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Hypomethylating Agents for AML

Panelists: Harry Erba, MD, PhD, Duke Cancer Institute; Naval Daver, MD, The University of Texas MD Anderson Cancer Center; Rami Komrokji, MD, H. Lee Moffitt Cancer Center; Mark Levis, MD, PhD, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center; Dan Pollyea, MD, MS, University of Colorado Cancer Center
Published: Thursday, Feb 13, 2020



Transcript: 

Harry Erba, MD, PhD: Before we go to some of those newer therapies, I want to have a very focused conversation on HMA [hypomethylating agents]. The thing that I continue to be confused by at ASH [the American Society of Hematology Annual Meeting] presentations is this: 5 days or 10 days of decitabine. Which is it? Naval?

Naval Daver, MD: Sure, I can start with that very easy answer: I don’t know. There are data, so I’ll just tell you the data.

We had the 10-day decitabine study initially done at The Ohio State University Comprehensive Cancer Center and then at Washington University School of Medicine, and it has been published. The Washington University study got a lot of publicity. It was published in the New England Journal of Medicine. They showed very high response rates in frontline, TP53-mutated AML [acute myeloid leukemia]: close to 80% to 100% response with very nice correlation showing allele burden clearance. Survival was up to 11 to 12 months, which in TP53-mutated AML is quite outstanding.

When you have it in the New England Journal of Medicine, it is almost like a change in standard of care. We at The University of Texas MD Anderson Cancer Center were reading that data, and we said, “Maybe. Maybe not. Let’s look at it.” We did a randomized small phase II study, DAC5 [decitabine 5-day] versus DAC10 [decitabine 10-day]. Luckily, we did this just before venetoclax because, otherwise, it would never have gotten done. We would not be giving this DAC5 [decitabine 5-day] or DAC10 [decitabine 10-day]. That study was published by Dr Nicholas Short from our group and was in The Lancet Hematology last year. What we saw was this: when we look at a general population, the response rates are quite similar, maybe a few percentage points higher. But statistically, there was no difference in the DAC10 [decitabine 10-day] arm.

When you look at TP53 again, what’s quite interesting is that TP53 patients don’t have a low response rate to HMAs, and I think this may be the conceptual issue. Their response rates are about 50% to 60%, with both HMAs. It’s just that the durability was poor, and the survival in the end was a slight trend for DAC10 [decitabine 10-day]. It was not significantly improved, but there was a trend.

Our conclusion was that maybe DAC10 [decitabine 10-day] a little better than DAC5 [decitabine 5-day]. It’s not a blockbuster difference, but then you have to put that into perspective when you’re going to combine it, which is what we’re going to do with venetoclax FLT3 IDH—that added myelosuppression, because you do get myelosuppression. You’re going to lose the benefit of using DAC5 [decitabine 5-day] or DAC7 [decitabine 7-day]. I would say either is fine. As a single agent, I would maybe like DAC10 [decitabine 10-day] more, but in combination.

Mark Levis, MD, PhD: I don’t think either was an advance for this disease.

Naval Daver, MD: I agree with that.

Mark Levis, MD, PhD: We need to look elsewhere.

Rami Komrokji, MD: But it has evolved as the standard for patients not fit for intensive chemotherapy. For all the combinations, they do have a role. When you look at the data in all the patients above the age of 70, the survival comes as good as intensive chemotherapy with that.

Mark Levis, MD, PhD: You mean for TP53-mutated patients?

Rami Komrokji, MD: Not only TP53-mutated patients, but all over. If you look at all patients above the age of 70 and you look at the median survival for patients, not selecting patients, it emerges that the survival comes almost equivalent to intensive chemotherapy.

Naval Daver, MD: It was HMA, right?

Mark Levis, MD, PhD: Yes.

Rami Komrokji, MD: We looked at 700 to 800 patients in our place, Moffitt Cancer Center, and we saw that the survival comes at the end the same. The benchmark for it, that the CR [complete remission] rates are low in those patients: 15% to 20% CR rates with the HMAs and leukemia. That became the benchmark we are comparing against. Although it emerged as a standard and it may be as good as chemotherapy, we have way more to improve on that.

Harry Erba, MD, PhD: So let’s get to that.

Transcript Edited for Clarity

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Transcript: 

Harry Erba, MD, PhD: Before we go to some of those newer therapies, I want to have a very focused conversation on HMA [hypomethylating agents]. The thing that I continue to be confused by at ASH [the American Society of Hematology Annual Meeting] presentations is this: 5 days or 10 days of decitabine. Which is it? Naval?

Naval Daver, MD: Sure, I can start with that very easy answer: I don’t know. There are data, so I’ll just tell you the data.

We had the 10-day decitabine study initially done at The Ohio State University Comprehensive Cancer Center and then at Washington University School of Medicine, and it has been published. The Washington University study got a lot of publicity. It was published in the New England Journal of Medicine. They showed very high response rates in frontline, TP53-mutated AML [acute myeloid leukemia]: close to 80% to 100% response with very nice correlation showing allele burden clearance. Survival was up to 11 to 12 months, which in TP53-mutated AML is quite outstanding.

When you have it in the New England Journal of Medicine, it is almost like a change in standard of care. We at The University of Texas MD Anderson Cancer Center were reading that data, and we said, “Maybe. Maybe not. Let’s look at it.” We did a randomized small phase II study, DAC5 [decitabine 5-day] versus DAC10 [decitabine 10-day]. Luckily, we did this just before venetoclax because, otherwise, it would never have gotten done. We would not be giving this DAC5 [decitabine 5-day] or DAC10 [decitabine 10-day]. That study was published by Dr Nicholas Short from our group and was in The Lancet Hematology last year. What we saw was this: when we look at a general population, the response rates are quite similar, maybe a few percentage points higher. But statistically, there was no difference in the DAC10 [decitabine 10-day] arm.

When you look at TP53 again, what’s quite interesting is that TP53 patients don’t have a low response rate to HMAs, and I think this may be the conceptual issue. Their response rates are about 50% to 60%, with both HMAs. It’s just that the durability was poor, and the survival in the end was a slight trend for DAC10 [decitabine 10-day]. It was not significantly improved, but there was a trend.

Our conclusion was that maybe DAC10 [decitabine 10-day] a little better than DAC5 [decitabine 5-day]. It’s not a blockbuster difference, but then you have to put that into perspective when you’re going to combine it, which is what we’re going to do with venetoclax FLT3 IDH—that added myelosuppression, because you do get myelosuppression. You’re going to lose the benefit of using DAC5 [decitabine 5-day] or DAC7 [decitabine 7-day]. I would say either is fine. As a single agent, I would maybe like DAC10 [decitabine 10-day] more, but in combination.

Mark Levis, MD, PhD: I don’t think either was an advance for this disease.

Naval Daver, MD: I agree with that.

Mark Levis, MD, PhD: We need to look elsewhere.

Rami Komrokji, MD: But it has evolved as the standard for patients not fit for intensive chemotherapy. For all the combinations, they do have a role. When you look at the data in all the patients above the age of 70, the survival comes as good as intensive chemotherapy with that.

Mark Levis, MD, PhD: You mean for TP53-mutated patients?

Rami Komrokji, MD: Not only TP53-mutated patients, but all over. If you look at all patients above the age of 70 and you look at the median survival for patients, not selecting patients, it emerges that the survival comes almost equivalent to intensive chemotherapy.

Naval Daver, MD: It was HMA, right?

Mark Levis, MD, PhD: Yes.

Rami Komrokji, MD: We looked at 700 to 800 patients in our place, Moffitt Cancer Center, and we saw that the survival comes at the end the same. The benchmark for it, that the CR [complete remission] rates are low in those patients: 15% to 20% CR rates with the HMAs and leukemia. That became the benchmark we are comparing against. Although it emerged as a standard and it may be as good as chemotherapy, we have way more to improve on that.

Harry Erba, MD, PhD: So let’s get to that.

Transcript Edited for Clarity
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