Educational content on VJHemOnc is intended for healthcare professionals only. By visiting this website and accessing this information you confirm that you are a healthcare professional.

Share this video  

iwAL 2019 | Novel approaches and targeted therapies in 2019 for AML

Here, Mark Levis, MD, PhD, from the Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, Cardiff University, Cardiff, UK, Andrew Wei, MBBS, PhD, FRACP, FRCPA, from Monash University, Victoria, Australia, and Torsten Haferlach, MD, PhD, of MLL Munich Leukemia Laboratory, Munich, Germany, explore novel therapies and treatment targets for acute myeloid leukemia (AML). This video was recorded at the International Workshop on Acute Leukemias (iwAL) 2019, held in Barcelona, Spain.

Transcript (edited for clarity)

Mark Levis:
This is Mark Levis at the second international workshop on acute leukemia here in Barcelona, May 2019, and I am joined by Torsten Haferlach and Andrew Wei after a lively morning session. And Torsten, you really started things off I think with a glimpse into where the next step is going to be. We have talked about this before, I know, it used to be the microscope, and we love the microscope, and it was cytogenetics, and we are wrapping our minds around next generation sequencing, but the next step I think is really going to be another quantum step...

Mark Levis:
This is Mark Levis at the second international workshop on acute leukemia here in Barcelona, May 2019, and I am joined by Torsten Haferlach and Andrew Wei after a lively morning session. And Torsten, you really started things off I think with a glimpse into where the next step is going to be. We have talked about this before, I know, it used to be the microscope, and we love the microscope, and it was cytogenetics, and we are wrapping our minds around next generation sequencing, but the next step I think is really going to be another quantum step.

Torsten Haferlach:
Yes. Well, we are at the beginning of this next step, but from our personal life and circumstances where we live in, we realized that there are many new things now that are in our smartphones or in our notebooks, and now these new technologies also move forward to the sequencing technologies, and they are moving very quickly. They are moving even more quicker than the smart phones are developed and that leads to these new options that we, in addition to the microscope and the chromosome banding analysis, can also use sequencing techniques for a gene, or genes, or even a genome. And this is fascinating times because we see that we know more and more about the patient’s cells, biology of the leukemia cells, and that already leads to very specific personalized treatment approaches.

Mark Levis:
But the challenge is to make it simpler, cheaper and spread it to the world so we can do this in a uniformed fashion as you know. In fact, I think we were talking about a project with a cell phone looking at a microscope and I know we are doing something like that as well. Literally, we are trying to reduce this technology to as simple as possible and cheap as possible.

Torsten Haferlach:
Yes. So, that is true. I think, first of all, we experience right now that all the phenotypical methods to address, for example the diagnosis of leukemia, it is not so easy to teach them and to learn them, and you will need a lot of time and training, over years and years to be really good. And this is a little bit different with those molecular techniques because you have the machines that if you set them up once, and then there is an assay that you may even buy, and then the bottleneck right now is by informatics because the software tools for the final examination and calculation of the respective findings, that is quite more in progress than the sequencing technology itself. And so we are now more trying to hire a bioinformaticians than morphologists to get with this data on the best place they should go.

Mark Levis:
So we are going to cram all of our experience into the smart phone, we are going to have artificial intelligence analyze thousands of data points to tell us what to do with the patient, but Andrew, then we have got to actually implement a clinical trial with a lot of exciting new agents, and maybe use artificial intelligence to interpret those. So how are we going to design trials with this in mind? I mean you just mentioned you wish you had some of these new techniques, but-

Andrew Wei:
Well, I think it is important for us to make sure that these new technologies are integrated into our studies, firstly, and second, that we collect the right samples, not just for now, but for the future and for instance, in trials that we are sitting up at the moment, we are even looking forward to the possibility that in a few years’ time, some of these technologies will be applied at the single-cell level. And at the moment, there are very few trials where it is serial data sets with acquired preserved single cells available. So we now collect and preserve cells every time a patient has a bone marrow especially on clinical trials such that when patients progress, we can really understand mechanisms of resistance, not just at the bulk-sequencing level, but at the single-cell level and I think this will really give us deeper insights than we have ever had before.

Mark Levis:
Yeah. So we have got our traditional agents, or hypomethylating agents. We have got a hoard of new small molecules, seemingly a new one every other month or so, we are having now immunotherapy and the oncologist, the leukemia doctors are actually having a bit of confusion over what do I do, and here is where in fact, we are probably going to have to use artificial intelligence to help us out.

Torsten Haferlach:
Yeah, but because there are so many things published and so many new drugs, and so many combinations of new drugs that even you, or we, who have to listen to talks every week get a little bit lost.

Mark Levis:
Andrew and I are confused on rounds as are you. What should we do?

Torsten Haferlach:
Yeah. And the patient will someday ask us, “Why didn’t you check this or that?” because they can also Google some new information and what Andrew just said, I think that is really of importance and it is quite strange that we can now even do genomes from one single cell. And so I do not say that is the future for tomorrow, but as you just pointed out, this combination of these new drugs and these new techniques, and the more and more needed individualized-treatment approaches, including MRD at the other hand of the laboratory story, we have to face that.

Torsten Haferlach:
And if we enroll and include this in studies, even if we now just freeze down the viable cells and the DNA for further investigations, we could go for a cohort of the patients that do not respond to a specific drug or for those who responded to a specific drug, and then we are getting also much easier into these drug applications or FDA improvement if we can demonstrate that it is only good for this group and it is not good for this group. Everyone will be happy to know this and not just start for all the patients the same story.

Mark Levis:
So just to finish, we have been talking about the, perhaps, somewhat more distant future, maybe five years, I am not sure. Andrew, I will put you on the spot. What is the next big thing that is going to hit us in the next year or two that is going to get a regulatory approval and keep us scrambling?

Andrew Wei:
Well, I think at this stage, we are still on this new wave of new drugs in terms of regulatory approval and I think it still has not ended yet. So I think practice change will most likely still come in treating patients with the right drugs early on in therapy. I think relapsed/refractory disease is still a big struggle. So I think within the next few years, what we would more likely, say particularly in older patients, is that we will use for instance IDH inhibitors in combination with hypomethylating agents as first line therapy for people with those targetable lesions. For those that do not have a targetable lesion, we might consider venetoclax with the generic cytotoxic drug like HMAs or low-dose ara-C, obviously FLT3 inhibitors in combination with either azacitidine or chemotherapy remains really important.

Andrew Wei:
However, I think in the future my vision will be to see the de-escalation of the use of chemotherapy and more use of double-targeted therapies because then we are likely to, I think, delay the onset of resistance because resistance will have to be linked to the drugs which we are using rather than using chemotherapy which just induces enormous non-selective drug resistance, and then you basically induce resistance to many things at the same time rather than just the very selective drugs you wanted to use.

Andrew Wei:
Furthermore, I think the possibility of using targeted drugs which may become resistant because of its partner and then switching with another partner, and keeping the sensitivity going, and I think this might particularly apply to a drug like venetoclax where true on-target resistance, as has been observed in CLL, is quite uncommon and quite delayed.

Mark Levis:
Okay. Well, exciting times gentlemen.

Read more...