Leukemia (AML/MDS) Moon Shots update

MD Anderson Cancer Center
Date: 06-30-2014


 [Background Music]

Lisa Garvin: Welcome to Cancer Newsline, a podcast series from the University of Texas, MD Anderson Cancer Center. Cancer Newsline helps you stay current with the news on cancer research, diagnosis, treatment and prevention, providing the latest information on reducing your family's cancer risks. I'm your host, Lisa Garvin. Today, we're talking with Dr. Guillermo Garcia-Manero, who is a professor of leukemia here at MD Anderson and he is also an expert on myelodysplastic syndrome, which happens to be half of one of our cancer moon shots. Welcome back, Dr. Manero.

Dr. Guillermo Garcia-Manero: Thank you, Lisa.

Lisa Garvin: Let's talk about myelodysplastic syndrome, to just kind of get a general overview before we dive in. So this is a set of diseases where we have immature blood cells. So kind of explain that, the genesis of the disease.

Dr. Guillermo Garcia-Manero: So, basically, this is a type of leukemia that is characterized by what we call bone marrow failure. As you are saying, the clinical manifestation of the disease is lack of appropriate formation of blood cells, either a low white count or low hemoglobin, meaning anemia or low platelet count or combinations of these. This is a disease that affects mainly older individuals or patients that have been exposed to other forms of chemotherapy, radiation therapy for other cancers. And it's a very complex group of diseases where patients could be in a very early stage of the disease with probably no need for any treatment and excellent outcomes without any treatment to older patients where the prognosis is actually poor.

Lisa Garvin: And you actually worked on a world staging tool for MDS, correct?

Dr. Guillermo Garcia-Manero: Right. So, we have developed a couple of prognostic models here at MD Anderson. We have also collaborated with what is now considered the standard prognostic model for this disease that is called IPSS that the thing is what you are referring to, that this is worldwide model that had almost 10,000 patients involved. So, these prognostic tools are important because they allow us basically to define specific subsets of patients from those that probably truly have preleukemic type of condition that is many times how doctors in community see this disease to another subset of patients that actually have prognosis that are as bad as those with patients with acute myelogenous leukemia.

Lisa Garvin: And it must be a struggle because you do have different subtypes of the disease that behave very differently. That must be a struggle as a clinician and researcher to deal with?

Dr. Guillermo Garcia-Manero:  Yeah, absolutely. And I think that's why it is becoming more difficult for us to actually report the progress that we're making, because I think what we're dealing with is what I call the microdissection of the disease so we took now about a small specific subset of patients. And I think we're actually making progress in some of them. When you look at them in totality, it's hard to see that. That's one of the difficulties of this disease. And that's very important for the patients because there're many different subsets of these patients with very different outcomes, probably potentially different therapeutic alternatives. So this is very important not just for research but also for the patient because it has implications in terms of, you know, what we do as clinicians. So, it's a particularly difficult decision that's context of heterogeneity.

Lisa Garvin: Now, myelodysplastic syndromes or MDS as we call in shorthand was combined with acute myelogenous leukemia in one of our cancer moon shots. Explain that. Apparently, a subset of MDS patients do progress to AML.

Dr. Guillermo Garcia-Manero: Right. So, traditionally, people let's say 15 years ago, thought that MDS was kind of a preface of the AML. So, they lumped together for many years. It is obvious over the last decade that these are two different diseases. But there's a group of patients probably depending on how you look at it from 10 to 30 percent of patients that go from MDS to AML. And there's another group of patients with AML that actually have MDS features. So these are people that present with leukemia. They never had the diagnosis of MDS before but actually the bone marrow has teach us suggested that probably that person has MDS as well or that the disease evolved from an MDS feature. So, there's a huge overlap between these two diseases in the middle. And there's a clear progression from MDS to AML in a significant fraction of patients. So, it made sense to put them together in this moon shot program but scientifically, clinically and biologically, more and more we see this as two different diseases with a big overlap.

Lisa Garvin: Well, and typically moon shot diseases were chosen because they were poised to have major breakthroughs that could translate to the clinic. And on the face of it, it sounds like this is a difficult set of diseases. Why it was chosen for a moon shot?

Dr. Guillermo Garcia-Manero: Well, I'm not sure Lisa that that's how these diseases were selected. You probably are right. I think that some--in some settings, these programs were selected maybe because of the depth of the clinical and research programs that go around it. So, it turns out that the leukemia department has been working on those diseases for 30 years or so. So there's quite a bit of expertise, data, and I think like deep knowledge of what the problems were, so I think that's why we're selected. It also happens that, I think, you know, MDS and AML, even if these are relatively small diseases worldwide or nationwide, they represent a huge fraction of the resources that MD Anderson itself uses to take care of patients. So, hospital basically, a third of the beds are leukemia related somehow. So this is a lot of what MD Anderson does, not say that the other programs at MD Anderson are not good. They are excellent. They're probably better. But this is a big chunk of what the work at MD Anderson is, you know, taking care of people with leukemia, AML and MDS. Even if the number of patients is smaller than breast cancer or colon cancer, these represent a huge fraction of what we do in the hospital for instance. So I think it's an important problem for us and I think it's a very important problem in society because these are diseases of aging. And as we get older, the frequency, the incidence of this disease is increasing. And as I mentioned earlier, this is very important. We are starting to see more and more patients with other cancers and other leukemias where we are now very successful. Like for instance, what is a typical example, multiple myeloma. When I was a fellow 15 years ago, survival of outpatient with myeloma was I guess two or three years. Now, these patients can live for a long period of time with the current therapies. But as their life expectancy expands because of their primary disease, unfortunately, the chances that they develop the secondary leukemias, AML, MDS also increases. So, we're starting to see patients with secondary disease that we never saw before just because they are surviving longer the primary disease. So this is an important problem, because now you have older population, high incidence of MDS, high incidence of AML, plus significant success in solid tumors, myeloma, lymphoma, all the leukemias like CLL for instance. We see an increase also apparently of the secondary leukemia. So, at the end of the day, this is an important problem in the hospital and in the nation. So, of course, my goal will be to potentially, hopefully limit the number of patients that requires stem cell transplant. Of course, stem cell transplant is a great tool but it's toxic. And it will be great to learn who really benefits from it, who doesn't really benefit from it. But for sure, it's curative on a specific subset of patients. So we need to figure that out. And I think that transplant is evolving from an approach maybe 10 years ago of very high dose chemotherapy with stem cell rescue to a much more sophisticated way of treating patients with leukemia and actually potentially other tumors. So, people have heard about these CAR cells that are now being investigated in many centers in the United States with great success in ALL and CLL. MD Anderson has a very nice program here for this type of approach as well. So, Dr. Champlin and his group of investigators, Dr. Cooper, Shpall and others are really trying to figure out more innovative biologically adapted approaches to stem cell transplant. But actually, some of them maybe actually pure immune approaches to therapy and maybe we should talk about the immune platform at MD Anderson later. But we're exploiting immunology knowledge in cellular immunology to really make transplant less toxic and also be associated with lesser risk of relapse, because what we're seeing over the last few years is that as the transplant doctors realize that perhaps this high dosage of chemo were too toxic. They adapted the way of doing these therapies with these many transplants, things of that nature. But what we're seeing is that unfortunately, that decrease in mortality and toxicity from the transplant is associated with increase in relapse rates. So the survival, in my opinion at least in MDS, doesn't seem to be improving with transplant, with conventional technologies. So, I think the future would be to combine these total therapies particularly develop newer approaches to transplantation. So, Dr. Champlin has, who's the head of transplant here at MD Anderson, has put together a very nice team of investigators that focus on this and they are looking at many different venues to really produce this type of immunological manipulation of the patient that I think that, you know, today usually what is going to have an effect on the patient.

Lisa Garvin: And I think that--I'm sorry, I don't mean to interrupt. But let's talk about immunotherapy, because that as a treatment regimen, it's kind of waxed and waned in popularity and now all of a sudden it's at the forefront of treatment of diseases such as AML and MDS. As such, we have a huge immunotherapy platform for moon shots. So it sounds like harnessing the immune system has become kind of the new avenue of research.

Dr. Guillermo Garcia-Manero: Yeah. And this is very interesting because what has happened is that the first trials of these drugs that you're talking about and, you know, we have investigators, like Jim Allison, that discover a lot of these pathways here at MD Anderson with these immune checkpoints. They were first tested in solid tumors particularly in melanoma, kidney cancer, things like these that are highly--that are known to have an immunological background. But data from our group, the lymphoma department, has shown actually that these pathways are also engaged in lymphoma, multiple myeloma and interestingly in myelodysplastic syndrome. So, we are now leading a number of clinical trials where we're using these PD-1 inhibitors, PD-L1 inhibitors, combinations, et cetera, in patients with myelodysplastic syndromes and in the lymphoma department in lymphoma, multiple myeloma. So this is very interesting because people were thinking about these treatments as solid tumor treatments. And this is actually an example of how beautifully this cross fertilization is happening where we, in leukemia, are taking the knowledge from solid tumors to apply these "new drugs" into the treatment of leukemia. So, we're running some of these trials as we speak. It's early to know whether they're going to have the same effect that, you know, they've shown in melanoma and so forth, but this is an area that we're excited and you are totally right that we, at least in leukemia department, we're not that interested for few years because they have tended to fail. But we strongly believe that this gives us now an opportunity to study and explore totally non-conventional types of therapies that are probably not cross resistant with your traditional form of chemotherapy of hypomethylating agents. So this gives us a totally new view of the disease. So there's a lot of excitement about this concept in leukemia.

Lisa Garvin: 'Cause I know one of the biggest problems with AML and MDS is that the relapse or--I'm sorry, not the relapse rate, but they acquire a tolerance to the treatment. So, is part of your research looking at trying to override that?

Dr. Guillermo Garcia-Manero: This is a very important question, Lisa. So, yeah, we have studies that are ready to start looking at this issue of--this is particularly in AML, of given these drugs in patients with what we call minimal residual disease, in other words, they look like they are cured from the leukemia but we know they will relapse. So the idea is can you give this type of treatment to basically--it's not a vaccine but maybe the public will understand this as a way to eradicate or vaccinate against the last remnants of the disease. That is actually what, in general, unfortunately kills patients with AML. In MDS, we are taking another lead that maybe is more aggressively but it's an important one. We published data last year that in patients where the Decitabine or Vidaza, these are two drugs that--and these are like the trade names so Azacytidine or Decitabine that have failed to the patient. What we published is that it appears that these immune deregulated pathways are there [phonetic]. So, we thought that actually we could rescue patients that have failed these compounds with this, meaning the hypomethylating agents, with these immune checkpoint modulators. So we are now in the middle of actually major trial with one of these PD-1 antibodies, and that study is two-thirds going. And in the next few weeks actually we'll be starting a very similar study for hypomethylating failure MDS with the PD-L1 antibody from another sponsor. So you're going to see a lot of the studies. And I think what's going to happen is that they'll probably be put together, PD-1 inhibitors with PD-L1 inhibitors potentially with hypomethylating agents and so forth. So this is an area that is new for me actually. And what is interesting is that the way we treat these patients in the clinic with these drugs may be vary from what we traditionally have seen with conventional. So it's actually a little bit of a learning curve even for leukemia doctors have been doing this for like 15 years.

Lisa Garvin: So what do you see in the coming year for the AML, MDS moon shot? It sounds like you've got a lot of clinical trials going. What else will be happening?

Dr. Guillermo Garcia-Manero: Well, we're working on, you know, with Dr. Hanash and his proteomic platform. We're working in doing a detailed proteomic analysis of MDS and AML. I think this may give us a lot of new potential new targets so it will leverage on that. Dr. Champlin is coming with a very ambitious program as I mentioned of new transplant mortalitieswith a lot of clinical trials in transplant. And Dr. Andreeff that is focusing in the AML is focusing on FLT3 that is a common mutation in AML. And his collaborators are developing a lot of new strategies to overcome this issue. And, again, going back to your first question, Lisa, of the microdissection of the disease, you know, this may not be like what you were telling me the Ibrutinib in CLL where apparently it works genetically. Here, the name of the game is going to be can we identify the best patients for this type of transplant and cure 90 percent? Can we identify the best treatment for the FLT3 mutated? Can we--And this would be a low-hanging fruit, can we improve outcomes of patients with hypomethylating failure MDS? So we're working on this angle. So my life is a little bit complicated right now because it's just trying to hold all these stuff together. And the progress is maybe a little bit not as fast as, you know, if you get one big drug and that behave right away but when it matures it would be the new standard of care.

Lisa Garvin: Well, it sounds like you have your work cut out for you. Thank you, Dr. Manero.

Dr. Guillermo Garcia-Manero: Thank you, Lisa.

Lisa Garvin: If you have questions about anything you've heard today on Cancer Newsline, contact askMDAnderson at 1-877-MDA-6789 or online at mdanderson.org/ask. Thank you for listening to this episode of Cancer Newsline. Tune in for the next podcast in our series.