ONCAlert | Upfront Therapy for mRCC

AML: Managing AEs With Venetoclax + Azacitidine

Targeted Oncology
Published Online:12:00 PM, Tue August 20, 2019

Harry Erba, MD, PhD: How about toxicity in that study? They saw no evidence of tumor lysis syndrome [TLS], clinical or laboratory. The induction mortality, 30-day mortality, was less than 5%. So it’s very well tolerated. Neutropenia, though, is seen. And I think some of the challenges we have in using this regimen are around TLS and around managing the myelosuppression.

In terms of TLS, I think we still have to be quite cautious about using this combination in patients with AML [acute myeloid leukemia]. It’s not free of the risk of TLS. I’ve clearly seen it in my own practice in patients who could have been included in the clinical trial. I’ve seen LDHs [lactate dehydrogenase levels] shoot up to the thousands and creatinine double. So I think we need to be very cautious, and if you’re not set up to monitor these patients closely as an outpatient, they should be admitted when you start. So that’s 1 issue. And remember, again, you need to have cytoreduction prior to starting this regimen.

The second is the neutropenia. Oftentimes the marrow is clear of leukemia after the first or second cycle, but the neutropenia will persist as long as the patient is taking venetoclax. In our population we do feel that you need to hold the venetoclax because there is persistent count suppression. As you alluded to, we’re a little more cautious about using myeloid growth factors in a myeloid leukemia, not that there’s much proof that it causes refractory disease, but still there is some concern about doing that, especially early on when you haven’t seen the response yet.

I think it’s very important for clinicians to know that in many patients you need to do that marrow very early on, day 21 to 28, and if it’s clear of disease or cytoreduction and the counts are still low, you need to hold venetoclax. This is really different from using azacitidine or decitabine, where we just marched on through every 28 days and didn’t expect a response for 4 cycles. And we’ve all become accustomed to just continuing at full dose. I think that’s the other thing that we have to be very careful about.

We don’t really have great guidelines of what to do during the maintenance phase with an HMA [hypomethylating agent] and venetoclax in terms of managing the myelosuppression. Do you shorten the duration of venetoclax? Do you lower the dose? Do you change the dose or schedule of the HMA? We don’t really know. Personally, I’ve shortened the duration of the venetoclax to allow some count recovery, but really there’s no 1 way of taking care of this. I think the clinician just has to be open to this, that they’re going to see neutropenia, and they have to be able to manage it. Then the final point is, unlike in CLL [chronic lymphocytic leukemia], AML docs really feel very strongly about using azole antifungals with induction chemotherapy until the neutropenia goes away.

We typically will use posaconazole because there is a label in the prophylactic setting, but it’s a strong CYP3A4 inhibitor. In the phase Ib experience, they did have a small cohort of patients, about 12, who received posaconazole, the extended-release tablets, and the patients received 50 mg and ramped up to 100 mg. The FDA mandated in the label that a dose be picked; the dose that was picked is 70. Not because 1 was better than another; 70 mg was actually not tested. I don’t give 70 mg because then you have to give 2 prescriptions: 50 and 20 mg. So I give patients 100 mg in combination with the azoles. If they then have a response and aren’t very neutropenic, you can stop the azole antifungal. I think those are some of the things we need to be careful of.

We’ve been very impressed by the duration of these responses in phase Ib; the median survival at first was estimated to be 18 months, maybe a little shorter in follow-up, around 15, 16 months, but still much better than you’d expect with an HMA. Now we’re going to see from the phase III study whether there is a survival benefit with the combination over azacitidine alone. I think that remains to be seen. I still think regardless of the survival benefit, getting patients into remission and having them not require transfusions is definitely a benefit in terms of quality of life.

Matthew Davids, MD, MMSc: Going back to the TLS risk for a little bit, you did allude to the fact that you’ve seen some TLS in your practice. Is there any particular risk factor that has been identified, any risk stratification scheme?

Harry Erba, MD, PhD: Not that I’ve seen. It’s not like CLL, where it’s been so well worked out. Our experience is much more limited with the studies that have been presented. Let’s face it, it’s fewer than 100 patients with that combination, and they’ve been selected not to have a high burden of disease. Where I’ve seen it, it has been in older patients and those who appear to have a normal creatinine, but they have some renal dysfunction. Patients who have some degree of circulating blast. This is where I’ve seen it. This is where I think we need to be careful. But in all patients, I think even if you treat them as an outpatient, you have to be prepared. Obviously, I start these patients all on allopurinol.

You brought up a very interesting way of monitoring patients and being cautious with patients with CLL when you’re treating as an outpatient. First is to identify in CLL someone who might be low risk, but you still will do things to try to mitigate tumor lysis syndrome and complications. And 1 of them was, before they even come in, take the dose at 6 in the morning, so that by the time they get into the clinic and have labs drawn, it might be noon and we can actually intervene before the clinic closes. That makes sense. I’m a little bit worried in AML that that might not be enough, because you’re seeing very robust activity with a single agent, and I’m not sure if the risk of tumor lysis in AML is really just with the single agent or the combination. And so is it possible that you have the drug onboard, but it’s not until you give the HMA later in the day. I think we have to be very cautious about just accepting that what’s done in the CLL world will translate easily into AML, and we have to be careful, especially during those first few days.

Transcript edited for clarity.

Harry Erba, MD, PhD: How about toxicity in that study? They saw no evidence of tumor lysis syndrome [TLS], clinical or laboratory. The induction mortality, 30-day mortality, was less than 5%. So it’s very well tolerated. Neutropenia, though, is seen. And I think some of the challenges we have in using this regimen are around TLS and around managing the myelosuppression.

In terms of TLS, I think we still have to be quite cautious about using this combination in patients with AML [acute myeloid leukemia]. It’s not free of the risk of TLS. I’ve clearly seen it in my own practice in patients who could have been included in the clinical trial. I’ve seen LDHs [lactate dehydrogenase levels] shoot up to the thousands and creatinine double. So I think we need to be very cautious, and if you’re not set up to monitor these patients closely as an outpatient, they should be admitted when you start. So that’s 1 issue. And remember, again, you need to have cytoreduction prior to starting this regimen.

The second is the neutropenia. Oftentimes the marrow is clear of leukemia after the first or second cycle, but the neutropenia will persist as long as the patient is taking venetoclax. In our population we do feel that you need to hold the venetoclax because there is persistent count suppression. As you alluded to, we’re a little more cautious about using myeloid growth factors in a myeloid leukemia, not that there’s much proof that it causes refractory disease, but still there is some concern about doing that, especially early on when you haven’t seen the response yet.

I think it’s very important for clinicians to know that in many patients you need to do that marrow very early on, day 21 to 28, and if it’s clear of disease or cytoreduction and the counts are still low, you need to hold venetoclax. This is really different from using azacitidine or decitabine, where we just marched on through every 28 days and didn’t expect a response for 4 cycles. And we’ve all become accustomed to just continuing at full dose. I think that’s the other thing that we have to be very careful about.

We don’t really have great guidelines of what to do during the maintenance phase with an HMA [hypomethylating agent] and venetoclax in terms of managing the myelosuppression. Do you shorten the duration of venetoclax? Do you lower the dose? Do you change the dose or schedule of the HMA? We don’t really know. Personally, I’ve shortened the duration of the venetoclax to allow some count recovery, but really there’s no 1 way of taking care of this. I think the clinician just has to be open to this, that they’re going to see neutropenia, and they have to be able to manage it. Then the final point is, unlike in CLL [chronic lymphocytic leukemia], AML docs really feel very strongly about using azole antifungals with induction chemotherapy until the neutropenia goes away.

We typically will use posaconazole because there is a label in the prophylactic setting, but it’s a strong CYP3A4 inhibitor. In the phase Ib experience, they did have a small cohort of patients, about 12, who received posaconazole, the extended-release tablets, and the patients received 50 mg and ramped up to 100 mg. The FDA mandated in the label that a dose be picked; the dose that was picked is 70. Not because 1 was better than another; 70 mg was actually not tested. I don’t give 70 mg because then you have to give 2 prescriptions: 50 and 20 mg. So I give patients 100 mg in combination with the azoles. If they then have a response and aren’t very neutropenic, you can stop the azole antifungal. I think those are some of the things we need to be careful of.

We’ve been very impressed by the duration of these responses in phase Ib; the median survival at first was estimated to be 18 months, maybe a little shorter in follow-up, around 15, 16 months, but still much better than you’d expect with an HMA. Now we’re going to see from the phase III study whether there is a survival benefit with the combination over azacitidine alone. I think that remains to be seen. I still think regardless of the survival benefit, getting patients into remission and having them not require transfusions is definitely a benefit in terms of quality of life.

Matthew Davids, MD, MMSc: Going back to the TLS risk for a little bit, you did allude to the fact that you’ve seen some TLS in your practice. Is there any particular risk factor that has been identified, any risk stratification scheme?

Harry Erba, MD, PhD: Not that I’ve seen. It’s not like CLL, where it’s been so well worked out. Our experience is much more limited with the studies that have been presented. Let’s face it, it’s fewer than 100 patients with that combination, and they’ve been selected not to have a high burden of disease. Where I’ve seen it, it has been in older patients and those who appear to have a normal creatinine, but they have some renal dysfunction. Patients who have some degree of circulating blast. This is where I’ve seen it. This is where I think we need to be careful. But in all patients, I think even if you treat them as an outpatient, you have to be prepared. Obviously, I start these patients all on allopurinol.

You brought up a very interesting way of monitoring patients and being cautious with patients with CLL when you’re treating as an outpatient. First is to identify in CLL someone who might be low risk, but you still will do things to try to mitigate tumor lysis syndrome and complications. And 1 of them was, before they even come in, take the dose at 6 in the morning, so that by the time they get into the clinic and have labs drawn, it might be noon and we can actually intervene before the clinic closes. That makes sense. I’m a little bit worried in AML that that might not be enough, because you’re seeing very robust activity with a single agent, and I’m not sure if the risk of tumor lysis in AML is really just with the single agent or the combination. And so is it possible that you have the drug onboard, but it’s not until you give the HMA later in the day. I think we have to be very cautious about just accepting that what’s done in the CLL world will translate easily into AML, and we have to be careful, especially during those first few days.

Transcript edited for clarity.
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