Myelodysplastic Syndromes: Translating Genetics to Clinical Practice - Episode 13
Transcript:Mikkael A. Sekeres, MD, MS: Let me end this section by asking each of you what agent you’re excited about, if you could talk a little bit about the mechanism of action, and some of the preliminary results you’ve seen. Maybe I’ll start with Rami because you’re on a roll.
Rami S. Komrokji, MD: I think in the lower-risk, we are really excited about the TGF (transforming growth factor)-beta inhibitors, and luspatercept is the drug that’s moving forward in this area. So, the background for this is that the TGF beta pathway is overexpressed or activated in MDS patients. There are many ligands that bind the super family of receptors for the TGF-beta, but they contribute to the myelosuppression in MDS, and they could be targeted. One approach targeting them is those fusion proteins that act like a trap, and they bind the ligands before binding the receptor.
There are two drugs that have been in studies, sotatercept—we conducted the studies in the US—and luspatercept—these studies were done originally in Europe. One of them targets the type 2A activate receptor, where the other one targets type 2B. These are very similar drugs; maybe sotatercept has a little bit bone remodeling effect, luspatercept has less. The first interest in those studies came when they were using them in healthy volunteers for osteoporosis and dose-limiting toxicity was actually erythrocytosis. It turns out that they work on improving later erythropoiesis, which is a little bit different from the ESAs (erythropoietic stimulating agents). Both studies have looked at lower-risk MDS patients. We divided the patients into what we call a high transfusion burden or a low transfusion burden. And both studies showed promising signal of response—especially for those that have a low transfusion burden that had less than 40 units in 8 weeks. And we’ve seen transfusion independence.
One thing that stood out as an observation early on, patients that had ring sideroblasts had higher responses, which led, actually, to more patients being enrolled in the European study extension phase of luspatercept, being old with ring sideroblasts. But, for those patients, especially if they have low transfusion burden, the response rate was more—there were more than 60%, 70%. Many patients became transfusion-independent. So, based on that, that study now had moved to a phase III randomized study called the MEDALIST, where patients are randomized between a placebo and luspatercept—and that study is active in enrolling patients. I think this is a promising agent, and going after a certain selected population that we hope, if those studies are positive, will translate for a new medication for patients with lower-risk MDS.
Mikkael A. Sekeres, MD, MS: Ellen?
Ellen K. Ritchie, MD: As a leukemia doctor, as well as an MDS physician, I’ve been really excited by seeing the results of immunotherapy, particularly in CLL (chronic lymphocytic leukemia) and ALL (acute lymphoblastic leukemia). And I’m excited about the next antibodies that may be targeting targets in myeloid diseases. So, I think that they are drugs that could be well tolerated in an older population. We talked about combinations before and, as leukemia doctors, how we like to go at it with both guns. What we don’t have in leukemia studies is, really, populations of people in their late 70s and 80s like we have in myelodysplastic syndrome, which is really a brave new world, actually, of treating patients.
I’m excited about the idea of, maybe, antibody therapy in older patients; it could be well tolerated, with less sort-of gun fire to the other regions of the body, and it’s something that they could tolerate a little bit better. The SGN trial—the CD33 plus a hypomethylating agent—it’s a combination therapy. But, again, it’s using something that might not be so suppressive of the blood counts, so it may be a really good thing to combine with a hypomethylating agent.
Mikkael A. Sekeres, MD, MS: Jamile?
Jamile Shammo, MD: Well, I think it’s important to come up with a second-line for MDS patients, particularly those with high-risk disease. And for that reason, I think I opted to participate in rigosertib trials. And I’m sure you know that the rigosertib is a dual kinase inhibitor that targets the PI3 kinase, mTOR pathway, and also polo-like kinases—which I learned that they actually have a role in stabilizing the mitotic spindle. And presumably if you interfere with that process, then that process of mitosis gets destructed and then the cells undergo apoptosis. So, the very initial phase I/II studies with rigosertib demonstrated that you can have reduction in the blast percentage, which is consistent with the initial mechanism of action of this drug.
It’s very interesting to see that in the phase III study, the one-time trial—that two patients who have high-risk MDS had failed the hypomethylating agent and then they were randomized to best supportive care versus rigosertib—did not actually achieve its primary endpoint of prolonged overall survival. However, when they went back and did an ad hoc analysis of the study, they demonstrated that people who actually did not achieve any response progressed through hypomethylating therapy. They are the ones who may actually have the survival advantage, which is the reason why this second phase III trial, known as the INSPIRE trial, is taking place. The international study of 30 different sites in over 200 patients is addressing the same question, with the difference that those patients would have to have less than nine cycles of hypomethylators, basically, and fit the criteria of having minimum of RAEB-1 and higher to then be randomized to this therapy versus best supportive care.
Interestingly, we have a patient that was on the one-time trial, ongoing for about 40 months. He’s the only one on the trial, and we would like to actually close this study if possible. So, it tells you that within any given patient population, there is someone who just does respond beautifully well, and it certainly would be very nice to be able to offer patients a second-line therapy for high-risk.
Mikkael A. Sekeres, MD, MS: It’s an unmet medical need. Well, I want to thank my co-discussants for a fabulous discussion today. I love when I sit at the table and I’m completely outclassed by the people around me, which happens all the time at home. It’s nice when it happens at work, too. We’ve covered a lot of ground related to the practice and management of MDS and how the field is rapidly evolving, and what we expect in the future. Before we end this discussion, I’d like to get final thoughts from each of the participants. I’ll start again with Dr. Komrokji.
Rami S. Komrokji, MD: I think, obviously, we discussed plenty of data today. I think there is excitement in the field. When you look back on the last 5 years, we definitely learned about the biology much more. I think we are all determined, as a group, that we need to change the natural history of this disease. We need to improve the outcome for our patients, and I think, hopefully, we’ll be able to achieve that in the coming few years.
Ellen K. Ritchie, MD: I think this is a very exciting time, actually, in this field. Sort of the confluence of interest in aging and interest in the development of this disease, I think we’re finding that there are mutations that occur as people age that may have dovetailed into the development of disease. And is there a potential that we could interfere in the early phase of patients who are developing MDS. I think that this is a really exciting avenue of study, and I really look forward to seeing what happens in the next few years.
Jamile Shammo, MD: I think I have two wishes for my patients. One is to be able to have a predictor of response. I don’t put people through cycles and cycles of therapy without knowing whether they’re going to be responders or not. And second is to be able to have much more or many more options for them for therapy, so that they don’t feel like this is it, and what’s next.
Mikkael A. Sekeres, MD, MS: We’re in a remarkable time in the study of MDS where our understanding of the biology is skyrocketing, and we can only hope that the therapies we have available to treat our patients are going to catch up soon. On behalf of our panel, we thank you for joining us today.
Transcript Edited for Clarity