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Changes to the European Guidelines for Treatment of APL

Insights From: Elihu Estey, MD, University of Washington School of Medicine Seattle; Ehab Atallah, MD, Medical College of Wisconsin
Published: Thursday, Jan 19, 2017


Transcript:

Ehab Atallah, MD:
Recently, the European group approved arsenic for patients with low- or intermediate-risk APL in upfront therapy. The reason behind that approval was updated results of a randomized trial that compared ATRA (all-trans retinoic acid)/arsenic versus ATRA and chemotherapy. And, actually, patients in the ATRA/arsenic arm did better. That study included patients with low- and intermediate-risk APL, and, based on that, arsenic was approved for that indication.

Elihu Estey, MD: Of those 2 drugs, I think most people think of ATRA first, but arsenic is a more effective drug than ATRA. Whereas, if you give people just ATRA by itself, you will produce remissions. In almost all of them, the remissions are very brief. They last a few months. Whereas, if you do the same thing and just give arsenic, you can cure probably 50% of the people. So, arsenic is the most important of those 2 drugs.

The guidelines call for giving arsenic and ATRA without chemotherapy in people with low white blood cell counts, generally less than 10,000. And that work really follows directly from work that we did in Houston at MD Anderson Cancer Center, maybe 20 years ago, where we gave people just ATRA and arsenic without chemotherapy. In turn, our work was derived from work that was done in China where they randomized people to ATRA alone, arsenic alone, or the combination, and they all got chemotherapy after that. But, despite getting the chemotherapy, there still was a difference in favor of the arsenic/ATRA compared to either arsenic alone or ATRA alone, and that’s where we got the idea to give people arsenic and ATRA. And our contribution was to say, “Well, let’s give it without chemotherapy.” After that paper, the European group and Dr. LoCoco did a randomized study unlike ours. Ours was just one treatment. They randomized people between the standard treatment, which was ATRA and chemotherapy, and the MD Anderson treatment, which was ATRA and arsenic without chemotherapy.

Ehab Atallah, MD: Currently, for frontline treatment of patients with APL, we use 1 of 3 different protocols. All 3 different protocols have arsenic upfront therapy. The first protocol we use is the APML4, which includes a combination of chemotherapy, ATRA, and arsenic. Another protocol we use is the combination of ATRA/arsenic alone. More recently, there was an AML17 trial where patients received ATRA and arsenic. However, the arsenic in that study was given at a higher dose, but was given less frequently.

Elihu Estey, MD: My experience has been positive. It’s generally well tolerated. And one thing that I think you can’t underestimate is people hate chemotherapy. The word “chemotherapy” conjures up so many bad images that probably were accurate 20 years ago, but are not as accurate today. But, just the idea of avoiding chemotherapy is very appealing to patients, and that I think is one of the most appealing parts about giving ATRA and arsenic.

Ehab Atallah, MD: My experience in using ATRA and arsenic as frontline therapy for patients with APL has been quite amazing. Ever since we started using arsenic in the upfront therapy, I have not had a single patient relapse after that treatment.

Elihu Estey, MD: I think we overestimated how often these guidelines—and I’m on numerous of these committees that come up with guidelines, ELN guidelines for sure—affect what doctors in practice do. The people who write the guidelines overestimate their importance, but, I think for some time now, the direction has been moving in the direction of just giving ATRA and arsenic without chemotherapy. And just based on conversations with physicians that call and say, “What should we do?”, that’s generally what they do.

I probably should interject something. Should people with APL be treated in the community by oncologists, say, in private practice or should they be treated in medical centers? There is a paper from Memorial Sloan Kettering and they looked at data from New York State. It was a SEER database, so it was a complete database, and what they found was that maybe 90% of people with APL were cured if they were treated in academic centers. That figure might only have been about 60% for people who were not treated in academic centers. So, I think it’s really important to emphasize that this is really the one type of AML, maybe many others as well, where you really should be treated in a place where there’s some experience treating it. Because, even though ATRA/arsenic is excellent therapy, it’s still very important, as important as the ATRA and arsenic, to give transfusions appropriately of platelets and clotting factors. The experience is invaluable there.

Ehab Atallah, MD: The EU approval of arsenic for the treatment of patients with newly-diagnosed APL I think will give more physicians assurance that this is a good option for their patients in the upfront therapy. And, I think, with the EU approval, more patients will receive arsenic in their frontline therapy.

To determine which patients benefit from treatment with arsenic, just about all patients with APL benefit from upfront treatment with arsenic therapy, whether low-risk where we would use only ATRA and arsenic or high-risk patients where we would use a combination of chemotherapy, ATRA, and arsenic.

Transcript Edited for Clarity
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Transcript:

Ehab Atallah, MD:
Recently, the European group approved arsenic for patients with low- or intermediate-risk APL in upfront therapy. The reason behind that approval was updated results of a randomized trial that compared ATRA (all-trans retinoic acid)/arsenic versus ATRA and chemotherapy. And, actually, patients in the ATRA/arsenic arm did better. That study included patients with low- and intermediate-risk APL, and, based on that, arsenic was approved for that indication.

Elihu Estey, MD: Of those 2 drugs, I think most people think of ATRA first, but arsenic is a more effective drug than ATRA. Whereas, if you give people just ATRA by itself, you will produce remissions. In almost all of them, the remissions are very brief. They last a few months. Whereas, if you do the same thing and just give arsenic, you can cure probably 50% of the people. So, arsenic is the most important of those 2 drugs.

The guidelines call for giving arsenic and ATRA without chemotherapy in people with low white blood cell counts, generally less than 10,000. And that work really follows directly from work that we did in Houston at MD Anderson Cancer Center, maybe 20 years ago, where we gave people just ATRA and arsenic without chemotherapy. In turn, our work was derived from work that was done in China where they randomized people to ATRA alone, arsenic alone, or the combination, and they all got chemotherapy after that. But, despite getting the chemotherapy, there still was a difference in favor of the arsenic/ATRA compared to either arsenic alone or ATRA alone, and that’s where we got the idea to give people arsenic and ATRA. And our contribution was to say, “Well, let’s give it without chemotherapy.” After that paper, the European group and Dr. LoCoco did a randomized study unlike ours. Ours was just one treatment. They randomized people between the standard treatment, which was ATRA and chemotherapy, and the MD Anderson treatment, which was ATRA and arsenic without chemotherapy.

Ehab Atallah, MD: Currently, for frontline treatment of patients with APL, we use 1 of 3 different protocols. All 3 different protocols have arsenic upfront therapy. The first protocol we use is the APML4, which includes a combination of chemotherapy, ATRA, and arsenic. Another protocol we use is the combination of ATRA/arsenic alone. More recently, there was an AML17 trial where patients received ATRA and arsenic. However, the arsenic in that study was given at a higher dose, but was given less frequently.

Elihu Estey, MD: My experience has been positive. It’s generally well tolerated. And one thing that I think you can’t underestimate is people hate chemotherapy. The word “chemotherapy” conjures up so many bad images that probably were accurate 20 years ago, but are not as accurate today. But, just the idea of avoiding chemotherapy is very appealing to patients, and that I think is one of the most appealing parts about giving ATRA and arsenic.

Ehab Atallah, MD: My experience in using ATRA and arsenic as frontline therapy for patients with APL has been quite amazing. Ever since we started using arsenic in the upfront therapy, I have not had a single patient relapse after that treatment.

Elihu Estey, MD: I think we overestimated how often these guidelines—and I’m on numerous of these committees that come up with guidelines, ELN guidelines for sure—affect what doctors in practice do. The people who write the guidelines overestimate their importance, but, I think for some time now, the direction has been moving in the direction of just giving ATRA and arsenic without chemotherapy. And just based on conversations with physicians that call and say, “What should we do?”, that’s generally what they do.

I probably should interject something. Should people with APL be treated in the community by oncologists, say, in private practice or should they be treated in medical centers? There is a paper from Memorial Sloan Kettering and they looked at data from New York State. It was a SEER database, so it was a complete database, and what they found was that maybe 90% of people with APL were cured if they were treated in academic centers. That figure might only have been about 60% for people who were not treated in academic centers. So, I think it’s really important to emphasize that this is really the one type of AML, maybe many others as well, where you really should be treated in a place where there’s some experience treating it. Because, even though ATRA/arsenic is excellent therapy, it’s still very important, as important as the ATRA and arsenic, to give transfusions appropriately of platelets and clotting factors. The experience is invaluable there.

Ehab Atallah, MD: The EU approval of arsenic for the treatment of patients with newly-diagnosed APL I think will give more physicians assurance that this is a good option for their patients in the upfront therapy. And, I think, with the EU approval, more patients will receive arsenic in their frontline therapy.

To determine which patients benefit from treatment with arsenic, just about all patients with APL benefit from upfront treatment with arsenic therapy, whether low-risk where we would use only ATRA and arsenic or high-risk patients where we would use a combination of chemotherapy, ATRA, and arsenic.

Transcript Edited for Clarity
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