Impact of Molecular Characteristics, Responses to Luspatercept in Patients with MDS

A roundtable discussion, moderated by Hana Safah, MD, of the Tulane University School of Medicine, focused on the latest data in myelodysplastic syndromes presented at the 65th ASH Annual Meeting & Exposition. Dr. Safah was joined by Jamile Shammo, MD; Andrew Brunner, MD; and Tiffany Tanaka, MD.

In the next segment of the roundtable series, Dr. Shammo shares her reaction to a study presented at the ASH Annual Meeting that assessed mutational burden and impact on primary outcomes in the COMMANDS trial.

Watch the next segment in this series.

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Dr. Safah: Let’s go through these abstracts that probably are going to shed some light on it. I’m going to start with Dr. Shammo here and talk about the first abstract is the impact of genomic landscape and mutational burden on primary endpoint response in the COMMANDS study.

Dr. Shammo: I think I’m glad to finally see that MDS [myelodysplastic syndromes] is being categorized according to the molecular characteristics of the disease. I am hugely in support of utilizing SF3B1 as opposed to ring sideroblasts (RS), without a doubt. But I think all of us want to know how does the response to luspatercept differ in patients who may have an additional mutation on top of their SF3B1? That was not something that was reported on up until this year’s ASH. Dr. [Rami] Komrokji and colleagues from the COMMANDS trial looked specifically to answer that question: Does the mutation burden matter when evaluating responses to luspatercept or erythropoietin for that matter in that clinical study? Patients who went on that trial had to have baseline analysis and included in that was next-generation sequencing. I like to think of this or the way the results were reported actually were relative to ring sideroblasts-positive versus those who were negative and then comparing their responses to either treatment depending on the mutation burden at baseline.

I think it’s, as we all know, most patients with MDS will have at least one mutation, some had two, some had three, some had four. Interestingly, a lot of patients in the luspatercept arm had more than four mutations compared to those who had erythropoietin. Granted, the stratification didn’t happen according to mutation burden at baseline. But nevertheless, these are data that we are being presented right now. What’s interesting is that if you looked at the RS-positive group, the mutation burden, even though it may include poor prognostic mutations, didn’t really affect the response. You continue to have a sustained similar response to luspatercept irrespective of the mutation burden.

On the other hand, in patients with RS-negative disease, mutation burden affected the response to erythropoietin. When you compare both treatments, luspatercept and erythropoietin, randomized patients had the same response rate taken altogether. The good news, I suppose you could say is that a mutation burden will not affect response to luspatercept. These are really novel and interesting data. The hope is that this will continue to be the case now that the drug is approved in frontline in the real-world setting.

Dr. Safah: Thank you so much. That’s very helpful. I think if I may add—number one, we have a drug that’s going to work, but also it’ll help us maybe with more studies understand more why do we see something different in the RS-negative patient compared to the RS-positive patient and what can we add to that? I think there will be some light to that with the discussion soon.