Panel Describes Dosing Considerations for Luspatercept in Lower-Risk MDS

A roundtable discussion moderated by Guillermo Garcia-Manero, MD, of the University of Texas MD Anderson Cancer Center, focused on the latest updates in lower-risk myelodysplastic syndromes (MDS). The panel included Jamie Koprivnikar, MD, of the Hackensack University Medical Center; Solly Chedid, MD, of Singing River Health System; and Thomas LeBlanc, MD, MA, of Duke Cancer Institute.

In the next segment of the roundtable series, the panel discussed dosing considerations for luspatercept.

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Dr. Garcia-Manero: This is something that I see in my practice, where physicians who are not very familiar with luspatercept struggle with this issue of the dose escalation schema that we use. How do you use the drug?

Dr. LeBlanc: We always have to remind people that you don’t give this therapy any closer than three weeks together. You generally give at least two doses at each dose level before you’re ramping up. You’re starting at 1 mg/kg, you can go up to 1.33 mg/kg after you’ve gotten two doses. If you’re still requiring transfusions after two doses at 1.33 mg/kg, you can go up to 1.75 mg/kg and then give at least three doses of that before you’re making a final judgment on whether the therapy is working.

I have to remind folks that transfusion independence is not the only meaningful endpoint with this treatment. That’s what you’re looking for at the starting dose level and the intermediate dose level, assuming the patient’s tolerating the treatment and not having any high-grade [adverse events (AEs)]. Especially when you get the maximum dose level, not everyone will be transfusion independent, but some of those patients will have meaningful improvements in their hemoglobin or reductions in the number of red cell units or frequency of transfusions needed, which can make those patients’ lives easier. It also helps us with reducing iron overload from transfusions.

If you’re seeing the gram of hemoglobin increase but the person’s still needing some blood, maybe they’re needing less blood less often, you can and should still continue the therapy at that maximum dose level as long as they’re tolerating it well. I do unfortunately see a lot of people start this therapy and either never dose escalate or stop it after three or four doses—especially if the patient has mild to moderate symptoms up front and prematurely abandon it, which is sad when we already have too few therapies for these lower-risk MDS patients.

Dr. Chedid: The difference with erythropoietin (EPO) is that with EPO, we don’t start it until your hemoglobin is less than 11 g/dL. Whereas with [luspatercept], I believe it’s 11.5.

Dr. Garcia-Manero: Somehow, the schema irritated European colleagues. They designed a study called Maximus, where they’re asking why it would be wrong to have 13 or 14 g/dL of hemoglobin instead of 11. Is 1.75 actually the right starting dose?

These doses were based on [US Food and Drug Administration] safety guidelines, and we need to respect and appreciate that. But I don’t think we’ve seen a lot of cardiovascular events. You could argue that one could be a little more aggressive in terms of the doses and perhaps allow for higher hemoglobin levels, as Tom was saying. It probably will be better in terms of the well-being of our patients. We’ll see what happens with that study.

Dr. Chedid: I’d be a little careful about using luspatercept over 11.5. When it was used for beta thalassemia and they were allowing hemoglobin to go up to 12.5 and even 13, they had a slightly increased signal for thrombosis. Below 11.5, they didn’t have that signal. Giving it when it’s less than 11.5 and even when you have to hold it, you wait until the hemoglobin goes above 11. That’s how the COMMANDS study is doing it.

Dr. LeBlanc: I’m excited about that study going right to the maximum dose level. That’s one of the issues that we see with inappropriate use of luspatercept, where people are throwing away the drug before it potentially helps the patient because they’re not following the dose escalation schema. If we could safely start at the higher level, that would be fantastic because it would make the drug easier to use. I have doubts about it from the standpoint of the initial AEs that you sometimes see when you start this therapy. We’ll have to wait and see.