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Future Treatment Approaches to AML

Insights From: Richard F. Schlenk, MD, University of Ulm; Harry Erba, MD PhD, University of Alabama ; Naval G. Daver, MD, MD Anderson Cancer Center
Published: Monday, Oct 15, 2018



Transcript:

Naval G. Daver, MD: There are a lot of new FLT3 inhibitors that are either available or soon to be approved. Midostaurin is already approved and should be used in combination induction for all FLT3-mutated patients, in my opinion. Quizartinib and gilteritinib will both, most likely, be approved in the next few months, so if you have a patient who relapses, you have 2 excellent options. Also, in the frontline setting, all of these drugs are being tested: we have the midostaurin data, but we’re waiting for the frontline quizartinib, gilteritinib, and crenolanib data. It’s possible that one of these may show better activity, resulting in a better frontline standard.

We have a lot of good options, which is a much better situation than 8 or 10 years ago when we had none. Now, in our most recent updates, we are getting 75% to 80% 5-year survival rates, which is very exciting for patients with FLT3 mutation. There’s also a number of other drugs being developed in acute myeloid leukemia. The IDH [isocitrate dehydrogenase] inhibitors are a very good discovery: As single agents, they’re giving us 35% to 40% response rates in relapsed AML. Again, this is better than response rates we would get with high-dose chemotherapy cocktails, with much less toxicity and better tolerability level. If we see a relapse patient, we check IDH and FLT3 because this will give us targeted options that are more potent, effective, and safer, with improved odds for patients to receive stem-cell transplants.
         
There are also other new immune therapies that are emerging for acute myeloid leukemia, which include antibody-based therapies such as gemtuzumab, bispecific antibodies, and immune checkpoints. A lot of these are showing early activity, so we’re very excited about them. One of the most significant breakthroughs at this time is a drug called venetoclax, which seems to be changing the treatment landscape of elderly patients with AML, just like the FLT3 inhibitors have done for the FLT3-mutated AML. We’re seeing doubling and tripling of overall survival. Additionally, for the first time in elderly AML, we’re looking at 45% to 50% long-term survival, whereas for 4 decades, we were stuck at 10% to 15%. So, overall, in young AML, older AML, relapsed AML, and FLT3 and IDH-mutated AML, there’s a huge shift. With that is going to come a lot of requirement for education. I think a lot of the community doctors are looking to CME [continuing medical education], talks, ASH [American Society of Hematology], and SOHO [Society of Hematologic Oncology] because now they know there’s a lot happening in AML; it’s no longer stagnant like it was for the last 4 decades.

Harry Erba, MD: There are a number of other FLT3 inhibitors that are in clinical development, and how to distinguish between the ones we have, the ones we will likely soon have, and the ones that are coming is difficult to discern at this point. It will likely be due to our baseline differences in toxicity profiling, comorbidities, and dosing. Now, having said that, I think the real movement has to be to improve the outcomes of these patients by combining them with other treatments. Of course, right now, we are focusing on the addition of FLT3 inhibitors to chemotherapy, since we’ve been using chemotherapy with curative intent for decades.

However, as we understand the pathogenesis of the disease better, I think it makes sense to consider the combination of these drugs together, such as different inhibitors that may target mutations co-present in a patient with AML, like an IDH mutation and FLT3, which is not uncommon at all. Secondly, it would be essential to use other drugs that may help aid the response to a FLT3 inhibitor. There’s preclinical data showing that BCL2 [B-cell lymphoma 2] inhibition and p53 [tumor protein p53] reactivation may be important in improving the efficacy of a FLT3 inhibitor. I look forward to combination studies of FLT3 inhibitors with other drugs that will impact the pathogenesis of acute myeloid leukemia.

Richard F. Schlenk, MD: We saw other agents being used very successfully as well, such as the BCL2 inhibitor. Venetoclax has also shown promising results for patients in the relapsed and refractory settings, in addition to new results in the first-line setting in combination with consolidation therapy, induction therapy, and other inhibitors such as ADH [antidiuretic hormone], IDH1, and IDH2. We will also have trials coming up in the first-line setting to see whether patients can be treated specifically according to the mutation.

We have also approved gemtuzumab, which improves the results for patients with acute myeloid leukemia. It is most effective in patients with an intermediate or good prognosis. We still, therefore, have patients with an unfavorable disease, as with the P53 mutation or patients with a complex karyotype.


Transcript Edited for Clarity
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Transcript:

Naval G. Daver, MD: There are a lot of new FLT3 inhibitors that are either available or soon to be approved. Midostaurin is already approved and should be used in combination induction for all FLT3-mutated patients, in my opinion. Quizartinib and gilteritinib will both, most likely, be approved in the next few months, so if you have a patient who relapses, you have 2 excellent options. Also, in the frontline setting, all of these drugs are being tested: we have the midostaurin data, but we’re waiting for the frontline quizartinib, gilteritinib, and crenolanib data. It’s possible that one of these may show better activity, resulting in a better frontline standard.

We have a lot of good options, which is a much better situation than 8 or 10 years ago when we had none. Now, in our most recent updates, we are getting 75% to 80% 5-year survival rates, which is very exciting for patients with FLT3 mutation. There’s also a number of other drugs being developed in acute myeloid leukemia. The IDH [isocitrate dehydrogenase] inhibitors are a very good discovery: As single agents, they’re giving us 35% to 40% response rates in relapsed AML. Again, this is better than response rates we would get with high-dose chemotherapy cocktails, with much less toxicity and better tolerability level. If we see a relapse patient, we check IDH and FLT3 because this will give us targeted options that are more potent, effective, and safer, with improved odds for patients to receive stem-cell transplants.
         
There are also other new immune therapies that are emerging for acute myeloid leukemia, which include antibody-based therapies such as gemtuzumab, bispecific antibodies, and immune checkpoints. A lot of these are showing early activity, so we’re very excited about them. One of the most significant breakthroughs at this time is a drug called venetoclax, which seems to be changing the treatment landscape of elderly patients with AML, just like the FLT3 inhibitors have done for the FLT3-mutated AML. We’re seeing doubling and tripling of overall survival. Additionally, for the first time in elderly AML, we’re looking at 45% to 50% long-term survival, whereas for 4 decades, we were stuck at 10% to 15%. So, overall, in young AML, older AML, relapsed AML, and FLT3 and IDH-mutated AML, there’s a huge shift. With that is going to come a lot of requirement for education. I think a lot of the community doctors are looking to CME [continuing medical education], talks, ASH [American Society of Hematology], and SOHO [Society of Hematologic Oncology] because now they know there’s a lot happening in AML; it’s no longer stagnant like it was for the last 4 decades.

Harry Erba, MD: There are a number of other FLT3 inhibitors that are in clinical development, and how to distinguish between the ones we have, the ones we will likely soon have, and the ones that are coming is difficult to discern at this point. It will likely be due to our baseline differences in toxicity profiling, comorbidities, and dosing. Now, having said that, I think the real movement has to be to improve the outcomes of these patients by combining them with other treatments. Of course, right now, we are focusing on the addition of FLT3 inhibitors to chemotherapy, since we’ve been using chemotherapy with curative intent for decades.

However, as we understand the pathogenesis of the disease better, I think it makes sense to consider the combination of these drugs together, such as different inhibitors that may target mutations co-present in a patient with AML, like an IDH mutation and FLT3, which is not uncommon at all. Secondly, it would be essential to use other drugs that may help aid the response to a FLT3 inhibitor. There’s preclinical data showing that BCL2 [B-cell lymphoma 2] inhibition and p53 [tumor protein p53] reactivation may be important in improving the efficacy of a FLT3 inhibitor. I look forward to combination studies of FLT3 inhibitors with other drugs that will impact the pathogenesis of acute myeloid leukemia.

Richard F. Schlenk, MD: We saw other agents being used very successfully as well, such as the BCL2 inhibitor. Venetoclax has also shown promising results for patients in the relapsed and refractory settings, in addition to new results in the first-line setting in combination with consolidation therapy, induction therapy, and other inhibitors such as ADH [antidiuretic hormone], IDH1, and IDH2. We will also have trials coming up in the first-line setting to see whether patients can be treated specifically according to the mutation.

We have also approved gemtuzumab, which improves the results for patients with acute myeloid leukemia. It is most effective in patients with an intermediate or good prognosis. We still, therefore, have patients with an unfavorable disease, as with the P53 mutation or patients with a complex karyotype.


Transcript Edited for Clarity
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