Acute Myeloid Leukemia: The Path to Personalized Medicine - Episode 1
Harry Erba, MD, PhD: Hello, and thank you for joining us today! There has been considerable progress in elucidating the pathophysiology of acute myeloid leukemia [AML], leading to FDA approval of several novel targeted agents and others in late-stage development. In this OncLive Peer Exchange® discussion, we will discuss new and more personalized treatment options, the role of “minimal disease testing” in managing AML, and emerging strategies for improving outcomes. We’ll discuss key clinical trials from the ASH [American Society of Hematology] 2018 Annual Meeting and how the newest research may apply to your clinical practice.
I am Harry Erba, professor of medicine and director of the Leukemia Program at Duke University.
Participating on today’s distinguished panel are: Dr. Naval Daver, associate professor, director at the Leukemia Research Alliance Program in the Department of Leukemia at MD Anderson Cancer Center.
Dr. Mark J. Levis, professor of oncology and program lead of the Hematologic Malignancies and Bone Marrow Transplant Program at the Sidney Kimmel Comprehensive Cancer Center.
Dr. Alexander Perl, associate professor of medicine at the Leukemia Program of the Abramson Cancer Center of the University of Pennsylvania.
And Dr. Raajit Rampal, assistant member, Leukemia Service, Memorial Sloan Kettering Cancer Center.
I look forward to a great exchange. Let’s begin.
At this year’s ASH meeting, there were a couple of very important abstracts presented on the management of leukocytosis. Before we get to all this targeted therapy, we have to remember that some of these patients present ill with very high white counts. There were 2 abstracts that were looking at the characteristics of patients with hyperleukocytosis.
It was a retrospective database review at several different centers, both in the United States and Europe. And there were over 1000 patients with AML with a white blood cell count of over 50,000. And what they saw in this retrospective review is that having a high white blood cell count was bad. I mean, the survival of these patients was worse. About a quarter of them had clinical evidence of leukostasis.
But in the accompanying abstract what was interesting is that they looked at the impact of leukapheresis, which has been a very common practice in patients with a high white count over 50,000 or 100,000. In their entire data set, I was actually surprised to see that only 15% of patients underwent leukapheresis. However, when they looked at the impact of leukapheresis in this retrospective review, there was no difference in survival if a patient underwent leukapheresis with intensive chemotherapy or not, calling into question what is the true value of the procedure. Now, in this abstract, they called for randomized trials to really understand the benefit, but I guess it begs the question, what do you do at your institution? This is what people are going to want to know when a patient with a high white count comes in. Even if they don’t have clinical symptoms, or if they do, do you have your patients undergo leukapheresis? Let’s start at the end of the table.
Naval G. Daver, MD: Sure. Yeah, I think that’s a great topic. I know we’re going to focus a lot on targeted and immune therapies, but we do get patients, as Dr. Erba mentioned, who come in with very high white count. The first 48 hours really is dealing with how we’re going to get them stabilized and suited before we get molecular immune information. So, in general, we have been doing very little to no leukapheresis for most of these patients. Even in patients who come in with let’s say white counts in the 100 to 150 range, our practice has usually been, of course we admit them. Or many times they’re coming through the emergency room anyways, we’ll give them Hydrea, anywhere between 4 to 8 grams which usually starts working within 24 hours. And we will give them 1 dose of cytarabine, and that could be 1.5 grams or 2 grams flat.
In fact, in many of the protocols that we have, because we do enroll a large proportion on to protocol at MD Anderson, we have allowed that 1 dose of cytarabine to be given and not exclude patients from study because we don’t think that that’s curative intent. With this approach, I would say about 95% of time we’re able to get those white counts down to below 60, 70 and then in the subsequent days going down further, and we’re comfortable with that. I think the only situation we would consider urgent leukapheresis is, let’s say somebody comes in with a very high white count, 150, 200, but more importantly if he’s got clear evidence of CNS [central nervous system] involvement, visual changes, acute shortness of breath, acute renal failure. And even then it’s kind of a discussion, because with the leukocytosis you need a central line, which is usually a wide bore, [and] there’s infection, there’s coagulopathy. So I would say very, very, very few cases, maybe less than 3% or 4%, we ever require or lean towards leukapheresis.
Harry Erba, MD, PhD: Mark?
Mark J. Levis, MD, PhD: So we approach it with trepidation. As Dr. Daver mentioned, putting in a large bore catheter in somebody who’s this sick is not trivial. So we typically take the tact of, you’ve got to show us evidence of leukostasis, of clinical organ involvement, and typically that’s an altered mental status or dyspnea that we can’t explain on imaging. So I share everyone’s reluctance. I’m not sure that I’m doing the right thing. My preference would be to cytoreduce with, in fact, start induction as opposed to leukapherese. But we had the tactic where we would give a dose of chemotherapy beforehand. The problem with that is, participating in nationalized trials, pretty much that precludes that patient. So we pretty much abandoned that practice at our institution. We leukapherese once a month, and reluctantly. You’ve got to show us evidence of leukostasis.
Alexander Perl, MD: We actually use it a lot more frequently at the other centers. Our concern has been historically that your first symptom of leukostasis could be that you get a head bleed and then suddenly we can’t really offer these patients as aggressive therapy because they may lose the ability to undergo intensive treatment. So we’ve been more aggressive. Again, some of this may have something to do with how quickly you can get a line placed, whether it’s done in IR versus at the bedside with somebody who is not doing these for a living. The ability to do this workup quickly, though, I think is important if it has an impact on outcomes. So if it’s going to take you the better part of the day to set up getting a line in place to do the apheresis, to bring in the blood bank to do that procedure, I’m not sure there’s a huge amount of benefit.
And the problem I have with wanting to have further benefit proven by a trial, it’s a very hard study to set up, to get consent for the patients who are just incredibly ill. It’s not clear to me that we’re ever going to have a perfect way to prove that there’s a benefit here. I think it just falls into one of these areas in medicine where I think we’re never going to have perfect evidence, but the chagrin factor is pretty high if you sit back and then something bad happens. I don’t know whether that’s better than using chemotherapy, certainly, but I certainly sleep well at night knowing that I’ve done the most aggressive therapy with this.
The big concern I have is in patients where there could be real risks of the procedure. So, in APL, we won’t pherese. I think that’s a national practice guideline, and I think it’s a reasonable one. The patients have significant coagulopathy. It’s just not safe to put these lines in, and you can pull out a lot of the clotting factors in the procedure and make them very, very sick from the procedure in a way that they weren’t before. So those are the situations where we’d be reluctant to do it.
Harry Erba, MD, PhD: Raajit?
Raajit K. Rampal, MD, PhD: I think our practices are mainly the same that others have talked about here. I think we don’t have great evidence either way, and so oftentimes this is relegated to a clinical decision. Our experience has been that unless a patient has overt clinical symptoms, such as dyspnea or other evidence of end organ damage, we try to shy away from it and use hydroxyurea or sometimes start infusional cytarabine to try to get the counts down before proceeding to therapy. Obviously there are practical concerns in terms of getting the line in, how quickly can that be done, is one delaying treatment by trying to get a line in. And so those are some of the practical considerations that also weigh into the decision. I think it is certainly not a clean-cut decision.
Harry Erba, MD, PhD: I agree. The problem with a retrospective analysis is that you don’t really know what were the other factors that drove the clinician in those 15% of cases to have a line put in and do pheresis. So the fact that the survival was the same with or without pheresis doesn’t take into account that those patients may have been sicker. At the institutions where I’ve practiced, we’ve had the same kind of practice guidelines. If the patient truly had clinical signs of leukostasis, then we do everything we can with the exception, just as you mention, of patients with coagulopathy where bleeding can occur afterwards.
Transcript Edited for Clarity