Acute Myeloid Leukemia Podcast

Acute Promyelocytic Leukemia: A Subset of Acute Myeloid Leukemia

Gail J. Roboz, MD; Farhad Ravandi, MD


April 14, 2022

This transcript has been edited for clarity.

Gail J. Roboz, MD: Hi, everyone. My name is Dr Gail Roboz, and welcome to Medscape InDiscussion. Today, we're going to be talking about acute myeloid leukemia (AML) and specifically a subtype of AML, called APL, or acute promyelocytic leukemia.

It is my great pleasure to have my friend and colleague join me for this discussion. Dr Farhad Ravandi is a professor of medicine in the Department of Leukemia at the MD Anderson Cancer Center in Houston, Texas, and is very well known for being a trailblazer in the space of APL and for really having led the treatment of this disease and changes in the treatment of this disease during the past two decades. So it's a great pleasure to have you here today, Farhad. Thanks for joining.

Farhad Ravandi, MD: Thank you very much, Gail. It's always a pleasure to be with you, even on Zoom.

Roboz: I want to open with a case because I think that this is a good way to kick off everybody's kind of thinking and have people remember it.

So, this is a 23-year-old woman. She's a college student of Hispanic background who went into urgent care with some mouth sores, and she had a little bit of a nosebleed and was feeling generally unwell. And, as per usual in the time of COVID, anybody only ever thinks of COVID. So, she went into urgent care. They did a COVID swab; they said she was negative, and go home and kind of drink tea, and a few days later, she really didn't feel well. She was having aches and pains, and she had a couple more nosebleeds.

So, she went back to urgent care thinking that, like all of her friends, maybe the COVID test had been a false-negative. They checked her again and said, no, you don't have it; just relax and go home, and you'll probably be fine. And there were no labs checked. Then, a couple of days later, she started having bruising diffusely, and she had two or three more significant nosebleeds when she went back to urgent care, I think it's worth noting that they said that probably the nosebleeds were because they had done so many COVID swabs. They finally did labs, and she was found to be floridly pancytopenic. She had a white blood cell count of 1. She had a hemoglobin value of about 7. She had a platelet count of 9000, and she was referred urgently to the emergency department for further evaluation and management.

Let me just stop there for a second. It's a moment for us to say that in the past couple of years, absolutely everything has been COVID. So it seems that that is one potential thing just to note: Not everything is COVID. But with that type of initial presentation, tell me about that in terms of what you're seeing for who walks into the office with what is going to turn out to be new APL?

Ravandi: Just like you said, APL is a relatively uncommon subset of acute myeloid leukemia, but I think of it as a sort of a poster child for all the other subsets because over the past two or two and a half decades, we have identified the molecular pathogenic causes of AML. And also, we have identified targeted therapies. As a result, we now have a disease that we treat without chemotherapy in most patients.

Like you said, this disease is highly curable now, and because of that, everybody should have a high suspicion for APL when you have a young patient who is having unexplained nosebleeds. I think the first thing any primary care doctor should do is to run a complete blood cell count (CBC) because you will find some abnormalities, even the platelet count for these, even 120, you have to start thinking what is going on here and start looking into it further. And low blood counts are one of the distinguishing features of APL. The majority of patients have low white blood cell counts at presentation. So with that, if you have any suspicion of APL, you have to start testing to identify the disease. Of course, the molecular test is pretty rapid; PCR takes about a day to come back. And the majority of pathologists can identify the typical morphologic changes of APL. But I think the moment you suspect APL, you need to give the patient all trans-retinoic acid (ATRA). If you have a young patient who is having bruising and really no good explanation and you're even remotely suspecting APL, there is no harm starting the patient on ATRA — as long as, if it is a young woman, the patient is not pregnant.

Roboz: I'm going to stop you for one second, because there are certain things to unpack here that I want to really, really dig into for the listeners. The first thing is super-important: low blood cell counts. People are somehow conditioned to be less scared of low blood cell counts than of high blood cell counts with acute leukemia. And I think that whenever somebody sees a white blood cell count of 150,000, then all of a sudden all the guns get set off, and everybody is running. But when somebody sees that 1.2 or that 2.1, they should start thinking that a lot of APL — a lot of this scary, rare but curable subtype — hinges on low blood cells counts. I think is a good kind of thing to put into the back of your thinking.

The second thing is that I did mention is that this was a young woman, but I mentioned that she was of Hispanic background. I wanted to get that in there because epidemiologically, you guys may see a lot of this in the Houston area. I know in Southern California, there is a lot, but there does seem to be a notable epidemiologic excess of APL in Hispanic patients. Is that correct?

Ravandi: Yeah, of course; it's been reported in several publications that have suggested that there's also an association with patients being overweight, and there is some even molecular mechanisms that can make sense of that. There is definitely a reported association with patients of what they call Hispanic background.

Roboz: So a little bit of epidemiology to keep in the back of one's mind is low blood cell counts. And something else you said, just to emphasize that even that platelet count of 120,000 — don't blow anything off, right? You have a young person coming in with nosebleeds and a platelet count of 120,000. You could say maybe you have a viral infection, go home, come back later. But I think that the low kind of getting that your heightened worry that wait a minute, why is this? Why is this young person coming in with a low platelet count and with a nosebleed, and then jumping forward to making the association of maybe giving ATRA — that's where we run into problems, right? Because this patient's being seen in an urgent care facility; what did they tell us in med school? You hear hoofbeats, you're supposed to be thinking of a horse, not a zebra. So you can't really fault somebody for thinking COVID when a generally healthy 23-year-old comes in in the middle of COVID. But how do we get that sort of heightened thinking to actually involve hematology-oncology right away?

I don't know about where you are in Texas, but in New York, I get calls all the time that many of the community hospitals don't even have ATRA. So even if they're thinking of it, there is already an emergency transfer to someplace that has ATRA. We just had that a week ago from a hospital that didn't have any. Just the thought has to be on your mind so that you can get the patient to the right place quickly.

Ravandi: I think it's very important, if you have any patient who has unexplained cytopenias, to start investigating them quickly. Even if you suspect it is a viral infection, I think if you have significant cytopenias, you should do a bone marrow test and alert your pathologist. And as I said, you don't even have to have molecular diagnostics. Most pathologists will recognize the majority of APL morphology, even the variant cases. That starts ringing bells, and the moment the pathologist comes back and says, well, you know, I think this could be APL — that's the time that if you have ATRA, you give it to the patient. If you don't, you get the ambulance and take the patient to the nearest center that does have ATRA. Again, this is important because, this is a subtype of AML; we're really talking about cure.

Roboz: Let's talk about ATRA for a second. So ATRA is not hanging scary chemotherapy on somebody. ATRA is hanging a vitamin A derivative. If you even remotely have the thought that somebody could possibly have APL, we tell people when heme-onc is involved, just give it. If it's not APL, it doesn't matter. And if it is, you have just saved somebody's life.

Now we're going to move this patient's case forward. She lands in an emergency room (ER). Hematology-oncology is called because you have low blood cell counts and the ER wants a heme-onc consult. I think for anybody listening who's ER, who's hematology-oncology: Get the ATRA, just get it. Don't think too hard. You're not hanging big, nasty chemo that you can't walk back from. You're hanging a pill that is going to start a process that in APL is going to make a huge difference in terms of limiting side effects. So for you guys, molecular diagnosis, having outstanding pathology, taking a look at this; for us, we're in a luxurious position of having this be pretty simple. But if you don't happen to have all of that, what's going to be fastest: fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR)?

Ravandi: We do this immunohistochemical test, which is very quick. We have results within 3 or 4 hours, but of course, that is not available in virtually anywhere else in the US; perhaps you don't even use it either. But of course, FISH can be done very quickly. Both of them are very fast. So I don't think there's a major difference. PCR is much more sensitive, and if both are available, I would probably go with PCR. But again, if you have either test, you should go with the one you have.

Roboz: I've talked to colleagues about this, and what they'll often do is call the pathology lab where they are, and if they're covering at a different hospital, they'll go in and say, Hey, I think I have a case of APL — which is faster for you guys? Who's there today? Is there a tech for FISH? But it's important for everybody to know that there are different modalities of identification of APL. The morphologic characteristic findings are one thing, but the molecular abnormality — a translocation between 15 and 17 — that is something that can be found by FISH or PCR, and you want to get whatever the lab gives you. While you're thinking about that, you can have started ATRA.

Roboz: So for us, at least, you're not waiting for a bone marrow biopsy; you're moving. You're already moving along. Does it happen for you guys, too, that you already know that it's APL before you've even done bone marrow biopsy?

Ravandi: Sure. And the other thing is APL is well described and well known for being associated with significant or severe coagulopathy. So that is where you should be moving, and if the patient comes to you with an abnormal coagulation screen, that is one of the most important early steps that should be taken. You should try to normalize the fibrinogen. We usually like it above 150. We try to normalize the international normalized ratio (INR) with fresh frozen plasma fibrinogen with cryoprecipitate and improve the platelet count. We try to give the platelet count above 50. These are very important first steps because the majority of early complications from APL are hemorrhagic problems, such as intracranial hemorrhage or pulmonary hemorrhage.

Another thing that's important is that we've looked at this extensively in our population. There is a lot of volume that we give to these patients with these factor concentrates and products. You really need to keep an eye on that because one of the potential problems that you will notice in the next few days of therapy of APL is differentiation syndrome. You don't want your patient to be volume-overloaded because that can complicate the picture, and you really need to pay careful attention to the fluid balance, input and output, right from the beginning.

Roboz: So, talk about differentiation syndrome for a minute and how you guys manage that. Let's say that you're starting out with that nice low white blood cell count. You're starting ATRA. Tell us, first of all, what's going to be added to ATRA at MD Anderson? What is going to be the standard chemotherapy? What is standard management, and what do those first few days look like?

Ravandi: As you mentioned, a standard of care has now been established for what we call standard-risk APL. In patients with a white blood cell count less than 10 at presentation, that's a combination of ATRA and arsenic trioxide. This is what we have been doing now for 18 years and what has been proven to be the right thing to do in a randomized, multicenter European study that compared ATRA and arsenic vs ATRA plus idarubicin — which is the previous standard — or AIDA regimen or the PETHEMA regimen. Clearly, both regimens are good, but ATRA and arsenic is even better. There is even a survival advantage for ATRA and arsenic.

You mentioned procedures. I want to bring this in because about a third of patients with APL don't have standard risk. They have a high white blood cell count above 10, and there are occasional patients who have very high white blood cell counts. So don't be fooled if your patient comes in with a white blood cell count of 150 and your pathologist says it's APL, and you say, no, APL patients don't have a high white blood cell count. It does happen, and the procedure you mustn't do is pheresis — you shouldn't put a line in and start. There are exceptional situations, but if we manage the patient appropriately, you should not use the pheresis procedure. And also, you should never think about doing a lumbar puncture in a patient with APL.

Roboz: "Whatever it is, don't stick a needle into their back" is absolutely true. So the combination of ATRA and arsenic is, in fact, the standard of care. I'm not 100% sure that everybody is on board with getting rid of chemotherapy. We actually got rid of it a long time ago when you guys did, because we had an attending here who had come from MD Anderson. So we were very quick to dump chemotherapy. But every once in a while, you do start ATRA, and all of a sudden the white blood cell count, which was starting out low, is now 30,000 or 28,000. The question is, do we add in a little bit of Hydrea (hydroxycarbamide)? Do you give a dose of idarubicin, or do you give your favorite, which I think is gemtuzumab? How do we decide what to do if the counts are moving in an upward direction after having started low?

Ravandi: As you mentioned, for high-risk patients — that's patients whose white blood cell count is over 10, and even standard-risk patients whose white blood cell counts start below 10 but rise to above 10 — we do use a dose of gemtuzumab ozogamicin. In the original publications, we actually wrote 9 mg/m2, but we have decided to give a slightly lower dose of 6 mg/m2, unless the patient has a very high white blood cell count. If the patient comes in with a white blood cell count of 100 and you know it's APL, we use both gemtuzumab and even a dose of idarubicin — a small dose of idarubicin, like 6 mg/m2 or even 12 mg/m2, just to gradually bring the white blood cell count down. We prefer these two drugs, gemtuzumab and idarubicin, because they're totally effective agents for APL.

They have significant single-agent activity. In fact, anthracyclines were first shown to be the more effective drugs for APL, and that's why the AIDA regimen or the PETHEMA regimen did away with cytarabine in order to give more anthracycline. So, we believe that by giving a drug that is actually active in APL, you do the patient more of a favor.

Now, of course, the randomized study was done by Professor Lo Coco. They used hydroxyurea, and I think that's a reasonable approach. And many Europeans, or perhaps many people in the US, use hydroxyurea when the white blood cell count is high. I'm not talking about the high-risk patients. I'm talking about the standard-risk patients when the white blood cell count rises. I do think in high-risk patients, you need to start with the addition of chemotherapy or gemtuzumab, and there is an Australian regimen, for example, that uses ATRA, arsenic, and idarubicin for high-risk patients. It is highly effective. And as I mentioned, we use ATRA, arsenic, and gemtuzumab ozogamicin.

Roboz: So, we have the patient, we have a diagnosis, and we have the patient's coagulopathy managed. They were either high-risk out of the gate, and they got something to bring down that white blood cell count. Or they had a little bit of differentiation, perhaps a little bit of an increased count. Both arsenic and ATRA can contribute to that. We brought that down. Let's say we sprinkled in a little bit of steroids, a little bit of chemo. I think the important thing is, don't stop the treatment. So, if the white blood cell count is going up, manage it. We treat right through the differentiation with dexamethasone. Unless you have a very, very significant ATRA-mediated side effect — like pseudotumor cerebri or something where you really have to interrupt — the goal is to push on, get the patient into remission, and now they're in remission.

Sometimes I get a consultation that the patient with APL is in remission, but they had a complex karyotype or an FLT3 abnormality, which is common in APL. I get these patients for a consultation for transplant in the remission setting. And I worry a little bit about that because our thinking and teaching in the papers suggests that neither a FLT3 abnormality nor a complex karyotype — which, in other AML settings, might shift you to that allotransplant route due to an inferior prognosis — in APL, I think that isn't the case. Can you talk about that point a little bit?

Ravandi: You're quite right. Essentially, when you have highly effective therapeutic strategies, all of those things that you did in the past that try to predict which patient does worse, which patient does better — all of these predictors of outcome are annulled. And I think with APL now, we do have a highly effective therapy to which there is no resistance. The combination of ATRA and arsenic, if it is done correctly and properly, there should be zero resistance to it. A very small New England Journal of Medicine paper describes some rare mutations that could cause arsenic resistance or ATRA resistance, but that's exceedingly rare.

And also, you need to remember that some patients have variant classifications that can have the morphology of APL — for example, the t(11;17) translocation — and don't respond as well or not at all to ATRA and perhaps arsenic. But with the exception of rare cases, you should not see any resistance to ATRA and arsenic.

In regard to FLT3 and complex cytogenetics, in the ATRA and arsenic era, there are no data to suggest that they are adverse; in the ATRA and chemotherapy era, they were slightly more adverse in terms of predicting a lesser likelihood of cure. FLT3 occurs in about 50% of patients with APL. I would not use FLT3 inhibitors in APL. Quite a few years ago, David Grimwade and colleagues published a preclinical study that showed that the FLT3 inhibitor was essentially canceling out ATRA in APL cells. So, it's probably not going to be a good idea. But again, you have a couple of agents to which there is no resistance, so I don't see any reason the treatment should change — unless, as I mentioned, you have the rare variant cases with variant translocations.

Roboz: I think that what we're saying is that we have a curable disease. It's rare, but it's curable. You've got to focus — put it in your mind kind of all the time. Think about APL. Make sure to get the diagnosis. Make sure to handle the coagulopathy; you have to get ATRA and arsenic into the patient. And those are glitchy drugs. For docs who may not have a ton of familiarity with some of the nuances of getting that treatment in, your Journal of Clinical Oncology paper has a little picture of how to get the regimen in with 4 weeks on, 4 weeks off of the arsenic, and then 2 weeks on, 2 weeks off of the ATRA. I love that little picture, and I give it to patients and to my friends who are doctors so that they can follow it.

You have to get the drugs in because it's curative therapy. And if the potassium is low and the EKG is weird, then fix the potassium and get the arsenic in. But don't stop the curative therapy, I think is a really strong message. The first strong message, is don't let the patient come to any harm with the coagulopathy. Once you fix that, don't stop getting the treatment in.

Now the patient is in remission. They're doing great. You got them through, everything's solid. Everybody is on board with the arsenic and ATRA. Do we have to check PCR for a while in the blood or follow? Do we need other bone marrow biopsies? As we make sure the patient is cured, what do we need to follow?

Ravandi: That's a very great point that you brought up. Of course, we do a bone marrow exam on about the 28th day of therapy, and it's absolutely crucial to remember that if the PCR is positive, that does not mean treatment failure at that time. Please don't refer a patient for allogeneic transplant if they're persistent PCR at the end of induction or the first month. If the patient is, however, PCR-positive 3 months after that, then you need to worry. And I have to tell you: In 18 years of doing this, I have occasionally seen patients who have had the situation that after 4 months, they're still PCR positive. You first have to confirm it, and you repeat the testing. Maybe do bone marrow biopsy or even peripheral blood analysis in a week or two. And then if it is persistently positive, then you have to worry.

Roboz: That's a very good wrap-up. And hopefully, we have convinced everyone to focus on APL. Thank you so much for your attention.

Ravandi: Thank you. Gail.


High Prevalence of Obesity in Acute Promyelocytic Leukemia (APL): Implications for Differentiating Agents in APL and Metabolic Syndrome

High Frequency of Acute Promyelocytic Leukemia Among Latinos With Acute Myeloid Leukemia

Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial

Effective Treatment of Acute Promyelocytic Leukemia With All-Trans-Retinoic Acid, Arsenic Trioxide, and Gemtuzumab Ozogamicin

All-Trans-Retinoic Acid, Idarubicin, and IV Arsenic Trioxide as Initial Therapy in Acute Promyelocytic Leukemia (APML4)

Resistance to Arsenic Trioxide and Retinoic Acid Therapy in Acute Promyelocytic Leukemia

Relationship Between FLT3 Mutation Status, Biologic Characteristics, and Response to Targeted Therapy in Acute Promyelocytic Leukemia

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