Pre-Conference Perspectives on Hematologic Malignancies - Episode 13
John Leonard, MD: We have a question that came in from the audience around brentuximab and AVD, that combination. I think you addressed it in your discussion. But maybe in a broader sense, we have the potential now to use it up front, to use it in the relapsed pretransplant setting, posttransplant setting. Where do you think that’s all going to settle out? Is it going to be everywhere? Is it going to be here, there? How is that all going to play out, considering we’re going to have studies that, to some degree, are positive at the back end, are positive at the front end? It wouldn’t surprise me if, somewhere in the middle, it’s positive. How do we settle all that out? I don’t think these patients are going to be on this drug indefinitely. And clearly, a lot of people don’t need it because the vast majority of people are cured without brentuximab. So, where do you think we’re going?
Anas Younes, MD: So, that’s what happens when we have a single agent that gives you 75% response rate in this setting. That will be moved and combined in a frontline pretransplant and posttransplant setting and that’s what we’re seeing. So, I’m not surprised about that. The question is, is it going to benefit everyone? I don’t think it will benefit everyone, and it’s going to come down to biomarkers and subset analysis. We need to look at the subsets, who benefitted the least in the randomized trial and not offer them this drug, and the subset who benefit the most and then we offer this drug.
John Leonard, MD: AML seems to be getting more and more complicated, and we’re moving from cytogenetics to molecular markers and now targeted drugs. When you’re seeing a newly diagnosed AML patient, how do you tackle that? I know that you’re setting off a lot of these studies, but what do people in practice need to know about them, and where do you think the future is for those that are really actionable today?
Alexander Perl, MD: I think the base question of “Is this patient fit for intensive therapy?” or “Are they unfit for intensive therapy?” remains. I think we have appropriate therapies for each of those bins or categories, but we have a lot more choices now. And so, that gets a lot trickier. And the real question is, how much data do you need before you pull the trigger and say this is the right therapy? And actually, I think the answer today is you need a lot more therapy than you used to because you have more options. When it used to be if you were fit, you got 7 and 3. If you were unfit, you got a hypomethylating agent or low-dose ara-C. That was easy. We didn’t need to wait for anything to come back. You could tell when the patient walked in the room by interviewing them.
Now, we actually need tests back. So, for example, for Vyxeos, there’s a drug that has a proven benefit in patients with therapy related leukemia, you can get that off history. But it also has a proven survival benefit in patients with certain karyotypes. So, maybe you need to wait for some karyotypic data back. We need flow data to know that Mylotarg is effective, but we also know that Mylotarg is not an effective treatment for patients with high-risk karyotypes, so you want to have both of those. And of course, I mentioned the FLT3 inhibitors, which are effective in patients with FLT3 mutations, but we don’t really know what they do in patients who don’t have those mutations. They don’t have a proven benefit, so you want to have those data.
It’s gotten a lot more challenging and really what we’ve done is we started to come up with a frontline shotgun approach to sending off a bunch of tests that will be actionable. We want to know if the patients have a core binding factor mutation, which would predict response to Mylotarg. We want to know whether they have a FLT3 mutation. We will ultimately want to know if they have an IDH mutation, we’re not using those drugs frontline, and we want to send all of the next-generation sequencing so that later on we have enough information to do risk stratification.
But right now, it’s probably going to take several days, after seeing a patient who’s stable, to say, “I have enough information to say here’s your best therapy.” That’s primarily for older patients where we know waiting a few days probably is not going to impact. In younger patients, we don’t know that we want to wait on them because they can get sick quickly and we want to treat them as aggressively as possible. There are some data to even say that that might be deleterious to way too long. So, it gets a little bit tricky. I think in my practice, I want to at least get a small amount of genetic data before I’d say what to treat patients with.
John Leonard, MD: Quickly, and I think I know the answer, but the question came in, in myeloma, we have so many active drugs. And it seems like when we combine them in the up-front setting, the toxicities are not overwhelming. Should we be using all of the best drugs up front? Should we be saving them? Should we use 2 drugs first and then 3 drugs later? Should we be moving to 3 and 4 drugs early and then use what we haven’t later? What’s your sense of where that’s going? I know it’s an abstract question at this point probably.
C. Ola Landgren, MD: Well, if you look at the data, I think the field has come to a point where, if you look in the relapse setting, for example, all the trials that have been published the past 12 to 24 months show that 3-drug combinations are superior to 2-drug combinations. So, we have already done that for a long time in upfront treatment. Now, the question is on the table, for example, an IMiD, proteasome inhibitor, dexamethasone combination, will you benefit from adding a monoclonal antibody to that? So, those studies are in the works right now. There are multiple of those studies looking at different combinations. I think the proof will be obviously in the pudding. We will have to see if that extra fourth drug will deliver deeper responses that are also sustainable. Those data are not yet there, but the field is moving very fast in that direction.
I think with so many drugs available, and we have the opportunity to monitor deep responses, we have passed the old point where we used to hold all the drugs, or the few drugs, we had back, do one at a time. We can give a lot of very good drugs up front, and if the disease comes back, we still have very many more to choose from. Even if the disease comes back—and again, usually it lasts for quite some time—you can go back and reuse the ones you used many lines back and it still can work. So, I think that’s a new kind of direction on the field.
John Leonard, MD: The last question and then I’m going to go around and just ask you all to give 1 minute on your big other things that you think the audience should get a sense of. But first, Anas, just one question that came in was about relapsed mantle cell lymphoma. And in a general sense, patients who had chemoimmunotherapy initially, they relapsed. When are you using ibrutinib? When are you using acalabrutinib now? What other things are you thinking about in those patients, just in a nutshell, any big picture thoughts for the audience?
Anas Younes, MD: If someone had a mantle cell lymphoma treated with BR, for example, now progressed, you ask, what do I do? I tend now to use BTK inhibitors as second-line therapy because the data suggest that the earlier the line you use, the better the benefit. So, I used to use ibrutinib before. Now, we have acalabrutinib. Honestly, I haven’t used it yet since it has been approved. I look forward to using it the first time around, but for now, I think ibrutinib is as good as anything else.
Transcript Edited for Clarity