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Managing anemia in LR-MDS
What You Need to Know About Managing Anemia in Patients With Lower-risk MDS in 2025

Released: July 25, 2025

Expiration: January 24, 2026

Rami Komrokji
Rami Komrokji, MD
Maximilian Stahl
Maximilian Stahl, MD
Amer Zeidan
Amer Zeidan, MBBS, MHS
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Key Takeaways
  • When managing patients with lower-risk myelodysplastic syndromes (MDS) who have transfusion-dependent anemia, healthcare professionals should be aware of luspatercept-associated fatigue and the need to monitor blood pressure closely in those with a history of hypertension.
  • Although both luspatercept and imetelstat received FDA approval for second-line management of anemia for patients with lower-risk MDS, the toxicity profile and patient goals should be taken into consideration when deciding between the 2 agents.

In 2023, luspatercept was approved by the FDA for the management of erythropoiesis-stimulating agent (ESA)-naive anemia in adults with very low- to intermediate-risk myelodysplastic syndromes (MDS) who may require red blood cell (RBC) transfusions, regardless of ring sideroblast status. Prior to 2023, luspatercept was approved for adult patients with very low- to intermediate-risk MDS with ring sideroblasts with anemia after ESA failure who require ≥2 RBC units over 8 weeks. Another option for ESA-refractory anemia is imetelstat, which was approved by the FDA in June 2024 for adults with low- to intermediate-1–risk MDS with transfusion-dependent anemia requiring ≥4 RBC units over 8 weeks who have not responded to, have lost response to, or are ineligible for ESAs, regardless of ring sideroblast status.

In this commentary Rami Komrokji, MD; Maximilian Stahl, MD; and Amer Zeidan, MBBS, MHS, answer audience questions posed by healthcare professionals (HCPs) attending a live webinar held on June 1, 2025 that are related to the management of anemia in patients with lower-risk MDS (LR-MDS) and provide practical clinical insights on optimizing care for patients receiving luspatercept or imetelstat.

How do you manage adverse events in patients with LR-MDS who are being treated with luspatercept?

Maximilian Stahl, MD:
Luspatercept is a well-tolerated drug, but HCPs must look out for worsening hypertension in patients with a history of hypertension, especially if it is poorly controlled. Some patients experience fatigue that is unrelated to the underlying anemia and persists despite improvements in hemoglobin levels. In rare cases fatigue is troublesome enough to warrant a dose hold or reduction, and sometimes discontinuation.

Amer Zeidan, MBBS, MHS:
Fatigue can be tricky to manage with MDS. The relation between hemoglobin levels and the degree of fatigue is complex and not linear, and adding luspatercept complicates its management. In my experience, worsening fatigue with luspatercept is not usually significant enough to warrant discontinuation and typically improves within the first few cycles, especially once hemoglobin levels improve to approximately ≥10 g/dL. Although fatigue generally resolves, it is important to counsel patients about this adverse event before starting luspatercept.

Although hypertension is not generally an issue with luspatercept, HCPs need to watch for it. Some patients experience anxiety from frequent visits to the clinic, and this is reflected in their blood pressure. I do not make decisions on treatment adjustments based solely on clinic visits. I ask my patients to monitor and log their blood pressure at home and then determine whether an intervention is needed.

Rami Komrokji, MD:
I agree with Drs Stahl and Zeidan. In clinical trials the rate of discontinuation with luspatercept linked to adverse events was low. To your point, HCPs should always ensure that if a patient has hypertension, it is controlled.

Fatigue with luspatercept is an interesting phenomenon that is not well understood. It can be discordant from the blood counts typically noted during the first few cycles of luspatercept treatment. The phase III MEDALIST and COMMANDS trials looked at the use of luspatercept in the settings of ESA failure or ESA-naive disease and reported rates of fatigue of approximately 27% and 20%, respectively. The slightly lower rate reported in COMMANDS may be because MEDALIST enrolled patients post-ESA failure with a higher transfusion burden.

When the treatment goal is to increase blood counts, the risk of thrombosis must be considered, but thrombosis is not observed with luspatercept in patients with MDS. Another advantage of luspatercept is that it is not myelosuppressive, and it can be used even if a patient has borderline platelet and neutrophil counts based on data from MEDALIST showing trilineage responses. HCPs occasionally see some improvement in platelet and neutrophil counts, and despite this not being the goal of treatment, it can be beneficial.

A patient with LR-MDS with DNTM3A and SF3B1 mutations that is non(del5q) has transfusion-dependent anemia (Hb 7 g/dL) and is receiving 6 RBC units/8 weeks after ESA failure. Tests confirm that the patient has not progressed to high-risk disease. How would you manage this patient’s anemia?

Rami Komrokji, MD:
For this patient with a high transfusion burden, the 2 available options are luspatercept and imetelstat. In MEDALIST, luspatercept was compared with placebo in a population of patients with ESA-refractory LR-MDS. In total, 38% of patients in the luspatercept arm achieved transfusion independence for ≥8 weeks during Weeks 1-24–the study’s primary endpoint–vs 13% in the placebo arm (P <.001). For a subset of patients who were highly transfusion dependent, 9% achieved transfusion independence for ≥8 weeks during Weeks 1-24. However, in patients with a high transfusion burden at baseline, luspatercept resulted in a ≥75% reduction in RBC transfusion burden ≥24 weeks in 18% of patients (vs 6% with placebo). Use of imetelstat is supported by data from the phase III IMerge trial that compared imetelstat to placebo in the same patient population. In IMerge the rates of ≥8-week transfusion independence were approximately 40% and responses were durable with an accompanied hemoglobin increase. Moreover, transfusion independence responses were consistent across subgroups, including patients with a high transfusion burden (>6 RBC units/8 weeks). One potential downside to imetelstat is the high rate of myelosuppression. Grade 3 or 4 thrombocytopenia and neutropenia occurred in approximately 60% of patients treated with imetelstat, but rates of febrile neutropenia and clinically meaningful bleeding were low (<1% and 2.5%, respectively). Knowing that grade 3 or 4 neutropenia and thrombocytopenia is likely to occur with imetelstat, HCPs should keep in mind that dose modifications or holds may be needed, and in some cases, treatment will need to be discontinued. As mentioned previously, myelosuppression is not usually observed with luspatercept.

Amer Zeidan, MBBS, MHS:
I think this is an outstanding summary, and as you said, this case fits both the MEDALIST and IMerge data. Do you have a preference between imetelstat and luspatercept?

Rami Komrokji, MD:
I think preference depends on patient goals and I would discuss both options. The argument for imetelstat is that the patient has a high transfusion burden, and I think the chances for a response are higher than with luspatercept. The downside is the significant myelosuppression with imetelstat. If the treatment goals are increased hemoglobin levels and complete transfusion independence, imetelstat would be my recommendation. If the patient does not want to come to clinic weekly or biweekly to check blood counts and is willing to accept potential dose delays or reductions and transfusions for the first 2 months while response is assessed, I would recommend luspatercept. After 2 months, a potential change in treatment can be assessed.

Amer Zeidan, MBBS, MHS:
Dr Stahl, do you have a strong preference for imetelstat or luspatercept?

Maximilian Stahl, MD:
I appreciate Dr Komrokji’s more nuanced view, and that is what I would do in clinic. If I were forced to choose, I would recommend luspatercept. However, sequencing should also be considered. A secondary analysis from IMerge showed that imetelstat works well after luspatercept. We have much less data for luspatercept after imetelstat. For this patient, I would use luspatercept first because imetelstat might work in the second-line setting.

Amer Zeidan, MBBS, MHS:
I think this is a very good example of why it is important to understand the clinical trial data, patient goals, and what each patient values the most, whether it be transfusion independence, freedom from frequent visits to the clinic, potential dose interruptions, growth factor support, or other specific factors.

In terms of sequencing, which weighs on my mind, we know that imetelstat works after luspatercept, but we do not yet have data on luspatercept after imetelstat. I am always concerned about the need for subsequent treatment if a drug does not work well for any given patient. This is even more concerning now that there is more than one choice for treatment post-ESA.

Your Thoughts
What are your thoughts and experiences related to managing anemia in patients with lower-risk MDS? How are you managing your patients with significant, persistent fatigue while receiving treatment for LR-MDS? Answer the polling question and join the conversation by leaving a comment. Also, visit the program page to download slides from the live event, and be sure to return later to view the on-demand webcast.

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In your clinical practice, how often do you consider a dose reduction or discontinuation of luspatercept in your patients with lower-risk MDS who are experiencing fatigue?

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