Yang Highlights Positive COMMANDS Trial Data for Luspatercept in MDS

Jay Yang, MD

Professor

Wayne State University School of Medicine

Karmanos Cancer Institute

Detroit, MI

CASE SUMMARY

• A man aged 70 years was diagnosed 1 year ago with low-risk ring sideroblast–negative myelodysplastic syndrome (MDS) with multilineage dysplasia, moderate anemia, and ring sideroblasts in 4% of nucleated erythroid cells.
  • SF3B1 mutation negative
  • No 5q deletion
  • No family history of cancer or significant genotoxic agent exposure
  • In the past 8 months, he received single-unit packed red blood cell transfusions 3 months apart.
  • Revised International Prognostic Scoring System (IPSS-R): Low
• Work-up to assess disease status and response to anemia management:
  • Serum erythropoietin (EPO): 250 mIU/mL
  • Ring sideroblast negative
  • Hemoglobin: 8.3 g/dL
  • White blood cell and absolute neutrophil count: within normal limits
  • Platelet count: 250,000/μl
• Treatment options were discussed with the patient—either continue transfusions as needed, erythropoietin-stimulating agent (ESA) subcutaneously every week, or luspatercept-aamt (Reblozyl) subcutaneously every 3 weeks.
• Luspatercept was chosen as the appropriate option for this patient based on patient convenience/rationale.

PEERS & PERSPECTIVES IN ONCOLOGY: What role do ESAs and luspatercept play in managing low-risk MDS?

YANG: Looking at the NCCN guidelines, we are talking about patients with symptomatic anemia, not deletion 5q, who do not have ring sideroblasts. So, low-risk [MDS]. If your serum [EPO] is less than 500 mU/mL, then you have 3 different preferred treatment options: [2 different] ESAs or luspatercept. According to the NCCN, one is OK using either of those treatment options for this group of patients. That is very reasonable.¹

I think for a serum EPO of less than 500, epoetin alfa [Procrit] or luspatercept are both reasonable treatment options. But what if your EPO is greater than 500? Imetelstat [Rytelo] has the phase 3 data. In my mind, just going by level of evidence, imetelstat would be the preferred agent. I do not think luspatercept is a bad idea. With patients on luspatercept, there is a response rate in patients with non–ring sideroblast anemia. That is not how the phase 3 COMMANDS study [NCT03682536] was designed, but it is an easy option.²

If a patient has an IDH1 mutation, ivosidenib [Tibsovo] is approved for MDS with an IDH1 mutation. Enasidenib [Idhifa] does not have that approval, but [some data support its use]. If we are looking at an IDH2 mutation, there are not as many data, but off-label use could be considered if there are no other viable options.

Can you discuss the background and design of the COMMANDS trial?

This study looked at adults with very low-, low-, or intermediate-risk MDS, based on the IPSS-R collectively, lower-risk MDS.² These patients had less than 5% blasts in their bone marrow and required 2 to 6 packed red blood cell units per 8 weeks before enrollment and [before random assignment]. This was a group of patients with varying levels of transfusion dependence, from lower to higher transfusion burdens. Serum EPO levels had to be less than 500 U/L to qualify. Patients were stratified by their baseline serum EPO level, transfusion burden, and ring sideroblast status. Notably, MDS with deletion 5q was specifically excluded, so this study did not include patients with lenalidomide [Revlimid]–responsive MDS.

Patients were randomly assigned 1:1 to receive either luspatercept or an ESA. Luspatercept was dosed at 1 mg/kg subcutaneously every 3 weeks. Nonresponders could have their dose titrated to 1.33 mg/kg or 1.75 mg/kg as needed. ESA was started at 450 U/kg subcutaneously once weekly. For an average person weighing 60 kg to 70 kg, this equates to around 30,000 units per week. This dose could also be escalated during titration. Response assessments were conducted at 24 weeks, and then every 24 weeks thereafter.

For baseline characteristics, the groups were well-balanced. The median age of patients was 74 years, most patients had low-risk MDS per IPSS-R, the median serum EPO was 85 U/L, 79% had EPO levels less than 200 U/L, 20% had EPO levels between 200 and 500 U/L, 73% of patients were ring sideroblast positive, and 61% had SF3B1 mutations. The median transfusion burden was 3 units per 8 weeks prior to enrollment, 36% of patients required more than 4 units per 8 weeks, platelet counts were normal, as expected, and pretransfusion hemoglobin was 7.8 g/dL.

What do the data tell us about transfusion independence with luspatercept vs ESA therapy?

It is important to compare response rates between luspatercept and epoetin alfa. The primary end point was red blood cell transfusion independence lasting at least 12 weeks with a concurrent mean hemoglobin increase of at least 1.5 g/dL. This end point is more robust vs older studies, which often used 8-week transfusion independence. In the intention-to-treat population, the response rate was 60% with luspatercept vs 35% with epoetin alfa.³ Clearly, luspatercept showed a higher response rate and percentage of transfusion independence compared with epoetin alfa.

The subgroup analysis is even more intriguing—although the primary findings are already significant. The first group of patients was categorized based on their transfusion burden—less than 4 units vs greater than 4 units per 8 weeks. The response rate with luspatercept was consistently better than epoetin alfa, regardless of whether patients had a low or high transfusion burden. However, patients with a high transfusion burden had a notably low response rate to epoetin alfa, at just 20%, which is lower than desired. Baseline serum EPO levels also played a role in predicting response. Both low and high EPO levels favored luspatercept over epoetin alfa, although overall responses were better in patients with lower EPO levels and lower transfusion burdens. For patients with higher EPO levels, 200 to 500 mU/mL, the response rate to epoetin alfa was particularly low, at only 11%.

Response rates were also examined based on SF3B1 mutation and ring sideroblast status. Patients with SF3B1 mutations or ring sideroblasts responded well to luspatercept, showing significantly better outcomes vs ESA. For patients without SF3B1 mutations or ring sideroblasts, the response rates between luspatercept and ESA were fairly similar. However, it is important to note that these comparisons were not truly randomized for these subgroups, so [although] the numbers appear close, this may not conclusively establish equivalence.

When evaluating the duration of transfusion independence lasting at least 12 weeks, luspatercept again outperformed ESA. The median duration of transfusion independence was 126 weeks with luspatercept vs 89 weeks with ESA. This shows that for patients who responded and achieved transfusion independence, luspatercept provided a more sustained benefit.

In terms of adverse events [AEs], the most reported AEs included fatigue, edema, anemia, back pain, dizziness, and headache. These were generally similar between luspatercept and ESA but were slightly more frequent with luspatercept. Grade 3/4 or serious toxicities were rare. Infections occurred at similar rates in both groups, whereas diarrhea, nausea, and dyspnea were slightly more common with luspatercept. Hypertension, an AE commonly associated with agents that increase erythropoiesis, was also slightly higher with luspatercept and is worth monitoring in clinical practice. Overall, serious AEs were minimal.

What were the key takeaways from the long-term data regarding the effectiveness of luspatercept vs ESA?

With longer follow-up tracking outcomes from week 1 through the end of treatment, not just at 24 weeks, the key takeaway is that response rates for both luspatercept and ESAs improve over time as patients continue treatment.⁴ The response rates increase to 70% for luspatercept vs 43% for ESA, which is intuitive as prolonged treatment allows more patients to achieve benefit. This also highlights the time to the first red blood cell transfusion after initiating therapy. As expected, patients who do not respond to therapy require transfusions relatively early, leading to a shorter time interval before the first transfusion. However, luspatercept demonstrates an improvement in delaying the need for transfusions. Another [outcome measure] depicts the change in hemoglobin levels, showing a consistent and significant increase in hemoglobin with luspatercept, with a mean rise exceeding 1.5 g/dL.

After reviewing the COMMANDS data, several points stand out regarding efficacy and safety. Luspatercept appears to be well tolerated, with minimal toxicities reported in both the trial and clinical experience. This makes it an easy and safe option for [treating] these patients.

Can you further discuss the dosing recommendations for luspatercept?

According to the label, if a patient is still not transfusion-independent after 2 doses of luspatercept, the dose should be increased to 1.33 mg/kg.⁵ If, after another 2 doses, transfusion independence is still not achieved, the dose should be increased further to the full dose of 1.75 mg/kg. After 3 more doses at the full dose, if the patient still has not achieved transfusion independence, treatment should be discontinued, as they are unlikely to respond. Additionally, there are scenarios where patients may be exceptional responders. If their hemoglobin exceeds 11.5 g/dL, or if there is a significant increase in hemoglobin of 2 g/dL after 1 dose, treatment should be held or dose adjustments considered.

The main takeaway is that about 70% of patients required dose escalation with luspatercept.⁶ Most patients need a dose escalation at some point. Before starting luspatercept, transfusion independence was observed in about 28% of patients in a real-world study.⁷ After the first dose, this number increased to 48%, and for patients requiring dose escalation, transfusion independence rose further to 64%. This emphasizes that dose escalation is often effective and should be pursued when appropriate.

For most mutations, luspatercept showed a benefit, with the exception of CBL mutations, although this subgroup had few patients, so conclusions are limited.⁸ Patients with SF3B1 mutations strongly favored luspatercept, which aligns with its known efficacy in this subset. Regarding mutational burden, patients with lower mutational levels had a higher likelihood of responding to luspatercept compared with ESA. This is likely [because] SF3B1 mutations are often solitary or found alongside only 1 or 2 other mutations, whereas patients with higher mutational burdens may have more complex disease that responds less favorably.

In summary, dose escalation with luspatercept can significantly enhance transfusion independence. When considering genomic testing and mutational burden in treatment decisions for patients with lower-risk MDS, the presence of mutations like SF3B1 and a lower overall mutational burden can help guide the choice of therapy and improve outcomes.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Myelodysplastic syndromes, version 2.2025. Accessed January 20, 2025. https://tinyurl.com/2s4y78m9}

_{2. 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}

_{3. 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}

_{4. Zeidan AM, Platzbecker U, Della Porta MG, et al. Clinical benefit of luspatercept treatment (tx) in transfusion-dependent (TD), erythropoiesis-stimulating agent (ESA)–naive patients (pts) with very low-, low- or intermediate-risk myelodysplastic syndromes (MDS) in the COMMANDS trial. J Clin Oncol. 2024;42(suppl 16):6565. doi:10.1200/JCO.2024.42.16_suppl.6565}

_{5. Reblozyl. Prescribing information. Celgene; 2024. Accessed January 16, 2025. https:// tinyurl.com/mtsbehxu}

_{6. Komrokji RS, Platzbecker U, Della Porta M, et al. MDS-234 reduction of transfusion burden (TB), hemoglobin increase, and dose titration in the COMMANDS study of luspatercept versus epoetin alfa (EA) in erythropoietin-stimulating agent (ESA)-naive patients with transfusion-dependent (TD) lower-risk myelodysplastic syndromes (LR-MDS). Clin Lymph Myel Leuk. 2023;23(suppl 1):S358-S359. doi:10.1016/S2152- 2650(23)01174-6}

_{7. Patel K, Chatterjee D, Hughes C, et al. Real-world dose escalation and outcomes among patients with lower-risk myelodysplastic syndromes receiving luspatercept in clinical practice. Presented at: 29th European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract P768. Accessed January 20, 2025. https:// tinyurl.com/yck3kpwt}

_{8. Komrokji RS, Hayati S, Ugidos M, et al. Comparative analysis of clinical benefit by genomic landscape and mutational burden of luspatercept versus epoetin alfa in lower-risk myelodysplastic syndromes (MDS) in the phase 3 commands study. Presented at: 29th European Hematology Association Congress; June 13-16, 2024; Madrid, Spain. Abstract P749.}