Safety and Efficacy of Luspatercept in Frontline Setting in Patients with MDS

Oncologists review study design and discuss key safety and efficacy data of the COMMANDS trial investigating luspatercept in frontline setting in patients with lower-risk MDS.


Hetty Carraway, MD: I’m so pleased that you talked with us a little bit about the PACE study [NCT01749514] and the MEDALIST study [NCT02631070]. And you led very nicely to the story that we’re now excited about with regard to the COMMANDS trial [NCT03682536].

This study focused on patients that were dependent on 2 to 6 transfusions within an 8-week time period. They were low-risk MDS [myelodysplastic syndromes], with and without ring blasts. Patients on this study received either luspatercept [Reblozyl], ESA [erythropoiesis stimulating agent]-based therapy, or epoetin alfa. Patients were randomized in a 1:1 upfront setting to receive 1 or the other. The question we were hoping to answer is if luspatercept will actually be able to be used in the upfront setting in a way that might be better in terms of outcome compared to ESA-based therapy, which has been the gold standard of the treatment of patients with low-risk MDS with anemia.

It was a little bit different than the MEDALIST study, which looked only at patients that had lost response to ESA-based therapies. That patient population was different than the COMMANDS study, which is in the upfront setting. The end points are also different with regard to accomplishing transfusion independence.

Patients needed to meet 2 criteria: They needed to become transfusion-independent, and they needed hemoglobin elevation greater than 1.5 grams per deciliter. It was pretty stringent with regard to hematologic improvement also because they were looking at a duration of 12 weeks, not just a duration of 8 weeks.

The secondary end points looked at 8 weeks, 12 weeks, 24 weeks. Additionally, it looked at duration of that transfusion independence. Some of that data was presented here at this year’s ASCO [American Society of Clinical Oncology annual meeting]. About 59% of the patients on this study became transfusion-independent with both of those criteria. Only about 30% of patients receiving EPO [erythropoietin] had met this criteria. The duration of that was also longer for patients that had received luspatercept.

I will say though that the patient population was a little bit different in regards to the percent SF3B1, or percent ring sideroblasts SF3B1-mutated, or the percent ring sideroblasts that were in the entire cohort. So 70% of the patients that were in the COMMANDS study were either ring sideroblasts-positive or harbored an SF3B1 mutation. This is a lot higher than what we would normally expect for a lower-risk MDS population.

Ralph Boccia, MD, FACP: Close to 60% of patients are going to be transfusion-independent in the entire population, closer to 75% in the population of patients that were ring sideroblast-positive. You can expect 3 out of 4 patients to have at least a hematologic improvement, or in 58% a hematologic improvement plus transfusion independence, which is a big deal. Iron overload is not a fun thing to treat.

Hetty Carraway, MD: The patients that were enrolled in this study had a low transfusion burden. Those things would mean that we should start therapy in patients sooner, or at least at a time where they don’t have a high transfusion burden. Some of that will have an impact on the way we are practicing, especially in terms of how important is it for us to identify patients with lower-risk MDS versus higher-risk MDS. This may underscore some of that importance.

Ralph Boccia, MD, FACP: During the evaluation of the MEDALIST trial, different quartiles of transfusion dependency were looked at and the response rates for each one. It was very clear that the patients with the lowest transfusion burden had 60% to 70% response rates were the patients who were transfusion-dependent, requiring 6 or more units, had 10% to15%. Earlier disease management does affect outcomes and can be disease-modifying.

Hetty Carraway, MD: It is important to highlight the safety parameters with luspatercept versus ESA-based therapy. We need to see all of the data when it comes out with regard to safety, [and] also patient-reported outcomes. That data is yet to come out and to see how it impacts their quality of life.

Transcript edited for clarity.

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