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Clinical and Practical Data On Use of Retinoic Acid and Arsenic Trioxide in APL

Insights From: Elihu Estey, MD, University of Washington School of Medicine Seattle; Ehab Atallah, MD, Medical College of Wisconsin
Published: Tuesday, Jan 24, 2017


Transcript:

Ehab Atallah, MD:
The history behind the approval of arsenic in the frontline setting is that arsenic has been used for quite some time in the relapsed setting. And, when it was found to be effective in patients with relapsed APL, it was evaluated in patients with newly diagnosed APL in combination with chemotherapy. Around that same time, other studies were being done where chemotherapy was taken out of the treatment and patients were treated with ATRA and arsenic alone. Amazing results were seen with just using ATRA and arsenic, with more than 90% survival and cure rate. Based on that small study—it was a randomized study that compared ATRA/arsenic versus ATRA/chemotherapy—patients who received ATRA/arsenic actually had less toxicity and had better survival when compared to ATRA and chemotherapy.

Given that the median age for patients diagnosed with APL is around 40, having an option of a treatment regimen that does not contain chemotherapy is very appealing to those patients to reduce the chances for both immediate and late toxicity. Not only is it appealing for the younger patients, but also for older patients that are unable to tolerate chemotherapy. ATRA and arsenic are much, much better tolerated than chemotherapy.

Elihu Estey, MD: During the initial phase of treatment, arsenic is given at 0.15 mg/kg a day, and you do that for 3 weeks. Then, you can stop and allow the blood counts to come up. And when the blood counts come up, generally what happens is the patient is in remission, but the treatment has to continue. Generally, people would get 0.15 mg/kg of arsenic 3 days a week, and we did it on a 4 weeks on, 4 weeks off schedule. In addition, they get ATRA, as well, so the combination continues.

Ehab Atallah, MD: When we’re using an ATRA/arsenic regimen, it’s very important to complete both the induction and the consolidation parts of the regimen, and really stick with the whole regimen. Giving ATRA and arsenic is difficult for our patients because they have to come in every day for 4 weeks in a row to receive the arsenic. However, when we compare that with the side effects of chemotherapy, it is much, much better tolerated. In addition, in the more recent AML-17 trial, which gave the arsenic at a higher dose but less frequently, the outcomes of those patients were just as good with the daily administration and just as well tolerated.

One of the important things that we have to do as physicians is to explain to our patients that adherence to their protocol is really necessary in order for them to be cured. Once patients understand that, understand why they have to come in every day, and also understand that this keeps them away from having to get chemotherapy, they’re much more likely to be adherent.

Elihu Estey, MD: The differentiation syndrome refers to the way these drugs work, they cause the immature promyelocytes to become more mature cells. And when that happens, the white blood cell count goes up because now you’re making many more of these mature cells. Clinically, it presents as difficulty breathing and fever, and the difficulty in breathing reflects the movement of fluid from the blood into, for example, the lining around the lung and into extracellular spaces, so people accumulate fluid. That’s the hallmark of the differentiation syndrome. The best way to suspect it is, for example, to obviously weigh the patient. Generally, when people have the differentiation syndrome, they’ll gain fluid weight. And once it’s suspected, then people are treated with steroids, which is a very effective treatment for differentiation syndrome. There are some places where the steroids are just given prophylactically to prevent the differentiation syndrome.

Ehab Atallah, MD: When patients receive treatments with arsenic, there are several side effects that we have to watch for. First is the differentiation syndrome. Patients who take ATRA/arsenic and develop a differentiation syndrome are, in that case, treated with steroids. Another common side effect of arsenic is QT prolongation. Patients need to have an EKG twice a week for the first week and then weekly, thereafter. If there is any QT prolongation, adjustments need to be made to the treatment. Finally, because of the QT prolongation, we have to monitor the potassium and magnesium twice a week in the first week, and then at least once a week after that depending on the clinical situation. We aim to keep the potassium above 4 and the magnesium above 2. We always check the patients and supplement them if needed. And, if we have a patient who’s requiring frequent intravenous supplementation, then we try to supplement them orally at home so they don’t have to come in and receive intravenous supplementation.

Another side effect that was seen in the trials with arsenic was hepatic toxicity. In those patients that develop elevated ALT or AST, the drug was held, restarted again at a lower dose, and then escalated back up again. From clinical experience and from clinical trials, we have not seen patients who needed to discontinue arsenic therapy because of hepatic toxicity.

Transcript Edited for Clarity
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Transcript:

Ehab Atallah, MD:
The history behind the approval of arsenic in the frontline setting is that arsenic has been used for quite some time in the relapsed setting. And, when it was found to be effective in patients with relapsed APL, it was evaluated in patients with newly diagnosed APL in combination with chemotherapy. Around that same time, other studies were being done where chemotherapy was taken out of the treatment and patients were treated with ATRA and arsenic alone. Amazing results were seen with just using ATRA and arsenic, with more than 90% survival and cure rate. Based on that small study—it was a randomized study that compared ATRA/arsenic versus ATRA/chemotherapy—patients who received ATRA/arsenic actually had less toxicity and had better survival when compared to ATRA and chemotherapy.

Given that the median age for patients diagnosed with APL is around 40, having an option of a treatment regimen that does not contain chemotherapy is very appealing to those patients to reduce the chances for both immediate and late toxicity. Not only is it appealing for the younger patients, but also for older patients that are unable to tolerate chemotherapy. ATRA and arsenic are much, much better tolerated than chemotherapy.

Elihu Estey, MD: During the initial phase of treatment, arsenic is given at 0.15 mg/kg a day, and you do that for 3 weeks. Then, you can stop and allow the blood counts to come up. And when the blood counts come up, generally what happens is the patient is in remission, but the treatment has to continue. Generally, people would get 0.15 mg/kg of arsenic 3 days a week, and we did it on a 4 weeks on, 4 weeks off schedule. In addition, they get ATRA, as well, so the combination continues.

Ehab Atallah, MD: When we’re using an ATRA/arsenic regimen, it’s very important to complete both the induction and the consolidation parts of the regimen, and really stick with the whole regimen. Giving ATRA and arsenic is difficult for our patients because they have to come in every day for 4 weeks in a row to receive the arsenic. However, when we compare that with the side effects of chemotherapy, it is much, much better tolerated. In addition, in the more recent AML-17 trial, which gave the arsenic at a higher dose but less frequently, the outcomes of those patients were just as good with the daily administration and just as well tolerated.

One of the important things that we have to do as physicians is to explain to our patients that adherence to their protocol is really necessary in order for them to be cured. Once patients understand that, understand why they have to come in every day, and also understand that this keeps them away from having to get chemotherapy, they’re much more likely to be adherent.

Elihu Estey, MD: The differentiation syndrome refers to the way these drugs work, they cause the immature promyelocytes to become more mature cells. And when that happens, the white blood cell count goes up because now you’re making many more of these mature cells. Clinically, it presents as difficulty breathing and fever, and the difficulty in breathing reflects the movement of fluid from the blood into, for example, the lining around the lung and into extracellular spaces, so people accumulate fluid. That’s the hallmark of the differentiation syndrome. The best way to suspect it is, for example, to obviously weigh the patient. Generally, when people have the differentiation syndrome, they’ll gain fluid weight. And once it’s suspected, then people are treated with steroids, which is a very effective treatment for differentiation syndrome. There are some places where the steroids are just given prophylactically to prevent the differentiation syndrome.

Ehab Atallah, MD: When patients receive treatments with arsenic, there are several side effects that we have to watch for. First is the differentiation syndrome. Patients who take ATRA/arsenic and develop a differentiation syndrome are, in that case, treated with steroids. Another common side effect of arsenic is QT prolongation. Patients need to have an EKG twice a week for the first week and then weekly, thereafter. If there is any QT prolongation, adjustments need to be made to the treatment. Finally, because of the QT prolongation, we have to monitor the potassium and magnesium twice a week in the first week, and then at least once a week after that depending on the clinical situation. We aim to keep the potassium above 4 and the magnesium above 2. We always check the patients and supplement them if needed. And, if we have a patient who’s requiring frequent intravenous supplementation, then we try to supplement them orally at home so they don’t have to come in and receive intravenous supplementation.

Another side effect that was seen in the trials with arsenic was hepatic toxicity. In those patients that develop elevated ALT or AST, the drug was held, restarted again at a lower dose, and then escalated back up again. From clinical experience and from clinical trials, we have not seen patients who needed to discontinue arsenic therapy because of hepatic toxicity.

Transcript Edited for Clarity
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