Leukemia Highlights from the 2018 American Society of Hematology, with Guillermo Garcia-Manero, MD

February 19, 2019
Download MP3 (11.04 MB/15:53)

In this podcast, Cancer.Net Associate Editor Dr. Guillermo Garcia-Manero will discuss some of the new research in leukemia and myelodysplastic syndromes, or MDS, that was presented at the 2018 American Society of Hematology Annual Meeting, held December first through fourth in San Diego, California.



ASCO: You’re listening to a podcast from Cancer.Net. This cancer information website is produced by the American Society of Clinical Oncology, known as ASCO, the world’s leading professional organization for doctors who care for people with cancer.

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses.

In this podcast, Cancer.Net Associate Editor Dr. Guillermo Garcia-Manero will discuss some of the new research in leukemia and myelodysplastic syndromes, or MDS, that was presented at the 2018 American Society of Hematology Annual Meeting, held December first through fourth in San Diego, California.

Dr. Garcia-Manero is the Deputy Chair of Translational Research and Professor, Department of Leukemia, at The University of Texas MD Anderson Cancer Center in Houston, Texas. He is also the Chief of the Section of Myelodysplastic Syndromes at MD Anderson Cancer Center.

ASCO would like to thank Dr. Garcia-Manero for discussing this topic.

Dr. Garcia-Manero: Hello, I'm Guillermo Garcia-Manero. I am 1 of the leukemia physicians at the University of Texas MD Anderson Cancer Center, where I also serve as the chief of the section of myelodysplastic syndromes. I'm happy to do this podcast today, trying to highlight a few of the studies that were presented at ASH this past December 2018. I have to start saying that this is basically mission impossible because the good news is there were so many important presentations, with active meaning for our patients, with new drugs, and that makes the selection of these 4 presentations extremely difficult. I'm going to mainly focus on presentations on myeloid malignancies, mainly MDS and AML.

And I'm going to start with the first presentation. It's a very important phase III trial that was conducted all over the world, known as the MEDALIST trial. This study was, again, a phase III trial, was presented by Dr. List from the Moffitt Cancer Center, but it was a large effort, basically, countries all over the world. And the idea here was to test the activity of a compound known as luspatercept. This is a brand-new drug. This is an antibody that basically has the capacity to affect signaling of TGF-beta pathway in MDS. And the hypothesis is that by doing so, it may promote the capacity of the bone marrow to produce red cells and therefore improve or ameliorate anemia. As all of you know, anemia is a major complication of multiple disorders, in particular, myelodysplastic syndrome.

So the study was a randomized study. The patient population was for a specific subset of patients with myelodysplastic syndrome that are known as patients with refractory anemia with ring sideroblasts. And these patients had received already prior therapy, mainly with a growth factor, drugs like erythropoietin. The study had what they call a 2:1 randomization, meaning that for each 3 patients, 2 got into the investigational compound, luspatercept, and 1 into placebo. This drug has already been tested on prior phase I, phase II studies and is extremely safe, and we know that we can administer this compound every 21 days. The major endpoints of the study were basically to see what was the rate of transfusion independency, and that actually is measured every 8 weeks. This is criteria that investigators in the field pick. And there were other endpoints, like 12 weeks, and then also measuring increases in hemoglobin and, importantly, of course, duration of response.

This data was quite significant, and it's probably one of the first phase III trials for patients with myelodysplastic syndromes that is positive in many years. The primary endpoint, again, that was transfusion independency in the first 8 weeks, was met. So patients on the luspatercept arm had an improvement in their transfusions. The [inaudible] was close to 38% versus 13% for those patients who were on placebo, and this was highly significant. Most importantly, when the investigators looked at the duration of response, this was also significantly in favor for those patients that received luspatercept. So, in other words, not only was there higher response rate with this new agent, the response is also longer. So that is very important. And then, as I mentioned earlier, in general, these compounds are extremely well tolerated without a major, significant toxicity issue.

So we are excited about these results because it may be—of course, this drug is not yet approved by the FDA. But the expectation will be that this would be an excellent compound for this first subset of patients with myelodysplastic syndrome. But there is already an ongoing phase III trial for patients with MDS, low risk, that have not received any prior therapy. So we're moving into front line with this particular compound. And there was also some very interesting data in patients with thalassemia, that was also positive. So it has implications beyond myelodysplastic syndrome.

I am not sure what the future development of this compound will be, but I think it's going to have multiple applications in solid tumor malignancies, potentially as an adjunct in patients receiving induction chemotherapy for acute leukemia. And there are also some ongoing clinical trials in myelofibrosis. So that was very exciting.

The second study that I would like to highlight is a study known as TELESTO, and this is basically a clinical trial where patients with low-risk MDS were randomized to received iron chelation with a drug known as deferasirox or not. Why this is important is because, over a decade ago, this compound, deferasirox, was approved for patients with a number of disorders, including myelodysplastic syndrome, that had evidence of iron overload. So in myelodysplastic syndrome, because of the need for red cell transfusions, it is not uncommon that patients will accumulate iron. And that in itself can result in complications for the patients, such as liver damage, heart damage, etc. So, despite the fact that this drug was approved, the way it was approved was on non-randomized clinical trials. So we never actually knew for a decade whether there was true benefit to this compound or intervention in patients with lower risk disease and anemia with iron overload. And why this is important to know is because this drug, although it's an oral compound, it can have some side effects that can be significant, and there's also a cost issue with this approach for our patients.

The study was actually designed many years ago. I was part of the group that designed this clinical trial. And originally, it was designed to test whether iron chelation was going to result or not only in improvement in overall survival. And the original design was going to involve, I believe, over 800 patients. When the study was opened, it became clear that this was not going to be feasible because this drug had already been kind of embraced by the community as a standard of care. So the study actually was then modified with the advice of the authorities, mainly the FDA, and it became this study where the main endpoint was event-free survival.

Similar to the study that I discussed earlier, this had 2:1 randomization, and patients were randomized into deferasirox or placebo. And because these are tablets, that was quite easy to do. Again, the main objective was to evaluate event-free survival, but we were also interested in looking at overall survival and other biomarkers like ferritin levels, [inflammatory?] responses, and some of the comorbidities that are associated with iron chelation.

The study, again, was positive. And what these investigators—and this data was presented by Dr. Angelucci, who is from Italy—clearly indicated that there was a longer event-free survival for those patients that were treated with the iron chelation drug deferasirox compared to those that do not. And, indeed, actually, the risk reduction was almost 37%. So this data is important because it establishes a potential role for iron chelation in our patients. Now, there is a major limitation, of course, of this drug. That is, unfortunately, we cannot really measure or state that the overall survival benefit was clearly achieved by this compound. That said, actually, there was an improvement also in overall survival for patients treated with this compound, but the hazard ratio was significantly higher than that for event-free survival. And again, this study is likely not powerful enough to really clearly demonstrate an improvement in survival, although it clearly demonstrated this other event-free survival improvement. The other limitation of the trial is that we don't know why the event-free survival is better. That is something that is not clear from this data analysis. But the reality is that, in my mind, this is the only and probably will never be repeated randomized phase III trial of iron chelation. And I think it shows that this is associated with a clinical benefit for our patients.

The next study that I would like to present is a study for patients with acute myelogenous leukemia, and this was a study presented by Dr. Maiti from Houston. And it's one of the multiple studies that looked at the addition of venetoclax to drugs like decitabine or azacitidine for patients with acute myelogenous leukemia. As many of you know, during the meeting, this new agent venetoclax, or ABT-199, was approved for patients with AML. And this was based on a number of clinical trials that had been done at multiple centers. So there were multiple presentations, but I can tell you that this was one of the most exciting topics of the ASH meeting, the addition of ABT-199, or venetoclax, to either decitabine or azacitidine for patients with AML.

So venetoclax, or ABT-199, is a drug that modifies apoptosis. Basically, the idea is that enhances cell death in these leukemia cells. And data from Dr. Konopleva and other investigators have indicated that there is synergism between venetoclax and the hypomethylating agent, either azacitidine or decitabine. And there are a number of studies showing actually very high response rate with these compounds.

But I highlighted this study because it looks like a different alternative schedule. Here, the investigators gave 10 days of decitabine with venetoclax for basically every day of the month, and they reported an overall response rate that was over 90%. And what I think is striking, that half of these patients with acute myelogenous leukemia achieved what we call minimal residual disease status. So they were MRD-negative with this therapy, indicating that there was eradication of the leukemia clone. The follow-up on this study was short, but the survival actually was close to over 95%. So we all believe that this very exciting data, whether you administer this with 10 days of decitabine or 5 days of decitabine or with azacitidine. And it's likely now becoming the standard of care for most patients that are receiving a hypomethylating agent for acute myelogenous leukemia. So this is extremely good news for our patients, and it will open up to multiple other combinations.

And to finish, I will bring one of the last presentations in myelodysplastic syndrome. But I think that this is a topic that has also implications for other myeloid malignancies. So this is Abstract Number 465, and I had the opportunity to present this poster. So this is a study performed mostly in Houston, where we combined azacitidine with drugs that are known as immune checkpoint inhibitors, drugs like nivolumab or ipilimumab. The hypothesis for this is that it turns out that the leukemia cell or the MDS cell express molecules like PD-1, CTLA-4 on their surface. And similar to what you see in solid tumors, where these compounds are extremely effective, for instance, for melanoma and other solid tumors, it is possible that these compounds could also have activity in these myeloid diseases. So we have tested these in a clinical trial, combining these immune checkpoint inhibitors with azacitidine. And we have tested this in patients with high-risk MDS that have not received prior therapy or in patients with relapsed refractory disease that already have failed a hypomethylating agent like azacitidine.

The study actually has accrued almost 100 patients, and we believe that this data is very important. So what we first found was that the combination in the front line of immune checkpoint inhibitor, such as nivo or ipilimumab with azacitidine, is associated with a very high response rate. So the overall response rate, for instance, with azacitidine-nivolumab was over 70%, and it was over 60% with AZA-ipilimumab. But that's not what I think is important from this presentation. What was important was that the duration of response, particularly in the combination of azacitidine and ipilimumab with a follow-up on this clinical trial of around 20 months—this is quite a long number—had not been reached. And we have not had data like these in any of the prior studies that we have done with doublets, for instance, with HDAC inhibitors or other compounds. Now, there is a limitation of this, that the incorporation of this immune checkpoint can be toxic. This is something that solid tumor oncologists are familiar with, but it's a little bit new for us. It can cause things like pneumonitis—this is lung inflammation—colitis, skin rash. These sometimes are difficult to treat, so this is not ready for standard-of-care type of approach. But I think it's going to be an important part of the armamentarium for our patients with myelodysplastic syndrome.

So with that, I would like to conclude, perhaps, do a very quick summary. I presented to you 4, what I think, very important presentations. The first one was a new drug for MDS called luspatercept. This may be very important to treat anemia, and we are excited about future development of these compounds. The second presentation was about iron chelation in MDS. This has been an area of huge debate in our field, and this data I think supports further the use of these types of compounds for our patients with iron accumulation. Third, the data with ABT-199, or venetoclax, with decitabine in AML is really important. And I think it's now established as the standard of care for those patients not fit for chemotherapy. And finally, this data with immune checkpoint inhibitors indicates that there may be an important role for these compounds also in MDS, and other presentations at the ASH meeting in AML suggested kind of the same. And with that, I want to thank you for this opportunity and your time.

ASCO: Thank you, Dr. Garcia-Manero. Learn more about leukemia and MDS at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show on Apple Podcasts or Google Play.

Cancer.Net is supported by ASCO’s Conquer Cancer Foundation, which funds breakthrough research for every type of cancer, helping patients everywhere. To help fund Cancer.Net and programs like it, donate at conquer.org/support.