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FAQs on LR-MDS
Experts Answer Key Questions on Managing Anemia in Patients With Lower-Risk MDS

Released: July 08, 2024

Expiration: July 07, 2025

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Key Takeaways
  • For patients with RBC transfusion–dependent lower-risk MDS with ring sideroblasts, luspatercept as frontline therapy showed superior efficacy when compared with ESAs in the phase III COMMANDS trial and should be considered the preferred therapy in that context.
  • Benefit from luspatercept may be optimized by following response-adapted dosing, and treatment with luspatercept should be continued until clear evidence of treatment failure.
  • In June 2024, imetelstat was approved by the FDA for adults with low-risk 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.

Ninety percent of patients with myelodysplastic syndromes (MDS) become anemic and more than one half of those become transfusion dependent. In lower-risk MDS, the goal is to manage anemia and other cytopenias, thereby improving patient quality of life and risk of disease progression.

Several options exist for managing anemia with lower-risk MDS. Frontline options include erythropoiesis-stimulating agents (ESAs), and luspatercept a fusion protein that binds TGF-β superfamily ligands and promotes erythroid maturation. In 2023, luspatercept was approved by the FDA for the management of ESA-naive anemia in adults with very low–risk to intermediate-risk MDS who require red blood cell (RBC) transfusions, regardless of ring sideroblast status. Before that, luspatercept was approved for anemia failing an ESA and requiring 2 or more RBC units over 8 weeks in adult patients with very low–risk to intermediate-risk MDS with ring sideroblasts. Another option for ESA-refractory anemia is the newly approved telomerase inhibitor imetelstat. Imetelstat was approved by the FDA in June 2024 for adults with low-risk 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 from a live webinar on June 2, 2024, on the management of anemia with lower-risk MDS including questions on luspatercept and imetelstat. 

For a patient with lower-risk MDS with ring sideroblasts, with an SF3B1 mutation and no del(5q) who has an erythropoietin level of 390 and receives RBC transfusions at 3 units every 8 weeks, can luspatercept administration be delayed until response to ESA is assessed?  

Rami Komrokji, MD:
There is clear evidence from the phase III COMMANDS trial that this patient would benefit more from luspatercept in the frontline. Luspatercept leads to a higher rate and more durable transfusion independence when compared with ESA. 

Maximilian Stahl, MD:
I would also treat this patient with luspatercept, but we understand that in the community setting, physicians often give ESA initially. If this patient received ESA as first-line treatment, we have evidence from the phase III MEDALIST trial that luspatercept is also effective after ESA failure. In the MEDALIST trial, luspatercept resulted in superior RBC transfusion independence for patients with lower-risk MDS after ESA failure.

Amer Zeidan, MBBS, MHS:
I also agree with both of my colleagues on this approach. I hope that in the future, we will have randomized large trials showing superiority of the combination of luspatercept with ESA compared with either drug alone in the frontline setting making this question about which agent to choose less relevant.

Once the maximum dose of 1.75-mg/kg luspatercept has been reached, how many injections would you give before discontinuing treatment?

Maximilian Stahl, MD:
For patients who do not achieve transfusion independence, luspatercept dosing can be increased to 1.75 mg/kg every 3 weeks and should be continued until treatment failure. Failure in clinical trials and failure in clinical practice does not always mean the same thing. Patients who have minimal adverse effects and occasionally need a transfusion are not technically transfusion independent but are still benefiting from the drug. A reduced transfusion burden without achieving transfusion independence can be meaningful for patients if they only come every couple of weeks or months for a blood transfusion compared with every week.

Rami Komrokji, MD:
I agree. There is a cumulative benefit to treatment that can be missed in clinical trials. In clinical practice, I would not immediately stop luspatercept because of the occasional transfusion. I would continue luspatercept until transfusion burden begins to increase, as that is a clear indication of therapy failure. 

Amer Zeidan, MBBS, MHS:
I also agree that even if there is no full transfusion independence after 3 injections at the highest dose, continuation of luspatercept could be considered for patients who achieve a clinically meaningful reduction in transfusion burden.

Does SF3B1 become negative with luspatercept or imetelstat? Is your goal a molecular response in those patients? 

Maximilian Stahl, MD:
The goal of MDS treatment is not necessarily a good molecular response. The most important thing is whether the patient is feeling better and are blood counts improving.

We have data from the phase III IMerge trial showing a reduction in the VAF of SF3B1, TET2, DNMT3A, and ASXL1, which are commonly mutated in MDS. There was also a correlation between the reduction in SF3B1 variable allele frequency with increase hemoglobin levels and RBC transfusion independence. With that, I think we have too few data to say that treatment with imetelstat or luspatercept changes the biology of MDS in terms of progression to leukemia and other endpoints by eradicating the disease clone. 

Amer Zeidan, MBBS, MHS:
I agree with Dr. Stahl. Although we hope that imetelstat would prove to be disease modifying, I would currently aim for clinical—and not molecular—responses. As more patients are treated and followed up for longer periods of time, we will get more insights into this issue.

Would imetelstat work better than luspatercept with additional genes being identified?

Maximilian Stahl, MD:
In the COMMANDS trial, treatment benefit of luspatercept was highest for patients with MDS with ring sideroblasts and SF3B1 mutations. However, I am unaware of any specific mutation known to predict a benefit to imetelstat. I would use imetelstat in patients with MDS with wild-type SF3B1, and this accounts for a large proportion of patients with MDS.

Amer Zeidan, MBBS, MHS:
I also agree that there are no specific genes associated with response to imetelstat, although patients with ring sideroblasts/SF3B1 mutation seem to always respond better.

With the results of the COMMANDS trial, will erythropoietin disappear from the first line of therapy for patients with MDS and anemia?

Amer Zeidan, MBBS, MHS:
This is unlikely to happen in the near future because of logistical and cost considerations, especially for patients without ring sideroblasts/SF3B1 mutations. I think we also need to understand how well ESAs work after luspatercept failure and the impact of different sequences of therapy. Ultimately, combining luspatercept with ESAs might be the best approach, but we need trials to answer this question.

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