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Venetoclax-Based Regimens as First-Line Therapy in AML

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: Friday, Jan 25, 2019



Transcript:

Naval G. Daver, MD: Venetoclax is a BCL2 inhibitor. BCL2 is a very important antiapoptotic pathway that plays a major role in many malignancies, specifically we know in CLL, AML, [chronic lymphocytic leukemia, acute myeloid leukemia] also in ALL [acute lymphocytic leukemia], and some other lymphomas. So by blocking the BCL2, we’re basically antagonizing the antiapoptosis. So it’s a double negative. So basically by blocking antiapoptosis you’re promoting apoptosis, which is good because apoptosis are results in shrinkage and death of the tumor. That is a known mechanism of action. We do think there are some off target potential activities and other pathways that may be at play, but they haven’t been completely elucidated.

Venetoclax was valued at a single agent in relapsed/refractory AML. It was a study led by Dr Marina Konopleva, MD, PhD, from our institution and published a couple of years ago in Cancer Discovery. And it showed that a single-agent venetoclax has a response rate of about 15% to 20%. Nothing earthshattering. Most responses are very short lived, 4 to 6 weeks, so not very exciting to pursue in that approach.

We subsequently looked at in combination, the frontline setting with 2 trials. One was a trial of azacitidine with venetoclax, and the other was low-dose cytarabine with venetoclax. What we saw was very amazing. The response rates we saw with azacitidine-venetoclax were 70% to 75% when we looked at the Cri [complete remission with incomplete blood count recovery]. And the median overall survival was 17 to 18 months.

Now it’s important to know what this compares to. So with single-agent azacitidine we had one-third the response rates, about 20% to 25%, not 75%. And the median overall survival was 8 to 9 months not 18 months. And these are elderly patients, either above 75 or 60 to 75 years who are not fit for induction based on either having kidney problem, liver problem, cardiac issue, poor performance status, whatever it may be. And historically the expected 3-year survival for these patients over the past few years, has been 10 to 15 percent. There’s a number of SEER database publications, institution publications from us and others. And now we have with the azacitidine and venetoclax an expected 3-year survival of 45%. So this is the first time where we can really tell our elderly AML patients who are not fit or even above 75 years, that you actually have a good shot at having a long-term survival, which to us as leukemia doctors is really, really impressive and makes us feel that there’s much progress.

So now the other part where we’re using venetoclax is with low-dose cytarabine. A parallel study showed a little bit lower response rate, about 55% or so, but this study I think has a very unique aspect. And in the azacitidine-venetoclax study we excluded people who had received prior azacitidine, either for MDS [myelodysplastic syndromes] or AML, because the response rates, which we saw in that population by adding venetoclax were low.

However, with the low-dose cytarabine/venetoclax, even people who had received azacitidine as single agent for MDS have a response rate of about 50%. So I think this will be the treatment that we will choose at The University of Texas MD Anderson Cancer Center, and we are, for people who have MDS and receive 4 to 6 or more cycles of azacitidine, the quote/unquote, [HMA (hypomethylating agent)] failure group. And both of these drugs I think have individual use in these different settings, and both are 3 to 4 times better when you look at responses and survival than AZA [azathioprine] or low-dose araC [cytarabine] alone. So this is excellent.

With the azacitidine and venetoclax we did notice that the median survival is 18 months, which is about double of 8 to 10 months published in phase III studies with azacitidine alone or decitabine alone. The durability of responses given in the FDA label is a bit of a statistical anomaly because it depended on when the cut was made. And a lot of the patients who were represented in that label were actually still ongoing treatment. And so the duration only gives a part when we made the analysis and submitted to FDA, but in fact they are ongoing.

So, what we see when we look at the aggregate study, which included the initial dose escalation and subsequent smaller expansions that are not included in the label we do have about 100 patients where we can look at the duration response and it seems to be in the range of 10 to 12 months or so. So this is by far more than what we saw with AZA or DEC [decitabine] alone where the duration where the duration response was usually 4 to 6 months, and we think that this is why we’re seeing the overall survival benefit with combinations.
The low-dose cytarabine and venetoclax study has also been presented and has been approved for the FDA. I think this combination is maybe considered for patients who are very frail for HMA, which is rare but we do sometimes see patients who are 80 plus and even azacitidine-decitabine may be too much for them.

The other advantage if the low dose cytarabine can actually be given by home infusion or injection. And so patients may not have to stay or come to the infusion unit daily for 7 days like with azacitidine. And, there is the group of patients who have MDS, who have been treated with 4, 6, or more cycle of azacitidine and they are usually resistant to subsequent azacitidine-venetoclax, at least in our experience, and I know a lot of other investigators across the country have similar experience, but they seem to still be sensitive by switching from azacitidine to a low-dose cytarabine-venetoclax backbone, and that’s probably where I would use that combination. It shows about 50% to 55% CR [complete response]/CRi rates. The survivals are still low, in the 10-month or so range, but at least those are in remission with better quality of life.

In general, at this time based on our experience, the published and presented data, as well as the label, we would focus on elderly AML patients, specifically those who we think cannot get induction therapy like 3-plus-7 or FLAG-IDA.

We do have some follow-up, about a 2-and-a-half, 3-year follow-up, and we are seeing the survival is about 45 percent at 2-and-half, 3 years, which is good. But, this is not the same that we get with FLAG-IDA or induction chemo, especially in patients who are fit and who do not have adverse risk features. In those patients, these include patients with core-binding factor, NPM1 mutated, CEBPA in mutated, even FLT3 mutated, we do get 3-year survivals leukemia of 70% or higher. So I think there’s still some time before we can make the leap, or the switch, from going from elderly, nonfit, nonchemo eligible truly patients to fit, healthy young patients. I think we need to explore some triplets, which we are doing with azacitidine, venetoclax, addition of some targeted therapies, and then once we can get to 65% to 70%, 2-and-a-half, 3-year survival, I think, which is what we hope to go to, then we can start looking and replacing 3-plus-7. But today, I don’t think the data are mature enough to make that step and that’s not what we’re doing or recommending here at MD Anderson for the younger patients.

Transcript edited for clarity.
 
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Transcript:

Naval G. Daver, MD: Venetoclax is a BCL2 inhibitor. BCL2 is a very important antiapoptotic pathway that plays a major role in many malignancies, specifically we know in CLL, AML, [chronic lymphocytic leukemia, acute myeloid leukemia] also in ALL [acute lymphocytic leukemia], and some other lymphomas. So by blocking the BCL2, we’re basically antagonizing the antiapoptosis. So it’s a double negative. So basically by blocking antiapoptosis you’re promoting apoptosis, which is good because apoptosis are results in shrinkage and death of the tumor. That is a known mechanism of action. We do think there are some off target potential activities and other pathways that may be at play, but they haven’t been completely elucidated.

Venetoclax was valued at a single agent in relapsed/refractory AML. It was a study led by Dr Marina Konopleva, MD, PhD, from our institution and published a couple of years ago in Cancer Discovery. And it showed that a single-agent venetoclax has a response rate of about 15% to 20%. Nothing earthshattering. Most responses are very short lived, 4 to 6 weeks, so not very exciting to pursue in that approach.

We subsequently looked at in combination, the frontline setting with 2 trials. One was a trial of azacitidine with venetoclax, and the other was low-dose cytarabine with venetoclax. What we saw was very amazing. The response rates we saw with azacitidine-venetoclax were 70% to 75% when we looked at the Cri [complete remission with incomplete blood count recovery]. And the median overall survival was 17 to 18 months.

Now it’s important to know what this compares to. So with single-agent azacitidine we had one-third the response rates, about 20% to 25%, not 75%. And the median overall survival was 8 to 9 months not 18 months. And these are elderly patients, either above 75 or 60 to 75 years who are not fit for induction based on either having kidney problem, liver problem, cardiac issue, poor performance status, whatever it may be. And historically the expected 3-year survival for these patients over the past few years, has been 10 to 15 percent. There’s a number of SEER database publications, institution publications from us and others. And now we have with the azacitidine and venetoclax an expected 3-year survival of 45%. So this is the first time where we can really tell our elderly AML patients who are not fit or even above 75 years, that you actually have a good shot at having a long-term survival, which to us as leukemia doctors is really, really impressive and makes us feel that there’s much progress.

So now the other part where we’re using venetoclax is with low-dose cytarabine. A parallel study showed a little bit lower response rate, about 55% or so, but this study I think has a very unique aspect. And in the azacitidine-venetoclax study we excluded people who had received prior azacitidine, either for MDS [myelodysplastic syndromes] or AML, because the response rates, which we saw in that population by adding venetoclax were low.

However, with the low-dose cytarabine/venetoclax, even people who had received azacitidine as single agent for MDS have a response rate of about 50%. So I think this will be the treatment that we will choose at The University of Texas MD Anderson Cancer Center, and we are, for people who have MDS and receive 4 to 6 or more cycles of azacitidine, the quote/unquote, [HMA (hypomethylating agent)] failure group. And both of these drugs I think have individual use in these different settings, and both are 3 to 4 times better when you look at responses and survival than AZA [azathioprine] or low-dose araC [cytarabine] alone. So this is excellent.

With the azacitidine and venetoclax we did notice that the median survival is 18 months, which is about double of 8 to 10 months published in phase III studies with azacitidine alone or decitabine alone. The durability of responses given in the FDA label is a bit of a statistical anomaly because it depended on when the cut was made. And a lot of the patients who were represented in that label were actually still ongoing treatment. And so the duration only gives a part when we made the analysis and submitted to FDA, but in fact they are ongoing.

So, what we see when we look at the aggregate study, which included the initial dose escalation and subsequent smaller expansions that are not included in the label we do have about 100 patients where we can look at the duration response and it seems to be in the range of 10 to 12 months or so. So this is by far more than what we saw with AZA or DEC [decitabine] alone where the duration where the duration response was usually 4 to 6 months, and we think that this is why we’re seeing the overall survival benefit with combinations.
The low-dose cytarabine and venetoclax study has also been presented and has been approved for the FDA. I think this combination is maybe considered for patients who are very frail for HMA, which is rare but we do sometimes see patients who are 80 plus and even azacitidine-decitabine may be too much for them.

The other advantage if the low dose cytarabine can actually be given by home infusion or injection. And so patients may not have to stay or come to the infusion unit daily for 7 days like with azacitidine. And, there is the group of patients who have MDS, who have been treated with 4, 6, or more cycle of azacitidine and they are usually resistant to subsequent azacitidine-venetoclax, at least in our experience, and I know a lot of other investigators across the country have similar experience, but they seem to still be sensitive by switching from azacitidine to a low-dose cytarabine-venetoclax backbone, and that’s probably where I would use that combination. It shows about 50% to 55% CR [complete response]/CRi rates. The survivals are still low, in the 10-month or so range, but at least those are in remission with better quality of life.

In general, at this time based on our experience, the published and presented data, as well as the label, we would focus on elderly AML patients, specifically those who we think cannot get induction therapy like 3-plus-7 or FLAG-IDA.

We do have some follow-up, about a 2-and-a-half, 3-year follow-up, and we are seeing the survival is about 45 percent at 2-and-half, 3 years, which is good. But, this is not the same that we get with FLAG-IDA or induction chemo, especially in patients who are fit and who do not have adverse risk features. In those patients, these include patients with core-binding factor, NPM1 mutated, CEBPA in mutated, even FLT3 mutated, we do get 3-year survivals leukemia of 70% or higher. So I think there’s still some time before we can make the leap, or the switch, from going from elderly, nonfit, nonchemo eligible truly patients to fit, healthy young patients. I think we need to explore some triplets, which we are doing with azacitidine, venetoclax, addition of some targeted therapies, and then once we can get to 65% to 70%, 2-and-a-half, 3-year survival, I think, which is what we hope to go to, then we can start looking and replacing 3-plus-7. But today, I don’t think the data are mature enough to make that step and that’s not what we’re doing or recommending here at MD Anderson for the younger patients.

Transcript edited for clarity.
 
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