COMMANDS Trial Shows Positive Result in MDS Despite Pandemic

Amer Zeidan, MBBS

Associate Professor of Internal Medicine (Hematology)

Yale University

Medical Director, Hematology Early Therapeutics Research,

Leader, Myeloid malignancies Clinical Research Team

Director, Continuing Medical Education, Hematology

Yale Cancer Center

New Haven, CT

Targeted Oncology: Please discuss the trial behind luspatercept-aamt (Reblozyl) for patients with lower-risk myelodysplastic syndromes (MDS).

AMER ZEIDAN, MBBS: The COMMANDS trial [NCT03682536] was presented at the American Society of Clinical Oncology annual meeting in 2023.1 The paper has been published in The Lancet; what was published was the interim analysis. This is a little bit backwards because luspatercept-aamt [Reblozyl] was approved in the second-line setting.... Luspatercept removes transforming growth factor ligands, which have been shown to suppress erythropoiesis in the bone marrow. This drug was approved as a second-line treatment for ring sideroblast [RS]-positive disease.

This was the first trial that shows ever a drug beating ESAs [erythropoiesis-stimulating agents] in the frontline setting. The patients were randomly assigned in 1:1 fashion of luspatercept given subcutaneously 1 mg/kg, which is very important to remember. I'll talk about the dose escalation vs ESA. So what was given on this trial was a short-acting erythropoietin. But I think you can easily extrapolate this to the long-acting ESA.

[This was done in the] United States, but it was very tough to accrue. This protocol has a very rigorous escalation. This comes to, if you calculated, 40,000 international units. You start with 40,000, and you go up all the way to 80,000. This is the dose that you need to get to in MDS. This is one of the caveats I see in practice in the community, is that they give the patient 20,000, 30,000, or 40,000 international units. You need pharmacology for high doses of ESAs in patients with MDS. Most of the time, you're going to need to get to the 80,000, which is this 1000 mg/kg in most patients.

Patients had to have serum erythropoietin [EPO] level less than 500 U/L. The reason why they designed it this way, I always thought, patients who have an EPO level more than 500 U/L is one of the significant unmet needs for us. There isn't any drug that has been shown conclusively to work on those patients. The reason why they did less than 500 U/L is because they did not want to bias things against EPO, because we know it doesn't work for patients who are more than 500 U/L. The transfusion frequency was 2 to 6 units per 8 weeks. So those were patients who are getting frequent transfusions. They were not just slightly anemic. They were stratified by EPO level. Most patients had a hemoglobin level less than 8 g/dL.

Did COVID-19 affect the COMMANDS trial?

This trial started before COVID-19 started, and it was opened the whole time [during the pandemic]. When we had this trial open, in my center, we shut it down for almost a year because we were telling the patients, “Don't come to the [main] center; get blood locally.” It's a phase 3 trial, so it was amazing that this trial carried through until the end, which was important because it led to a positive result.

What was the efficacy and safety seen in this trial for treatment-naive patients with MDS?

The primary results were published in The Lancet.... The bottom line is that the transfusion independence with luspatercept was 60% compared with 38% [with ESA], so almost doubled. This is the first time ever we had a drug that beats ESA in head-to-head comparison in the frontline setting. When you look at the different subgroups, luspatercept worked across the different subgroups.

For those who have not used the drug, it's generally easy to give. The main issue in some patients is the fatigue, especially the first couple of cycles, it can be significant and doesn't correlate with anemia. But generally, if the patient pushes through, the fatigue tends to wear down and I personally think it is something related to the cytokines impact of the drug. But certainly, in most patients, it does not lead to discontinuation. The other thing is hypertension; some patients can get increase in their blood pressure, so you have to monitor for it and treat it. But generally, it's one of the easier drugs to give.

It's more like an ESA rather than hypomethylating agents [in terms of adverse events]. Many times, the nurse would call me about a hemoglobin [to see] what we should do rather than me seeing the patient every cycle like the way you do it with a chemotherapy. I think fatigue is very tricky; it's one of the trickiest things in management of patients with MDS because some patients come in with fatigue and they have a hemoglobin of 11 g/dL, while I have patients who have a hemoglobin of 7.5 g/dL and they don't feel anything. It's the same thing with the treatment—sometimes you improve the hemoglobin substantially and the fatigue does not get better. The 2 don't correlate and I think part of it is because it's not only driven by the anemia.

_Reference:

_{1. Platzbecker U, Della Porta MG, Santini V, et al. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial. Lancet. 2023;402(10399):373-385. doi:10.1016/S0140-6736(23)00874-7}