Duration of Response Contributes to Survival in COMMANDS Trial in MDS

Treatment strategies for low-risk myelodysplastic syndromes (MDS)focuses on management of anemia over than disease modification. Even with this paradigm, improvements in quality of life and overall survival (OS) are being achieved, as was discussed by Praneeth Baratam, MBBS, during a Case-Based Roundtable event in Charlestown, South Carolina. Baratam, associate professor in the Department of Medicine at the Medical University of South Carolina, reviewed the phase 3 COMMANDS trial (NCT03682536) of luspatercept (Reblozyl) vs an erythropoietin-stimulating agent (ESA) in low-risk MDS. He discussed the patient characteristics that were associated with a better transfusion independence response with luspatercept and showed how there was an improved duration of transfusion independence even in those without these favorable factors.

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This article is part 2 of a 2-part series from a Case-Based Roundtable event.

Targeted Oncology: How did the COMMANDS trial evaluate luspatercept in low-risk MDS?

Praneeth Baratam, MBBS: The COMMANDS trial is the upfront randomized treatment trial evaluating luspatercept and epoetin alfa in patients who are transfusion dependent, meaning at least 2 transfusions in 8 weeks—that’s how they defined transfusion dependence. [They were] patients with low-risk MDS, and it doesn’t matter whether they had ring sideroblasts [or] SF3B1 [mutation]. The one thing that mattered in the inclusion criteria is they only enrolled patients who had less than 500 U/L serum erythropoietin [EPO] level. For anybody with EPO level over 500 U/L…we apply these trial data in practice, but strictly speaking, they don’t apply. What they were looking for [as a primary end point] is transfusion independence.

[In terms of] the characteristics of all the patients who enrolled, the most important number is probably the SF3B1; these patients were about 63% in each of the arms. So about two-thirds of patients had SF3B1 [mutations]. In reality, the biggest critique of the COMMANDS trial is that there are a little too many patients with SF3B1 mutations, so that skewed their results a little bit….

What was the primary outcome of this trial?

Patients who were treated with luspatercept doubled their [transfusion independence] response from 35% to 60% [P < .0001].¹ That’s a remarkable feat, because you’re [improving responses by nearly 100%] compared with ESA. Now if you compare SF3B1 mutated vs unmutated patients…if it’s SF3B1 mutated, the difference is even more stark [70% vs 33%, respectively]. But…about half of all low-risk MDS patients do not have a SF3B1 mutation, and that’s where this difference was not statistically significant [45% vs 36%]. ESA and luspatercept were about equally effective in patients, even though luspatercept is higher numerically if they are not SF3B1 mutated, or if they are not ring sideroblast–positive [47% vs 50%]. So if there are no ring sideroblasts on the marrow and no SF3B1 [mutation], they’re about equally effective.

What outcomes were seen in the long term with luspatercept vs ESA?

There was long-term follow-up that was presented at the 2024 American Society of Hematology Annual Meeting and Exposition, showing that as you go into 1-year transfusion independence…and 1.5 transfusion independence, the duration persists, so luspatercept is definitely superior to ESA as you go along with time.²

Overall survival data were presented at the 2025 American Society of Clinical Oncology meeting.³ This was surprising, because up until this time, no therapy showed a survival advantage in patients with low-risk MDS. But these arms split after 3 years or so. For 3 years, patients [receiving] ESA and luspatercept survived similarly. But then after 3 years or so, patients [receiving] luspatercept have survived longer compared with ESA [piecewise analysis at ≥ 36 months; HR, 0.330; 95% CI, 0.128-0.853; P = .0221]. In my opinion, it’s because of the duration of response of luspatercept. I don’t think it’s disease modifying. There are 2 reasons why a patient may not die. One is…if they’re anemic, they’re more likely to die of heart attack or stroke, so if they had a longer duration of response—these are older patients—they’re less likely to die of heart attacks or strokes. But another reason why they may not be dying is if their disease is modulated by the treatment. I still don’t think luspatercept modifies the disease course. I think it’s still topical. It allows maturation of red cells. But I think because there is a longer duration of response, there is less likelihood of death.

With luspatercept, more people remain transfusion independent compared with ESA. So even if they’re ring sideroblast–negative or SF3B1 negative or have an EPO level less than 200 U/L, I would probably still pick luspatercept for this reason. Not because more people respond—an equal number of patients respond if EPO level is less than 200 U/L—but they tend to respond longer. Maybe there is a survival advantage because of that. For time to first red blood cell transfusion, patients [receiving] luspatercept had a longer duration before they ever needed a transfusion.

What stands out in terms of safety and tolerability in this trial?

[For] safety, I would comment that fatigue is an [adverse event] with luspatercept. Any-grade fatigue was reported in about 20% of patients in luspatercept arm, compared with 8% of patients [with ESA].¹ When I counsel my patients, I tell them that for a day or 2 you may not feel good, but you will recover by the third day. That’s typically my experience, and most patients, when they know that is how they would feel, they are ready for it.

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_{DISCLOSURES: Baratam previously reported honoraria from Rigel and GSK, and advisory board participation with Incyte, KITE, Ono Therapeutics, and Protagonist Therapeutics.}

_REFERENCES

_{1. Della Porta MG, Garcia-Manero G, Santini V, et al. Luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): primary analysis of a phase 3, open-label, randomised, controlled trial. Lancet Haematol. 2024;11(9):e646-e658. doi:10.1016/S2352-3026(24)00203-5}

_{2. Garcia-Manero G, Santini V, Zeidan AM, et al. Long-term response analysis of transfusion independence in erythropoiesis stimulating agent-naive patients with very low-, low-, or intermediate-risk myelodysplastic syndromes treated with luspatercept vs epoetin alfa in the COMMANDS trial. Blood. 2024;144(suppl 1):350. doi: 10.1182/blood-2024-194240}

_{3. Garcia-Manero G, Della Porta MG, Zeidan AM Overall survival (OS) and duration of response for transfusion independence (TI) in erythropoiesis stimulating agent (ESA)–naive patients (pts) with very low-, low-, or intermediate-risk myelodysplastic syndromes (MDS) treated with luspatercept (LUSPA) vs epoetin alfa (EA) in the COMMANDS trial. J Clin Oncol. 2025;43(suppl_16):6512.10.1200/JCO.2025.43.16_suppl.6512}