Disease Modifiying Therapy in Lower-Risk MDS


A closer look at disease modifying treatments in MDS, providing insights into their mechanisms of action and impact on the management of the disease.

Dr. Michael Savona: You've said it a couple times about how much six transfusions is. Transfusion a week. That's absolutely true. Not just on, well, it's an objective outcome that's improved. But the burden for patients, what do patients complain the most of? Other than the more thoughtful patients who do a lot of reading think about AML transformation. The biggest thing they complain about is getting it transfused. If you're not coming in and waiting for a crossmatch or if you live in the community, sometimes being admitted to the hospital, not having to do that as a huge improvement in patient quality of life. Not to mention the impact on the healthcare system if we're not having to manage this number of transfusions. I think those are important things to underscore. The other thing you mentioned, which I love for you to talk about more. I know you're like me, very excited about this. The disease modification. So just to kind of level set people, in MDS we talk a lot about disease modifying therapy for years that basically meant DNA methyltransferase inhibitors or hypomethylators or maybe lenalidomide. Other than it was transplant. Lower risk therapy like Luspatercept and definitely ESAs, we often considered as non-disease modifying at least modifying insofar as you might have less transfusions. You might feel a little better, but not changing the natural history of the disease. There's some clues here that we might actually be impacting more than just and this makes sense when you consider how this drug works as a polymerase inhibitor. We may be just impacting more than just counts. We may be actually changing the natural history of the disease in the patient.

Dr. Amer Zeidan: I completely agree with you, Mike. I think a lot of the excitement for many of us who have been involved in the trial, I think comes from that particular aspect. Because unlike several of the drugs like ESA, potentially Luspatercept, it doesn't seem that this drug only improves anemia. It's not just an anemia improving drug. While the best way to know this for sure is very long-term follow up to look at overall survival, risk of progression to leukemia, et cetera, we are seeing some biological hints that this is the case. So some of those aspects that we observed on the trial and actually I just came from a EM meeting in Frankfurt. And there was a lot of discussion about this. In the ASCO presentation, the focus was on the clinical data. But there were multiple presentations on the durability, but also specifically looking at the biologics of imetelstat and how does that translate on the patient sample studies. So Dr. Santini gave a very nice presentation looking at some of these. I think some of the highlights is that the variable allele frequency of the sum of the most commonly mutated genes in lower risk MDS such as SF3B1/2, and the NMT3 go down basically with the treatment and these are reductions-

Dr. Michael Savona: They go down, and they don't just go down a little, right?

Dr. Amer Zeidan: They go down significantly and suggesting that you are probably going after the clone of the disease. And also we are seeing some cytogenic clearance. Not many patients started with abnormal karyotype, but within those who started with abnormal karyotype, we are seeing more patients going into cytogenic clearance with imetelstat compared to placebo. Also, we are seeing hints that those who have reduction in the variable allele frequency of the SF3B1 for example, they have longer transfusion independency. Suggesting some correlation between this disease modification impact on the mutation and the clinical activity. I think this is very exciting data. We also saw some data suggesting that the ringed sideroblasts, the number of the ringed sideroblasts cells basically also goes down with the treatment. I think this all is probably suggesting that we are acting on the clone. I actually personally believe many people think of neutropenia and thrombocytopenia, lower risk MDS as necessarily a bad thing. Clearly, it can cause complications if not properly managed as you mentioned, and giving growth factor and treatment interruption. But for me, most of the drugs that disease modify in MDS such as HMAs, cause thrombocytopenia, neutropenia. I suspect personally that some of what we are seeing reflects that the clone, the MDS clone is going down. This is why you are seeing, because many of those neutrophils and platelets are coming from malignant hematopoiesis. Of course, this is a theory at this point. We are going to need some single cell analysis and other kind of ways to see how much is effective hematopoiesis coming back from normal clones versus just improvement of the malignant clone. But I think the level of excitement about this aspect is significantly high in the community.

Dr. Michael Savona: I think you're absolutely right. Not to speculate too much, but I would agree with you that the idea that these clonal progeny cells, all these clonal neutrophils as they die well, they go down just like when the modeling, remodeling of the marrow occurs with DNMTIs or hypomethylating agents, we see deeper drops in counts in the first few cycles. But once patients are on the stoichiometric right dose for them, sometimes the counts don't go down at all because they've maintained normal hematopoiesis again. I think there's a hint to this a little bit in this study.

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