndrome anyways. And quite frankly, during that first cycle, they’re coming in at least twice a week, maybe three times a week for transfusion support, because it’s a marrow failure syndrome.

I generally use an HMA. I think the response is about the same, taking into account that the low-dose AraC had some HMA failures, and that’s why it might be a little lower, but it’s really that I’m accustomed to using an HMA in that setting.

Matthew Davids, MD, MMSc: You mentioned that the durability of the response is generally good when you look at the overall population, but do you see differences in terms of molecular subtypes with that?

Harry Erba, MD, PhD: Yes. Unfortunately, the TP53 patients still have a very short duration of response. I have used it in that situation because chemotherapy leaves a lot to be desired as well, and my own experience has been that you can get a response, but the response is quite short. If you’re thinking about curative options for a patient, you need to get them quickly to a transplant.

Matthew Davids, MD, MMSc: As you’ve mentioned, the data that have been presented so far have been mainly in an older, frailer population. Have you extrapolated that to a younger AML population yet?

Harry Erba, MD, PhD: This is going to be a very important issue. I’m sure it’ll work there. Honestly, I will use that regimen in a younger patient with comorbidities who might not completely preclude chemotherapy, but especially in patients with high-risk disease, with P53, with complex karyotypes. The duration is short, but let’s face it, the goal in those patients is going to be to get them to a transplant. What I don’t know is treating them with intensive chemotherapy, getting them into remission, and then a transplant, is that outcome going to be as good as an HMA venetoclax-based regimen, achieving a remission and then transplant. We don’t know the answer to that yet. But in a patient who’s a little younger and infirm in some way, I do think it’s an option for them.

What I am concerned about, though, is that this is a regimen that will be more easily given outside major academic centers. You don’t need to admit these patients for therapy. I think we still need to remember, or at least think about, what is the goal of treatment right from the start? Is the goal of the treatment cure, or is the goal palliation? If the goal is cure, then we really have no data to support using HMA venetoclax in that setting, and we have to think about the most appropriate chemotherapy regimens to use to get a patient to a transplant.

Transcript edited for clarity.
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