Exploring Strategies in ESA-Refractory Lower-Risk MDS

A patient who becomes relapsed or refractory to erythropoiesis-stimulating agents (ESAs) has limited options. The shift in treatment involves greater use of targeted agents and increasingly personalized approaches, often informed by the patient’s molecular profile and specific disease characteristics.

In a discussion with participants, Hetty E. Carroway, MD, MBA, associate professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, addressed this challenging clinical situation.

This is part 2 of a 2-part discussion. Part 1 is available here: Addressing Second-Line Approaches in Low-Risk MDS.

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CASE SUMMARY

A 72-year old man with low-risk myelodysplastic syndrome (MDS) with symptomatic anemia presents with controlled hypertension and hyperlipidemia. Red blood cell (RBC) transfusions were needed every week initially. At 10 weeks, darbepoetin 150 μgwas initiated every other week.

• No del5(q) detected
• Ring sideroblasts: negative
• Laboratory results
  • Hemoglobin: 7.9 g/dL
  • Serum erythropoietin (EPO): 250 mU/mL
  • White blood cell count: 3500/μL
  • Absolute neutrophil count: 1800/μL
  • Platelets: 157,000/μL
  • Serum ferritin: 175 μg/L
  • Transferrin saturation: 28%

At week 16, darbepoetin increased to 300 mcg every other week (hemoglobin was 8.2 g/dL). At week 20, darbepoetin continued (hemoglobin was 9.7 g/dL). At week 36, hemoglobin was 8.2 g/dL.

Targeted Oncology: When considering low-risk MDS therapies, what is the range of treatment response times?

Hetty E. Carroway, MD, MBA: The duration of ESA therapy is usually about 6 to 8 weeks. After that, we typically move on to the next line of treatment, such as lenalidomide, which is given for closer to 2 to 4 months. Luspatercept has a 3-to-6-month timeline, and the same 6-month duration applies to hypomethylating agent (HMA)-based therapies. We try to keep patients on these treatments long enough to be confident that we’ve given the drug a fair chance. By that point, it becomes clear whether the disease has progressed or the therapy is simply not working—based on the synergistic effect of granulocyte colony–stimulating factor (G-CSF).

What are the criteria for ESA ineligibility?

When managing patients with hypertension, there is naturally a concern about their blood pressure becoming unstable as a result of ESA-based therapy. There are many factors to consider here, just as there are with any medication, but it is important to focus on identifying which patients are truly ESA-ineligible. According to the NCCN guidelines, ESA ineligibility is defined as having an EPO level greater than 500 mU/mL.¹

The registrational trial for erythropoietin-α in patients with lower-risk MDS demonstrated that all responders had EPO levels below 200 mU/mL.² We also have the formula from Eva Hellström-Lindberg, which uses serum EPO levels and transfusion burden to help predict the likelihood of a response to ESA-based therapy.³ [Although] that formula dates back to 2003 and may be considered outdated now, I am interested in redesigning it to include mutations. The goal is to better predict who will actually respond to these therapies, and I hope to see those types of refined tools emerge in the future.

Please discuss the second-line management after ESA-failure.

According to NCCN guidelines, the second-line management after ESA failure, you can see the preferred is imetelstat [Rytelo] in category 1 or luspatercept [Reblozyl], if not previously used, and then other recommended could still consider epoetin plus granulocyte colony-stimulating factor (G-CSF) or lenalidomide, or darbepoetin plus G-CSF or lenalidomide.

Please provide details on the luspatercept phase 3 MEDALIST trial (NCT02631070).⁴

This trial evaluated 229 patients with MDS and ring sideroblasts, as defined by the WHO criteria. The criteria required either greater than or equal to 15% ring sideroblasts, or greater than or equal to 5% ring sideroblasts plus an SF3B1 mutation, with less than 5% blasts, no del 5q, and an IPSS-R risk category of very low, low, or intermediate. Patients were either refractory or intolerant to ESA therapy, or ESA naive but with an EPO level greater than 200 mU/mL. The average transfusion burden was greater than or equal to two units over 2 months, and there was no prior treatment with disease modifying agents like immunomodulatory drugs or HMAs. Patients also had to meet specific requirements for neutrophil and platelet counts as documented.⁴

Patients were randomly assigned 2:1 to receive either luspatercept or placebo. Disease and response assessments were evaluated at week 25, and patients were followed for more than 3 years after the final dose. The primary end point of this study was transfusion independence for greater than 2 months during weeks 1 through 24. For patients receiving luspatercept, 38% achieved greater than or equal to 8 weeks of transfusion independence, 28% achieved greater than 12 weeks of transfusion independence, and 33% met that end point during week 1 through week 48. During weeks 1 through 24, almost 20% of patients receiving luspatercept achieved greater than 4 months of transfusion independence.⁴

Grade 3 fatigue and asthenia were observed in approximately 3% to 5% of patients. [Although] some patients may express a desire to stop treatment after exposure to the drug, such occurrences are rare and remain in the single digits, with very little gastrointestinal toxicity to report. Regarding treatment management, approximately 5% of patients required dose reductions due to adverse events, and 8% discontinued therapy entirely for the same reason. Notably, the rate of disease progression for those receiving luspatercept was no different than for those in the placebo group.⁴

Looking at the long-term efficacy with a median follow-up of 39.9 months, the data show that patients have generally done well on the therapy. Nearly half of the patients, specifically 49%, achieved transfusion independence for a period of greater than 2 months during the entire treatment window. Furthermore, 70% of patients achieved 2 or more response periods, with a median cumulative duration of response reaching 110 weeks.⁴

What did investigators find when they conducted a post hoc analyses of pooled data from the IMerge study (NCT02598661)?

In a post hoc analysis of imetelstat based on pooled data,⁵ investigators examined the duration of response in patients with ring sideroblast (RS)-negative, low-risk myelodysplastic syndromes (MDS). The analysis categorized patients into several cohorts, including treatment-naive individuals with erythropoietin (EPO) levels greater than 500 mU/mL, as well as those with prior ESA exposure and varying EPO levels ranging from 200 to over 500 mU/mL. While the data show that responses still occur in these categories despite higher baseline serum EPO, there appears to be an incremental decrease in both the likelihood and duration of response as those levels rise.

A significant point of discussion involves the potential confounding role of chronic kidney disease in these older patients. It is possible that serum EPO levels in this population may be more a reflection of renal dysfunction than the MDS itself. This distinction is critical, as anemia can decrease kidney perfusion, further exacerbating comorbidities and creating unique challenges for this subset of patients. Currently, the MDS community is still working to better isolate the impact of renal dysfunction to determine if these patients benefit from therapies differently than those with normal kidney function.

DISCLOSURES: Dr Carraway has received honoraria for advisory board memberships from AbbVie, Celgene/BMS, Genentech, Jazz Pharmaceuticals, Novartis, and Daiichi Sankyo; has received research funding from Celgene; has served on speakers bureau for BMS, Jazz Pharmaceuticals, Novartis, and Stemline Therapeutics; and has served on data safety monitoring boards for Astex, AbbVie, Takeda, and Syndax.

REFERENCES

1. NCCN Clinical Practice Guidelines in Myelodysplastic Syndromes, version 3.2026. Accessed March 8, 2026. https://www.nccn.org/professionals/physician_gls/pdf/mds.pdf.

2. Fenaux P, Santini V, Spiriti MAA, et al. A phase 3 randomized, placebo-controlled study assessing the efficacy and safety of epoetin-α in anemic patients with low-risk MDS. Leukemia. 2018;32(12):2648-2658. doi:10.1038/s41375-018-0118-9

3. Hellström-Lindberg E, Gulbrandsen N, Lindberg G, et al. A validated decision model for treating the anaemia of myelodysplastic syndromes with erythropoietin + granulocyte colony-stimulating factor: significant effects on quality of life. Br J Haematol. 2003;120(6):1037-1046. doi:10.1046/j.1365-2141.2003.04153.x

4. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382(2):140-151. doi:10.1056/NEJMoa1908892

5. Santini V, et al. Outcomes of imetelstat therapy in patients with ring sideroblast-negative(RS-) lower-risk myelodysplastic syndromes (LR-MDS) from the pooled IMerge study populations. Clin Lymph Myel Leuk. 2025;25(suppl):S226.