Navigating the Nuances of Post-ESA Treatment in Lower-Risk MDS

After the failure of frontline erythropoiesis-stimulating agent (ESA) treatment, patients with lower-risk myelodysplastic syndromes (LR-MDS) have 2 primary options: luspatercept (Reblozyl) and imetelstat (Rytelo). Both carry National Comprehensive Cancer Network Category 1 designation as preferred second-line agents following ESA failure.

Since there has not been a head-to-head trial comparing the 2 agents, second-line selection for practicing oncologists involves considering factors such as ring sideroblast (RS) status, erythropoietin (EPO) level, and transfusion burden. A patient case highlighting the decision-making process in second-line LR-MDS was discussed by oncologists at a virtual Case-Based Roundtable event moderated by Andrew Brunner, MD, a hematologist-oncologist at Massachusetts General Hospital in Boston, Massachusetts.

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This is part 2 of a 2-part series. Read part 1.

CASE SUMMARY

• The patient is a 72-year-old man LR-MDS with symptomatic anemia.
• No del(5q) detected, RS-negative. The patient has comorbidities of hypertension and hyperlipidemia that are both controlled.
• After diagnosis: red blood cell (RBC) transfusions needed every week initially
• Labs: White blood cell 3500/µL; absolute neutrophil count 1800/µL; platelets 157,000/µL; serum ferritin 175 mcg/L; transferrin saturation 28%
• Week 10: initiated darbepoetin 150 mcg every other week; hemoglobin (Hgb) 7.9 g/dL; EPO 250 mU/mL
• Week 16: darbepoetin increased to 300 mcg every other week; Hgb 8.2 g/dL; RBC transfusions needed once monthly
• Week 20: darbepoetin continued at 300 mcg every other week; Hgb 9.7 g/dL
• Week 36: RBC transfusions increased back to every 1 to 2 weeks; Hgb 8.2 g/dL

EVENT RECAP

Brunner opened by focusing on how to recognize when a frontline ESA is failing and second-line therapy is needed. He noted that 90% of ESA responders tend to show benefit within the first 12 weeks, and that he typically starts ESA treatment with darbepoetin or epoetin at maximum doses from the outset rather than titrating up; his reasoning is that it allows him to identify non-responders more quickly.

A participant noted the importance of re-checking EPO levels before switching agents, since a markedly elevated level coming off ESA would steer the second-line decision toward imetelstat over luspatercept, as luspatercept has a lower response rate at higher EPO concentrations.¹ Another participant asked about the optimal timing for the EPO re-check, noting that the available ESAs have varying half-lives.² Brunner acknowledged this as an open question and suggested checking levels when the next dose would otherwise have been due.

When the discussion shifted to second-line treatment selection, the participants were split between switching to luspatercept or imetelstat. One participant shared her view that there is a demonstrated practical advantage for imetelstat in RS-negative patients with high EPO levels.³ She added that administering imetelstat as a once-monthly intravenous infusion avoids the more frequent clinic visits required for ESA dose adjustments.⁴

Brunner next discussed pivotal data from the MEDALIST and (NCT02631070) IMerge trials, which support the use of luspatercept and imetelstat, respectively, in the second-line for LR-MDS. MEDALIST enrolled 229 patients with MDS with RS, no del(5q), and at least 2 units of RBC transfusions over 8 weeks, a meaningfully less transfusion-dependent population than what IMerge required. All patients were refractory/intolerant/ineligible to prior ESA treatment.

Patients were randomized 2:1 to luspatercept vs placebo. The primary end point of transfusion independence (TI) for at least 8 consecutive weeks during weeks 1 through 24 was met by 38% of luspatercept patients vs 13% of placebo patients (P <.001). At longer follow-up during weeks 1 through 48, 33% vs 12% of patients achieved TI for at least 12 consecutive weeks (P <.001). Long-term follow-up at a median of 39.9 months showed that 49% of luspatercept patients achieved TI for at least 8 weeks during the full treatment period, and of those responders, 70.7% had at least 2 response periods, with a median cumulative duration of 110.14 weeks.^1,5

Brunner noted that the safety profile of luspatercept in MEDALIST was generally well tolerated and distinct from imetelstat in one important respect: luspatercept does not cause meaningful cytopenias.¹ However, while grade 3/4 cytopenias are common with imetelstat, these events are typically brief, reversible, and manageable with dose delays, dose reductions, or growth factor support. More than 80% of these cytopenias resolve to grade 2 or lower within 4 weeks.^4,6

Regarding the IMerge trial of imetelstat, Brunner reviewed post-hoc pooled data specifically relevant to the RS-negative and post-ESA populations, aligning with the patient case being discussed. Among RS-negative patients treated with imetelstat (n = 78), 33% achieved at least 8 weeks of RBC-TI, with a median duration of 44 weeks for that end point, extending to 123 weeks for those who achieved at least 24 weeks of TI and 141 weeks for those reaching at least 1 year of TI.³

The pooled data also showed that imetelstat's clinical activity was maintained regardless of prior ESA response status patients who had responded to ESA, had been refractory to ESA, or were ESA-ineligible due to high EPO levels all derived benefit, with the best responses seen in the prior-ESA group with EPO below 200 mU/mL (8-week TI rate 50%) and the lowest, though still clinically meaningful, responses in the prior-ESA group with EPO above 500 mU/mL (8-week TI rate 24%).³

Brunner framed the practical choice between the 2 agents around 3 variables: RS status, EPO level, and transfusion burden. For RS-positive patients, luspatercept remains the agent with the most established efficacy data, as MEDALIST was specifically designed for and enrolled RS-positive patients; however, the post-hoc pooled data from IMerge showed that imetelstat is also active in RS-positive disease no head-to-head comparison exists between the 2 drugs in this setting.

For RS-negative patients, either agent is appropriate per guidelines, but imetelstat becomes increasingly attractive as EPO level rises and transfusion burden increases, since the IMerge population was more heavily transfusion-dependent than MEDALIST's, and imetelstat's mechanism is EPO-independent. Brunner also shared his view that for patients receiving 6 or more units of blood over the preceding 2 months, the probability of achieving full transfusion independence with luspatercept is lower, whereas imetelstat still carries a meaningful chance of that outcome.

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DISCLOSURES: Andrew M. Brunner has received consulting fees from Acceleron, Agios, BMS/Celgene, Gilead, Keros Therapeutics, Novartis, Takeda, and Taiho.

REFERENCES:

1. 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

2. Bohlius J, Bohlke K, Castelli R, et al. Management of cancer-associated anemia with erythropoiesis-stimulating agents: ASCO/ASH clinical practice guideline update. J Clin Oncol. 2019;37(15):1336-1351. doi:10.1200/JCO.18.02142

3. Komrokji RS, Platzbecker U, Zeidan AM, et al. Clinical activity of imetelstat by prior therapy in low-risk myelodysplastic syndromes: analyses from pooled IMerge data. Blood Cancer J. 2025;15(1):217. doi:10.1038/s41408-025-01444-0

4. RYTELO (imetelstat) injection. Geron Corporation; 2024. Accessed March 6, 2026. https://pi.geron.com/products/US/pi/rytelo_pi.pdf

5. Santini V, Giagounidis A, Sekeres MA, et al. Luspatercept efficacy and safety in patients with lower-risk myelodysplastic syndromes: long-term results from the MEDALIST trial. Blood. 2023;142(suppl 1):915-917.

6. Platzbecker U, Santini V, Fenaux P, et al. Imetelstat in patients with lower-risk myelodysplastic syndromes who have relapsed or are refractory to erythropoiesis-stimulating agents (IMerge): a multinational, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2024;403(10423):249-260. doi:10.1016/S0140-6736(23)01724-5