Panel Discusses COMMANDS Data 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 the four COMMANDS trial abstracts presented at the European Hematology Association (EHA) 2024 Congress.

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Dr. Garcia-Manero: At EHA in Madrid, there were multiple presentations about luspatercept that addressed four different aspects of [MDS]. Let’s go with the first one. This was a poster I had the privilege to present on multilineage responses in the COMMANDS trial. In the MEDALIST trial, we noticed that some patients treated with luspatercept also had an improvement in neutrophil count (HI-N) and in platelet count (HI-P). This was a post-hoc analysis where we saw these counts evolving. I don’t know that we understand 100% the mechanism by which luspatercept affects the erythroid pathway. In the COMMANDS study, we see a signal along the lines of what we saw on MEDALIST where you see some other hematological responses.

The platelet one is complex because a majority of these patients don’t have thrombocytopenia. It’s difficult to see a significant improvement in platelets if you already have a platelet count of two to 300,000. But there were patients who had neutrophil responses. This is not a drug that you’re going to give to a thrombocytopenic patient to see if the platelets improve. But it gives me a little bit of peace that if I use this drug in a patient that is already cytopenic, this is not going to exacerbate the cytopenia and it may be actually positive.

Does anyone have any takes on the other hematological responses seen in the COMMANDS trial?

Dr. Koprivnikar: In order to be eligible for the COMMANDS trial, patients with particularly severe neutropenia or thrombocytopenia were also excluded. In our real-world practice where we are treating some of these patients who have an [absolute neutrophil count] of less than 500 and platelets of less than 50,000, would we see a greater magnitude of benefit or more impressive responses even in patients who are more cytopenic who were excluded from COMMANDS? It will be interesting to get real-world data to color this multilineage response as well.

Dr. Garcia-Manero: Excellent. The second abstract is looking at how in the COMMANDS trial, there was some impact of luspatercept on biomarkers associated with inflammation, cardiac function, etc.

Dr. Koprivnikar: This study did also comment on some of the multilineage improvements, specifically within the leukocyte population. Patients treated with luspatercept did have improvement in total leukocyte counts, neutrophil counts, and lymphocyte counts. Although, what I think is more compelling is that luspatercept-treated patients did have a downregulation of inflammatory mediators.

Luspatercept-treated patients—but not patients who are randomized to receive epoetin alfa—had decreased levels of [N-terminal pro-B-type natriuretic peptide (NT-proBNP)], which is a marker of cardiac stress or inflammation. That is particularly of interest and while not direct evidence, may play into my decision when I’m making that calculus in a frontline patient about which agent I want to use.

I do think back to some of this data and these decreased levels of inflammatory biomarkers, particularly the well-validated NT-proBNP level. That was a very compelling report from this abstract and something we need to be exploring a little more. The question is, “Is this because these patients had higher hemoglobins, or does it have something to do with the modification of the inflammasome by luspatercept itself or the bone marrow microenvironment?” I would be interested to hear everyone else on the panel’s takes on this as well.

Dr. Leblanc: I never know what to do with these kinds of corollary studies. It’s exciting and interesting. It suggests that maybe there is something meaningfully different about stimulating the late-stage erythroid maturation part of the pathway as compared to stimulating the early-stage maturation part of the pathway. Ultimately, what’s going to drive my clinical decision-making is the response rates and durations of the therapy. It’s a nice proof of concept that this drug is doing something different in the patient. Maybe that’s part of what’s translating into these downstream improvements that we measure in people’s labs and transfusion needs. But I struggle with the application of the clinic.

Dr. Garcia-Manero: The next abstract is by Dr. Rami Komrojki. It suggests that in the COMMANDS trial, the mutational burden seemed to affect—in a negative way—more dose patients that were treated with an erythropoiesis stimulating agent (ESA) versus luspatercept. Jamie, what do you think about this data?

Dr. Koprivnikar: This is another reason why I would be likely to choose luspatercept upfront for my patients, to your point that the number of mutations seems to decrease the response to ESA-based therapy as part of COMMANDS. However, it had no effect on patients treated with luspatercept. I think that luspatercept truly is an efficacious drug for all comers, whereas the ESA-treated patients tended to have an inferior response as the mutational burden increased.

Dr. Chedid: Thinking of the pathophysiology of the disease, you have a hypercellular marrow with increased precursor stem cells in the bone marrow. The ESA is driving what’s already hypercellular, whereas luspatercept is allowing for maturation of those cells, potentially reducing inflammation. I like the fact that it’s reducing the BNP. If I gave the patient a blood transfusion, I would also expect that as their [congestive heart failure] improves, the BNP is also going to improve. It’s certainly chicken or egg, but it makes intuitive sense and I wish we saw that in [erythropoietin] agents as well. Since we see it in luspatercept, it certainly stacks onto the other numerous benefits of that product.

Dr. Garcia-Manero: The last [abstract] is by Dr. Valeria Santini from Italy. This is an updated analysis of luspatercept. What do you think about that updated presentation?

Dr. Koprivnikar: My takeaway from this presentation was confirming a lot of what we had seen in both the interim analysis and the final analysis of COMMANDS. Regards to that composite primary endpoint of a minimum transfusion-free period in association with a 1.5 g/dL increase in hemoglobin, luspatercept is superior to weekly epoetin alfa in the intention to treat patient population. Numerically, the length of response was greater with luspatercept. Solly, this is a point that you’ve made, but I think we can’t underscore enough the convenience of dosing, at least the way that these agents were dosed as part of the COMMANDS trial. The increased response rate and numerically longer duration of response are all with every three-week subcutaneous dosing versus weekly epoetin alfa as it was given on COMMANDS.

This abstract reiterates what we have seen in both the interim and presented final analysis of the COMMANDS trial. Not a lot of new information here, but reassurance on a number of points in terms of efficacy, safety, and duration of response that luspatercept has shown superiority to epoetin alfa.