What Do the Clinicians Say About Luspatercept?

A roundtable discussion, moderated by Guillermo Garcia-Manero, MD, of the University of Texas MD Anderson Cancer Center, focused on the latest data in the treatment of low-risk myelodysplastic syndromes. Dr. Garcia-Manero was joined by Jamie Koprivnikar, MD; George Yaghmour, MD; and Sangeetha Venugopal, MD.

In the next segment of the roundtable series, the panel addresses continued MDS research needs, including treatment sequencing, expanded patient inclusion in clinical trials, and earlier treatment intervention.

Watch the next segment in the series.

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Dr. Garcia-Manero: Moving forward, Sangeetha, now you have the COMMANDS trial phase III with a clear indication for RS-positive. I also agree with you RS-negative in the front line. There’s actually a study called the ELEMENT trial that is starting to accrue for transition-independent low-risk MDS [myelodysplastic syndromes]. I think there’s some ideas about doing some studies in CCUS [clonal cytopenia of undetermined significance], but from a practical perspective, where do you see actually your wish list? What do you think will be one or two situations where you think it will be worth studying a drug like this for patients with MDS?

Dr. Venugopal: As you said, this is my wish list. Lenalidomide has a duration of response, in del(5q) MDS, has a duration of response for about two years. What do we do after lenalidomide remains still an unanswered question. All of these, the luspatercept or the next drug that is under approval or imetelstat, they are all evaluated for non-del(5q) MDS. What do we do after lenalidomide in del(5q) MDS? That’s an unanswered question. We do have a lot of patients in the clinic after lenalidomide.

Dr. Garcia-Manero: I totally agree with you.

Dr. Venugopal: Yeah, and they are still lower-risk MDS, they haven’t progressed and you kind of tinker them with ESA [erythropoietin-stimulating agents] and HMA [hypomethylating agents] and you still don’t get enough responses. What do we do in these patients? That’s an important question to be addressed.

Dr. Garcia-Manero: I totally agree with you because those patients have been excluded from every study and the reason they’ve been excluded, it’s actually an FDA issue. Because there’s a label for a very effective drug, lenalidomide as you mentioned Sangeetha, they made you exclude those patients. But there’s actually, to my knowledge, not true scientific rationale of why you will not treat a del(5q)-negative patient with luspatercept. It’s just because there’s a very effective drug for those patients, we excluded them. The interesting thing is that people will be treated actually.

Dr. Venugopal: Yes, in the community.

Dr. Garcia-Manero: In the community. I agree with you that will be, I don’t know that you need to do randomized studies, but it will be very beautiful to see phase II data on what happens if I fail lenalidomide? Do they respond to luspatercept or not? I totally agree with you. George?

Dr. Yaghmour: Very great points and honestly, I would love to see a study also tell us, “You start the patient earlier and you intervene earlier.” You’re not going to put your patient on lifelong treatment. If there is a point that you can know that there is a specific duration of response, and you can stop. Then the need of reinitiation of the treatment at some point is this is going to be if you start the patient earlier and they’re not requiring too much of transfusion. The question is, a patient would require this treatment the rest of their life, what would be the end points for the duration? If you can stop at some point and see how many of those patients would maintain an overall survival, because we have improved the survival definitely in MDS, including low-risk MDS. We know anemia is a major prognostic factors for overall survival now based on a large database publication from many centers. I would like to see in the future also some study telling us about if we stop, when do we stop and what is going to happen to those patients?

Dr. Garcia-Manero: I think that’s very important. Then you also mentioned about survival. Traditionally, low-risk MDS, we never talk about this, but I think Dr. [Rami] Komrokji had that presentation at this meeting, or not too long ago, showing that in the MEDALIST trial responders live longer actually. To me, many years ago, I never understood, you improve your anemia, you’re going to live, but it’s actually significantly more complex. I would like to see some long-term analysis of survival from COMMANDS. I think that will really reinforce this issue. I think this question of when do you stop, particularly a drug that is probably not very cheap. So how many?

Dr. Yaghmour: Also transformation to a more advanced level or acute leukemia…

Dr. Garcia-Manero: What about you, Jamie?

Dr. Koprivnikar: think it’s a very interesting question. Is this really a disease-modifying agent? Is it just by virtue of the fact that it obviates the need for transfusions that we saw that increased survival benefit in MEDALIST? I agree with you. I’m really excited to see more mature data from the COMMANDS study.

Dr. Venugopal: My final thoughts for luspatercept is this is the first-line agent. Now I would be more prone to using, not even more prone, I would definitely use luspatercept in first line because this is the drug that is actually trialed in patients with non-del(5q) MDS. I’m looking forward to the data on how does this risk classifications, especially IPSS-R [Revised International Prognostic Scoring System], IPSS, and IPSS-M [Molecular International Prognostic Scoring System] matter in the context of luspatercept among patients with del(5q) MDS. I did see that the IPSS-M upstaged some 20% of patients from both IPSS-R and IPSS. I would want to know more about it.

One other thing I’m curious to know about is what is the role of TP53 because it was IPSS-R, so it did not take into account the molecular profile. What does the TP53 mutation do to those patients who were treated with luspatercept on this clinical trial? Did they stay the same or how did it progress? What is the leukemia-free survival, and what was the transfusion independence in those patients?