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iwAL 2019 | The future treatment of acute leukemias: part I
In part I of this discussion, Mark Levis, MD, PhD, from the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, Cardiff University, Cardiff, UK, and Andrew Wei, MBBS, PhD, FRACP, FRCPA, from Monash University, Victoria, Australia, look to the future of therapy and diagnostics for acute leukemias. This video was recorded at the International Workshop on Acute Leukemias (iwAL) 2019, held in Barcelona, Spain.
Transcript (edited for clarity)
Alan Burnett: My name’s Alan Burnett. We’ve been attending the second international workshop on acute leukemia’s in Barcelona. This is the second workshop. The aim of the workshops is really to assess where we’ve got to in these diseases and particularly where we go forward. The interesting thing I think, is that in the last 18 months or 2 years there’ve been a number of new drugs in acute myeloid leukemia for example, which have been approved...
Alan Burnett: My name’s Alan Burnett. We’ve been attending the second international workshop on acute leukemia’s in Barcelona. This is the second workshop. The aim of the workshops is really to assess where we’ve got to in these diseases and particularly where we go forward. The interesting thing I think, is that in the last 18 months or 2 years there’ve been a number of new drugs in acute myeloid leukemia for example, which have been approved. Some, most indeed, not on randomized information with survival endpoints.
Alan Burnett: So to discuss how the meeting’s gone, what highlights have fallen out of it, we have Andrew Wei from Melbourne, and Mark Levis from Baltimore, who are going to give us their perspectives on this couple of days. So Andrew, what do you feel the challenges are that have clarified themselves at this meeting?
Andrew Wei: I think in terms of acute myeloid leukemia, the major challenge I think still remains, how to get immune therapies to work better. We’ve tried many different types of technologies in terms of BiTEs and conjugated monoclonals, also CAR T-cells. Compared to ALL where really, immunotherapy is really dominating the field and transforming the lives of patients with that disease tremendously. We’re just not seeing that type of progress in AML. So at the moment we seem to still have to rely upon transplantation, risk stratification, and some new molecules which are helping us to help patients. But we still have a long way to go in this disease.
Alan Burnett: Yes, I mean given your contribution to the field, particularly with the venetoclax, I’m surprised you haven’t raised that as the great white hope of the future. So what do you think of some of the small molecules? What are the challenges there? Or targeted agent, shall we say?
Andrew Wei: I think they all have a contribution and we have in particular venetoclax, as you’ve mentioned, targeting BCL-2 FLT3 inhibitors, which Mark’s had major input into and also IDH inhibitors. Now it’s a matter of how do we perhaps use these drugs either in sequence or in combination, to try and combat the clonal diversity of AML, and I guess keep up with a disease which keeps adapting to the selective pressure we place against it.
Alan Burnett: Mark, I refer to perhaps the less rigorous criteria for drug approval, that seems to be around in the last two years, which is fine. I think they must have waited until I retired and then done it. Have you got any comments on that process? I mean it is a bit of a change the way the treatments have been assessed in the last little while. We had to stick to overall survival as the end point. We tried to persuade them disease free survival would be a better endpoint. That really wasn’t accepted.
Mark Levis: Well, it has been now to the point where the last word I heard literally from an FDA on another drug I was involved with was, “Well you can’t use overall survival as an end point. There’s too many confounding factors. You should use event free survival.” Which I found kind of ironic. But yes, there’s no question drugs are being seemingly waved through, but the approvals are logical. I’m not so sure that it’s necessarily the FDA that has gotten lighter. It’s as Charlie Schiffer always used to say, “You needed better drugs.” And the drugs have clearly gotten better. I think that’s kind of what I’ve noticed.
Alan Burnett: So in your particular field where you’ve led the understanding of the implications of FLT3 and its treatment, you did make some very good summaries of the merits of the candidates at the moment, to follow on from the midostaurin experience. So that presents a few difficulties. One, I guess if you’re trying to bring it first line, you’ve got to use standard of care, which includes midostaurin. But in terms of the benefits, or strengths, or weaknesses of the other agents, would you care to comment?
Mark Levis: Well, as I discussed I guess, they all three, I mean have strengths and weaknesses. But yes, with the newer agents they are chemically distinct. And you know, I’ve heard tell where we’ve got one, why do we need a second one? And I just roll my eyes and say, “Have you treated CML recently?” I use all five of the drugs approved for that thing, I’m glad that I’ve got them. So they are … and frankly, I’ll take more, I’ll take all I can get. But they are very different. I think I’m excited by the fact that I think we’re going to have high quality trials to tell us how to use these drugs. Which ones to use when. And they do make sense. So yes, I think, you know, quizartinib might work best early on and I think gilteritinib might work best later on. But there’s a few more coming down the road, we’ll see.
Mark Levis: I think the key actually is we probably got FLT3 inhibited, we’re going to have to do more. We’re going to have to start combining things. You know, we didn’t cure AML with daunorubicin. We cured it with dauno[inaudible 00:05:50]. Started on the road with dauno[inaudible 00:05:53] and the principal will hold the same, I think with these targeted agents.
Alan Burnett: And if you, you know, you’ve got … Do you think there are pharmacological implications in terms of how good these drugs are? I mean there was this story of interaction with other drugs or AXL antifungals for example. Sustaining the inhibitory activity or not etc. The ligand implications, etc. How do you see that now?
Mark Levis: We will still have to be … at the end we are pharmacists, we are pharmacologist. We use drugs to cure our patients. We don’t pull out a scalpel. So I think it is imperative that you need to know drug interactions. Just the mere thought that, okay, I’m opening up the blood brain barrier with these crazy T-cell mediated therapies in ALL, and now I’d better not be giving the patient imipenem which in fact I think I’ve done before.
So, okay, and that … so there’s a unique pharmacologic feature. I use the trick of an AXL to boost up gilteritinib to get a higher level into the central nervous system, which in fact you can do. On the other hand, when I combined itacitinib and gilteritinib with an AXL, I got LF liver function problems promptly. The drug interactions are all over the place and you’d better know about them.
Alan Burnett: So the trend that seems to me very clearly from the week is that nobody has a lot of confidence in just sticking now with monotherapy of the new agents, it’s all about combinations. How does a trial as to work out the best bet for combinations? Is that just how well he gets on with the company involved or are there any logical combinations that you would vote for?
Andrew Wei: I think when we use the single agent drugs, serial monitoring for resistance mechanisms is really important, because that can be quite helpful in informing us what might be a rational combination approach to go with. Then really we try and back that up with preclinical work, but ultimately the trial is the trial. Then there are candidate drugs which come through the system that might be useful for specific subsets of disease. Another issue with all of these new drugs is that when these drugs get approved, and start moving into the first line setting, all of the years that we’ve spent risk stratifying AML go out the window and we have to pretty much do it all again. Also there becomes diversity between risk stratification for countries that have access to these drugs, and countries which are behind and take time to get access.
Andrew Wei: So really it’s become a much more complex world in terms of drug availability, drug options, and even drug monitoring. You know, the Europeans are very strong with MRD and multi parameter gene panels. Whereas many other parts of the world are still very much evolving in this area.
Mark Levis: I think Torsten’s point about using artificial and machine learning is going to be necessary to be perfectly honest. Our brains aren’t going to be able to discern the patterns, but a treatment response to one of these agents that is noted, such as example when ven was given to an IDH mutant patient. Okay, that was noted, it was as simple finding, and then [inaudible 00:09:41] ran off and explained the biology of that afterwards. So we have some artificial intelligence approach can discern patterns that will then be carried back into the lab to explain the biology. We really may move the field, you know, ahead in leaps and bounds when we’re doing.
Alan Burnett: Yes, I mean we’ve been poor at explaining why treatment actually works in some patients, but we’ve been quite good at saying why it doesn’t work. But clearly there are drugs out there that don’t work well enough in enough patients, and that’s the reason it failed. But there’s still a lot of patients, even if you look at the gemtuzumab ozogamicin, intermediate risk overall, it’s not that big an effect. It is significant but not by much. But you can very quickly identify a population just based on white count cytogenic. You can very quickly get down to a subset where you can show clear benefit. But what I think you’re implying Mark is that Torsten will be able to talk about your drug handling biochemistry or enzymology, as well as your disease issues as well.
Alan Burnett: Then of course Japanese patients have different biology in handling their drugs so they have to have a different approval system, I think.