Luspatercept vs Epoetin Alfa for Anemia Therapy Among Patients With ESA-Naive, Transfusion-Dependent Lower-Risk MDS

Results from the Phase 3 COMMANDS Study 

Almost twice as many patients with anemia and with erythropoiesis-stimulating agent (ESA)-naive lower-risk (LR) myelodysplastic syndromes (MDS) requiring red blood cell (RBC) transfusions were able to achieve red blood cell transfusion-independence and an increase in hemoglobin levels with treatment with luspatercept versus epoetin alfa (EA), according to data from the phase 3 COMMANDS trial.

These results were presented at the Society of Hematologic Oncology (SOHO) 2023 annual meeting by Guillermo Garcia-Manero, MD, MD Anderson Cancer Center at The University of Texas, Houston, Texas.

Transcript:

Hello, my name is Guillermo Garcia-Manero from the Department of Leukemia at the University of Texas MD Anderson Cancer Center and I'm going to be discussing in the next few minutes the results from the COMMANDS trial that I had the opportunity to present at the SOHO meeting here in Houston the first week of September of this year.

The COMMANDS trial is a phase 3 randomized study of luspatercept versus epoetin alfa, an erythropoiesis-stimulating agent, for patients with lower-risk myelodysplastic syndrome with anemia, transfusion-dependent, that have not received prior therapy.

As you know, luspatercept is an antibody that modulates TGF-β pathway and it's already approved in the United States for patients with ring sideroblastic anemia that are not candidates for, or have basically stopped benefiting from, an ESA. In the MEDALIST study that led to the approval of luspatercept in second-line in ring sideroblastic (RS) anemia, we saw an appropriate toxicity profile to move this to first-line therapy as well as a phenomenon where patients with what we call lower transfusion burden had a higher response rate. Therefore, in my opinion, it was logical to move this to frontline disease.

The main difference also between the COMMANDS trial, that is what I presented at SOHO, and the MEDALIST trial is that the COMMANDS trial was not specific for, or restricted, I should say, for patients with ring sideroblastic anemia. It was for all patients with low-risk myelodysplastic syndrome. This data was originally presented at a major session at ASCO and at a plenary session at the EHA meeting, and finally published in the journal Lancet a couple of months ago.

Basically, in this study, COMMANDS, we randomized 178 patients in each arm. The primary goal of the study was improved response, and the response actually was very strictly defined by these 2 factors: one, the patients should have an increase in hemoglobin of at least 1.5 grams. In addition, the patient had to be transfusion-[independent] for 12 weeks over a period of the first 24 weeks of the study. So, in my opinion, very robust response criteria.

The study by an intent-to-treat analysis indicated that the response rate was close to 60% with luspatercept in first-line low-risk MDS anemic patients versus around 30% for dose in the control with the epoetin alfa, so very significant increase in response. In addition, the duration of response was significantly longer for luspatercept versus the epoetin alfa, around 122 weeks or so versus over 70 weeks for the control. Almost a year extra of transfusion independency. 

Both drugs were well-tolerated, there was no early mortality or increased risk of transformation. With this data, the FDA approved luspatercept for patients with MDS, low-risk disease, and anemia, candidates for transfusion, a couple of weeks ago.

It's going to be very interesting to see if this compound becomes a standard-of-care or if it changes our practice, as we had epoetin alfa and similar drugs, the ESAs, for several decades with us now, and they really constitute our standard-of-care. Now I think there's going to be more work done with this compound. I think there are studies going into patients that are transfusion-dependent. We may move into patients with CCUS.

But the key question that the community is asking is are there specific patients that may benefit, more or less, from the use of luspatercept? Indeed, to close this, what we saw on the COMMANDS trial is that patients with ring sideroblastic anemia, patients with high EPO level for instance, those with an EPO level more than 200, patients without ring sideroblastic anemia with an SF3B1 mutation, patients without those mutations, did actually much better in general with luspatercept.

But there was a group of patients with RS-negative disease in this study that we don't really a hundred percent understand well at this point, that did not respond as high as the other subgroups in the study. They actually had a similar response rate, although duration of response was also longer, with luspatercept. So, we need to understand the subset of RS-negative patients a little bit better.

But in general, we have a new drug now for patients with low-risk MDS in the frontline, and it's our opportunity to start maximizing how we treat these patients and of course, as investigators, focusing in the treatment of patients with myelodysplastic syndrome. Hopefully the next study will show some type of combination agent that approach, I should say, that renders basically a hundred percent response rate for this group of patients. Thank you very much for this opportunity and your attention.

Source:

Garcia-Manero G. Luspatercept versus epoetin alfa (EA) for treatment of anemia in patients with erythropoiesis-stimulating agent (ESA)-naive lower-risk myelodysplastic syndromes (LR-MDS) requiring red blood cell (RBC) transfusions. Presented at 2023 SOHO Annual Meeting; September 6-9, 2023; Houston, TX. Abstract MDS-234