Published on December 30, 2020
Review of Acute Myeloid Leukemia in 2020
While COVID dominated the world in 2020, research and treatment continued for acute myeloid leukemia (AML) patients and their families. In this year in review, Dr. Naval Daver, MD, of MD Anderson Cancer Center joins Patient Power co-founder Andrew Schorr to revisit interviews with AML experts and patients, discuss what is on the horizon for 2021 and answer questions about the new COVID vaccines.
This program is sponsored by AbbVie Inc. and Genentech Inc. These organizations have no editorial control. It is produced by Patient Power, and Patient Power is solely responsible for program content.
Transcript | AML Year in Review
Andrew Schorr: Hello, and welcome to Patient Power. I'm Andrew Schorr in California. Joining us from MD Anderson in Houston, Texas is a noted expert and a friend of ours who specializes in the treatment of AML, Dr. Naval Daver. Dr. Daver, welcome back to Patient Power.
Dr. Daver: Hi, Andrew. Yeah, always a pleasure and thank you for having me back.
Andrew Schorr: So, the purpose of this program is to really look back at 2020 with a lot of progress, really, and a lot of research, and a lot of thinking about AML. How do patients get the best treatment? And then we'll also look forward to 2021. Earlier in the year, we spoke to Dr. Jessica Altman, who we both know from Northwestern, and she had a comment about testing and that AML is not really one disease. So let's listen to that, and then we'll talk more about it.
What is Acute Myeloid Leukemia (AML)?
Dr. Altman: Acute myeloid leukemia is not one entity, it is a heterogeneous group of disorders the way we think about it now. And the disease is driven by genetic alterations. So, there are some alterations that we call cytogenetic abnormalities and we’ve known about them for decades. And over the last handful of years, we’ve understood that the cytogenetics do not truly, do not fully represent the genetic abnormalities we see in patients' leukemia cells. There are also mutations in the genetic structure or the DNA of the leukemia cells. And so, we test for genetic abnormalities by doing two large groups of studies, the cytogenetics and molecular profiling. And the molecular profiling is frequently done by something called next-generation sequencing where we can look for large numbers of mutations all at the same time.
Andrew Schorr: So, Dr. Daver, there's Jessica Altman talking about testing. It sounds like testing is really critical for the doctor and the patient now to know what version of AML you have.
The Importance of Testing for AML Patients
Dr. Daver: Yeah, absolutely. I think testing is the most critical aspect to both selecting the appropriate frontline therapy, which could make a major difference in the response and the outcome. And also in prognostication, we're using molecular testing, especially more and more to identify the risk group that the patient will fall in. And that can help us decide whether a stem cell transplant is needed or not. So, when we talk about testing in AML, especially the most important mutations are F-L-T-3, FLT3 because there's a targeted drug, FLT3 inhibitor approved in the frontline setting that has been shown to improve both response and survival.
And then looking at IDH1/IDH2, because there are now drugs that can target IDH1 and 2 currently approved in the relapse setting. But there are frontline studies showing that adding them even in the frontline setting could be effective. And in the third big group is secondary and therapy-related AML. And these can be identified by looking at the bone marrow chromosome cytogenetics. And if we see cytogenetics that are associated with secondary therapy AML, there's a drug called CPX-351 (vyxeos), which is approved and has shown to improve survival. So really it is very important to know what variety or what subtype of AML you have based on chromosome molecular testing because it could lead us to a different treatment with a better outcome.
Andrew Schorr: And I'll just say to our audience, look, depending upon where you or a loved one is diagnosed with AML, they may not be familiar with all this. And so that's where a call to a specialist in AML in the region or nationally, Dr. Daver, others, your doctor can be informed on what tests might be done or sent out, how it happens, so that everybody's on the same page with the treatment plan. Am I right, Dr. Daver?
Dr. Daver: Yeah, absolutely. I mean the field of AML is moving really, really quickly. And I mean really compared to almost all other malignancies right now, I think the development in the last two, three years in acute myeloid leukemia has been very quick. The only other time we remember so many drugs being approved as quickly was for multiple myeloma about 15 years ago. So it's hard for a community or [inaudible] where they see everything, lymphoma, solid tumor, to keep up to speed. But absolutely, I think things like AML, ALL, myelofibrosis, which are not the most common, it's great to always get input from an expert before proceeding with therapy.
Andrew Schorr: During the year we spoke to Dr. Alexander Drilon, who's at Memorial Sloan-Kettering in New York, and he spoke about how sometimes there are factors in someone's AML, for instance, could be another condition, that you have in common with people with even another kind of cancer and there could even be a drug for that other cancer that come into play.
What Does AML Have in Common with Other Cancers?
Dr. Drilon: Whereas in the past, we had looked at cancer through the lens of the particular cancer type. Now, we know that there's a different lens by which you can group cancers together based on these gene signatures that we find on comprehensive sequencing.
And because we know that these signatures can be shared across different cancer types, and I'll also add and across the different ages, one of the new strategies we've developed is what we call the basket trial, where essentially, the trial is like the basket, and any patient with that particular gene can get into the basket regardless of what the cancer type is or what it looks like under the microscope.
Andrew Schorr: Dr. Daver, is that where we're going now, is that we're understanding not just what's unique about a specific cancer, but where it may have something in common with another cancer?
Dr. Daver: Yeah, I think that what's happening is our understanding of the biology of not just acute myeloid leukemia, but of other types of cancers is dramatically improving. And so we're finding that there are particular pathways like the RAS pathway, or the VEGF pathway, or others that cross different cancers - immune pathways, T-cell activation, macrophage activation. And so we are borrowing knowledge from solid tumors and they're borrowing knowledge from leukemias.
And the basket trial is a very important way of drug development I think for acute myeloid leukemia, just like it has been for multiple myeloma in the future because with nine new drugs approved in the last three years, and two to three more, hopefully in the next couple of years, it's not going to be possible to do randomized studies, to look at every combination, every sequence, every maintenance setting. So we're going to have to get signals by looking at four or five different combos in one trial, get an idea of what's safe, what's most effective, and then move that forward rapidly because we're no longer needing to per se approve those drugs, but just find the optimum way to use them in the right setting.
Andrew Schorr: So, the point again, to underscore for our patient and family member audiences, you want to have your doctor or other doctors they consult with, have the clearest picture of your situation, so that whether it's drugs for AML, or maybe even knowledge that comes from other cancers is applied to you. So, then the question is, what do you do about it? So, let's hear from some patients who've had different treatments as it's evolved, and then we'll talk about the way things are changing.
Acute Myeloid Leukemia Patients Share Their Treatment Experiences
Steve Beuchler: When I was diagnosed, I just went in for a routine physical and my doctor said, “Your white blood cell count is abnormally low, I’m going to send you to a hematologist.” Well, one thing led to another, including a bone marrow biopsy, and they said, “Yep, you have AML, we’re going to start you off on the standard 7+3 treatment.” I did get into remission on the very first attempt, which bought me some time and I was able to look at my options and opted eventually for a double cord blood transplant.
Elaine Barr: I had the 7+3 chemotherapy regimen. Then they did a bone marrow biopsy. My blasts went from about 80% down to, I think it was 40%. And so, the standard treatment had not worked well enough. It had reduced the blasts, but not to the point where I’m ready to have a transplant. So, then they decided to put me on another treatment regimen, which includes shots of Vidaza (azacitidine) and pills of Venclexta (venetoclax). They gave me another bone marrow biopsy and the doctor here at Methodist Hospital called me and said, “I got your results, and I’m ecstatic.”
Pat Fife: It was a series of tests, and the tests culminated I did have AML leukemia. They put me on what has been mentioned before, the azacitidine and the venetoclax. Luckily, I didn’t have to go to the hospital. It could be done as an outpatient because it’s seven days of azacitidine and the venetoclax is taken by mouth. And I was able to go to the satellite for MSK that was ten minutes away from my house, which was wonderful. So, I had the first round of that, and I went back to the doctor. He did another bone marrow and he called me back as soon as the results came back. He was so excited because I had negative MRD and my blood counts came right back. So, at that point he referred me for a possible bone marrow transplant.
How Has AML Treatment Changed in Recent Years?
Dr. Daver: Historically the standard... And not long history. I mean, up to five, six years ago, the standard approach was to see if a patient was going to be a good candidate for intensive therapy, which was basically 7+3, which is a combination of two intensive drugs, anthracycline, cytarabine (Cytosar-U), or if not, then they would go on to what we call hypomethylating agents alone, which was Vidaza or decitabine (Dacogen). And we tried to get a lot of people onto the intensive therapy because the Vidaza or decitabine alone had a low response rate, 20%, 25%, and intensive chemo had about 75%, 80%.
So now what's changed is with the advent of Vidaza with venetoclax we now see that even this low intensity therapy, when you add the venetoclax to Vidaza, it pushes your response rate up from 25% to 75%, which is actually quite similar to what you get with intensive therapy, without the toxicity, long hospitalization, the GI effects, nausea, and all those problems. So we are seeing a shift, especially in older patients above 70, 75. And even in younger patients between 50 to 70 who have comorbidities, cardiac, liver, kidney problems, where we know they're going to be at risk when we try to give them the high dose chemotherapy. But in the past, we had no choice because the Vidaza alone is only 20%, 25% effective.
Now we say, well, we have therapy that can get 70%, 75% response. And we are now seeing data as one of the patients that we can even give the Vidaza, venetoclax and still go to transplant, and we're getting a much safer transition to transplant. And the post-transplant survivals based on some data shown is similar. So I do think there's a shift. Now what we don't know to be the devil's advocate, and also use the data where it should be is in a 30 or 50-year-old or 60-year-old who's very fit and could get intensive chemotherapy and potentially do well. If we do Vidaza, venetoclax, will we have five-year survival rates of 55%, 60%? We don't know that yet. The follow-up is only two, two and a half years. So I wouldn't yet switch completely, but we do have that option for older patients, more fragile patients, patients with comorbidities, and it's a good option now.
Andrew Schorr: So not everybody is fit enough for a transplant. So earlier in the year, we spoke with one of your colleagues at MD Anderson, Dr. Courtney DiNardo, let's hear from her about options that have shown a great deal of promise for people who, where transplant really wouldn't be an option and then we'll talk it on the other side.
Combination Therapy for AML
Dr. DiNardo: The average patient with AML is older. So, a median age of about 68. So, when we talk about kind of the standard intensive chemotherapy that is often considered the curative treatment options, that's really the minority of patients who are appropriate to receive that therapy. So, we have this, often, older patient population, where up until very recently we used lower intensity strategies, things like azacitidine, decitabine, low dose cytarabine. They are effective for sure. But unfortunately, the majority of patients didn't respond well.
The response rates with azacitidine alone were about 30 percent and were 66 percent with the combination. So more than doubling the initial remission rates. The remission rates happen early after about one cycle only. Patients that have been treated on this initial study since 2014 that are still in my care, and it's, what, six years later in ongoing response. So that's been really amazing.
Andrew Schorr: Dr. Daver, so there is Dr. DiNardo, your colleague, and she had helped lead research about venetoclax, I think in combination with another drug azacitidine that's showing great promise in many people, as she said are older. So how do you feel about this approach and really having an option for older people with AML not having transplant, but still having real hope?
Dr. Daver: Yeah, absolutely. So, the venetoclax combined with Vidaza has been a major, major breakthrough, in my opinion, probably the most important breakthrough in AML research and treatment. So we now have patients who are above 75 years of age, or patients who are 60 to 75 but have major comorbidities where we know the risk of them dying from the toxicity of the high dose chemo alone could be up to 30%. So in those patients where giving them cytotoxic chemo would just be really not a good option, we are seeing with Vidaza, venetoclax we can get 75% remission rate. Median survival is up to 16, 20 months. And even the three year survival rates are up to around 35, 40%.
And it's important to realize that this is very, very good because historically for those patients above 75, or those with comorbidities who could not receive intensive chemo, the remission rates were one third of that, about 25%. And the three year survival rate was only about 10%. So now we've gone from 10% to 40%, 45%. We're still not there yet, and there are new approaches being looked at to improve that, but at least having a half percent, half a shot at being alive three to four years is really quite amazing for our older AML patients compared to what we had in the last few years before that.
Andrew Schorr: Dr. Daver, we've had a lot of change, but still for quite a while, we've had the 7+3 regimen going to transplant. If somebody is younger, could be 60 even, but fit, does that still appear to be a good option?
What is the Role of Chemotherapy in AML Treatment Today?
Dr. Daver: I think this is a very important question. And I think sometimes in the community and some of the smaller academic, the data that's emerging may not be taken in the exact context the trial was done. So, for Vidaza, venetoclax, it's important to realize that this study was for people 75 years of age or older, or those who were younger than 75, but had a very clear documented comorbidity - organ dysfunction, such as renal failure, or cardiac drop in ejection fraction or pulmonary. So, it wasn't just any healthy 64-year-old who's walking or running every day and has very good organ function. I think for that kind of patient, and in our practice, this is what we do, I would still go with traditional induction therapy with or without the addition of targeted therapy, FLT3, IDH or others. We still know the five-year survival could be as high as 55%, 60%.
And as I said, with HMA (hypomethylating agent), venetoclax, the three-year survival is around 40%, 45%. So, we know the five-year survival will be lower. So, I don't think we have data to switch yet from anthracycline, cytarabine 3+7-like regimens to HMA, venetoclax in patients below 75, who do not have a clear comorbidity. Those trials are being done. There are randomized trials looking at that 3+7 against HMA, venetoclax in Europe and other areas. But until those data are available, I would still give induction if a patient is fit, healthy, below 70, and could tolerate it.
Andrew Schorr: Dr. Daver, so 2020 has been quite the year for all of us and people with blood related cancers and with these immune problems that go with it, the added worry is about our risk of having COVID-19.
How Has COVID Affected AML Patients and Doctors in 2020?
Dr. Roboz: March and April were horrible, scary. Diehard New Yorker here, watching pop-up hospitals go up in Central Park, watching the streets be deserted, everything closed. It felt like we had a patient on a ventilator in every bathroom in the hospital. It was horrible. I’m happy to say things are looking much better now. The number of COVID cases has dropped down dramatically. We are back to up and running, and all of our other clinical programs, clinical trials are back up and running again. And generally, much, much, much better in New York, thank God.
If there is any reason to believe that they have active disease, we are delaying a little bit to make sure that the COVID itself doesn’t become very active right as we’re starting chemo. But basically, the plan is to cure the curable, give the patients the therapy that they need. And certainly, in the height of the pandemic we were actually keeping patients in the hospital rather than having them go back and forth because the travel back and forth might have been dangerous.
Should Acute Myeloid Leukemia Patients Get the COVID Vaccine?
Dr. Altman: The more exciting question is who will get a COVID vaccine? Are the doctors going to recommend it? Are other healthcare providers going to recommend a COVID vaccine? I think all of us are very eager for this information. I don’t yet know which vaccine will be first available and what data yet we will have in terms of safety, both for healthcare providers, patients. But we’re eager to be able to review the clinical trial data. And I know at our institution, and I’m sure it’s the same at all institutions, we’ll be working closely with our infectious disease colleagues and determining recommendations within our center and listening to the CDC and other authorities.
Andrew Schorr: So, Dr. Daver, here we are as we record this at the end of 2020, and even right today as we do this, they're talking about whether there'll be a recommendation of approval of second vaccine, and there may be others coming. What is the risk, first of all, of complications of COVID to AML patients, whether they've had transplant or just drug therapies? It would seem like AML patients are at high risk.
Dr. Daver: Yeah, absolutely. I think 2020 has been a very odd and unique year and hopefully it's not repeated for many, many decades, for a lot of problems that have happened to a lot of people and especially to our patients and to our clinical research. It's a very high risk condition for patients with all leukemias. There have been reports published a few months ago from centers that were hit very hard in the initial phase in New York, as well as in Italy, showing that patients with any malignancy had a very high mortality in the range of 15% to 20% mortality if they had COVID.
And the heme malignancy patients, including leukemia, myeloma, lymphoma were at even higher risk. One of the reports from Albert Einstein, a large institution in New York, suggested up to 30% potential of mortality from COVID in patients with acute myeloid leukemia getting therapy. So I think AML patients have to be really, really careful. Now the good thing we have seen at MD Anderson is that we see very, very few AML and ALL, acute lymphoblastic leukemia patients with COVID, and I think this is partly because those patients are already taking many of the precautions that the CDC is recommending the general public to take for COVID.
So, they are usually very careful about hygiene. They use hand sanitizer, they avoid traveling to very crowded places. They often were already using masks. And so I think that population has taken this to heart and taken those precautions really, really seriously as compared to some of the general population. We've heard stories where a lot of those recommendations unfortunately, were flaunted with bad outcomes. So good news is we haven't seen too many. We have seen a few AML patients and our outcomes luckily have been better than what was reported in Italy and New York. And that may be because we have learned from a lot of their experiences and guidelines. But in the end of the day, 100%, very, very high risk, and we should do our best to avoid it in everybody, but most important in heme malignancy and transplant patients.
Andrew Schorr: Dr. Daver, as you know, there is a debate at the very grassroots level among Americans and in other countries too, whether or not they should get the vaccine. Some people are just hesitant, reticent, resistant, distrustful, perhaps from some experience they've had before. What are you saying to AML patients and their families about getting the vaccine, and also would you recommend that AML patients be earlier in the line to get it as the supply rolls out?
Dr. Daver: Yeah. I mean, I think one of the very unfortunate things about COVID and really this is, I think, much more in the U.S. is how much it's been politicized. I think the science is there. It's not missing. There's a lot of science on masks, on hand hygiene, on transmission, high-impact papers, a very diligent study. So it's just become a political debate about whether we believe it or not. But I mean, if you believe science, it's there. Now the vaccine, yeah. My recommendation… This is a question I'm getting from almost 80% to 100% of my patients, and of course we expect all patients to ask this. So the recommendation is, yes, we should get the COVID vaccine. High-risk patients, including leukemia, lymphoma, stem cell transplant, should be very early people to get that vaccine. Now, it's important to note that of the two vaccines, both Pfizer and Moderna, these are protein vaccines.
They actually do not contain an activated virus, unlike the flu vaccine and some of the others. So, the risk of getting an infection from this is zero because there's actually no infectious component. It's actually a protein that is produced. Side effects-wise, there's not a big worry. A lot of the drugs we give our patients, so things like FLT3 inhibitors, Jakafi (ruxolitinib), others were approved on studies of 300 to 500 patients. With the vaccine, there has been already 30,000 patient study showing safety. So if you're going to get leukemia drugs from your doctor with 400 or 500 patients, you should be comfortable getting the vaccine with 30,000 people already dosed, and now more than a million in the UK. In fact, I myself, I'm going to be getting the vaccine in the next two to three days. Everybody in our department has signed up for it.
And in the end of the day, I think what we don't know, and I will be cautious on that, is we do not know how effective the vaccine will be in leukemia and transplant patients. We don't know if it will give 97% protection like it did in the healthy volunteers. This is something we will learn on the job. My feeling is it will give some protection more than not having the vaccine at all, but I do not think it will be 96%, 97% effective, but I still think having some protection to COVID is better than none. And I would recommend it.
Andrew Schorr: Yeah, that's exactly what I was going to ask you is having some protection is better than none. So we'll still have to be cautious, and I'm a leukemia patient myself. We'll still have to be cautious, but hopefully with shot number one and shot number two, and us getting it earlier, that we will have some protection and you'll learn. We'll all learn together.
Dr. Daver: We'll all learn, yeah.
Andrew Schorr: We'll all learn together. All right. So, let's put all this together. So, it sounds like we've propelled through 2020 going into 2021 with knowledge about AML, testing options, treatment options, we're in a stronger position to help people live longer and live better with AML than ever before. Would you agree?
What Does the Future of AML Treatment and Research Look Like?
Dr. Daver: Oh yeah, absolutely. I think in the last three years we have had dramatic progress in all subsets. Older patients with AML, younger induction with additional of targeted therapies to induction, relapsed AML is quite amazing as I said. Some of the relapses, FLT3, IDH, we are talking about numbers of 70% to 80% people we can get into remission transplant. Three years ago people, if they said that, they would think you're crazy. It was 20%, 30%. So dramatic progress, and I only see this improving. Now, as we combine these drugs, yes, there are speed breaks we go through, there are myelosuppression concerns, optimization of schedule.
But all of this is not to say we won't do it. We just need to keep doing it better. Keep learning as you said, and get to better and better schedules. And I think we have the tools now, even in relapsed and older AML, to get us to high long-term cure rates. Three to five year cure rates. We just have to use them optimally and do the trials, which I think brings me to what I think is most important. A lot of people say, "Well, you have all these new drugs, is clinical trials important? And I think now like multiple myeloma was 15 years ago, more than ever, trials are critical because we actually have stuff that works. And if we can find the right ways to use them, we will improve the median survival from the current three to five years to 15 years, just like multiple myeloma did in the last two decades.
Andrew Schorr: I just want to underscore that. I've been in two clinical trials. The first one was at MD Anderson where they combined drugs in a new way, and it led to a much, much longer remission than people had ever experienced before. And so, I would urge our audience, we're partners with researchers like Dr. Daver and his colleagues around the world. We're in a partnership, and you may have the option of receiving tomorrow's medicine today as they answer scientific questions. So, a discussion about, is there a clinical trial that applies to me or my loved one at this point in the AML journey, which might be at the beginning, but it might be later. That's an important question to ask.
So, we underscored it about personalized medicine, we talked about a treatment is changing, we talked about COVID of course, and we talked about clinical trials. So important. Dr. Naval Daver, thank you so much for being with us, your dedication to patients, the work that goes on there at MD Anderson and your partner centers around the world. Thank you for all you do, and for being with us today.
Dr. Daver: Thank you very much, Andrew. Always a pleasure, and thank you for allowing us to share our knowledge with patients and helping them.
Andrew Schorr: Okay. I'm Andrew Schorr with Dr. Naval Daver, remember knowledge and advocacy for you or a loved one can be the best medicine of all.
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