Zeidan Reviews Past Treatment Options for Patient With Lower-Risk MDS

Amer Zeidan, MBBS

Associate Professor of Internal Medicine (Hematology)

Yale University

Medical Director, Hematology Early Therapeutics Research,

Leader, Myeloid Malignancies Clinical Research Team

Director, Continuing Medical Education, Hematology

Yale Cancer Center

New Haven, CT

CASE SUMMARRY

• A 70-year-old man was diagnosed 1 year ago with lower-risk myelodysplastic syndrome with ring sideroblasts (LR-MDS-RS)
  • Multilineage dysplasia
  • Moderate anemia (hemoglobin, 11.2 g/dL) and thrombocytosis (platelets, 500,000/μl)
  • RS in 4% of nucleated erythroid cells
• SF3B1 mutation negative
• Non-deletion 5q
• No family history of cancer or significant genotoxic agent exposure
• In the last 8 months, he received single-unit packed red blood cell transfusions 3 months apart
• Revised International Prognostic Scoring System: low
• Work-up to assess disease status and response to anemia management:
  • Serum erythropoietin (EPO): 250m U/L
  • RS negative
  • Hemoglobin: 8.3 g/dL
  • White blood cell and absolute neutrophil count: within normal limits
  • Platelets: 450,000/μl

Targeted Oncology: How would you treat this patient in your clinic prior to recent data?

AMER ZEIDAN, MBBS: If I saw this patient 3 to 4 years ago, or even last year before the COMMANDS trial [NCT03682536], this is someone I would consider for an erythropoietin-stimulating agent [ESA] for multiple reasons. [However], when the EPO level is above 200 U/L, and certainly when it's above 500 U/L, the ESA is much less likely to work. There isn't a specific cutoff; it's a continuum. The higher the EPO level, the less likely to work. Now the literature is different, but I would say most of the literature, if your EPO level is above 200 U/L, the chance of response [is lower].¹ There are data with ESA where there was no response,² which I don't think is [accurate], because I certainly have seen responders.

But from the COMMANDS trial, which used ESA as a control arm and the response rate was 7% if your EPO level was above 200 U/L.³ It certainly does not work in all the patients. But in the absence before we had luspatercept-aamt [Reblozyl] and imetelstat [Rytelo], what was your other option? You either kept the patient going on transfusions or you gave the patient hypomethylating agents [HMAs]. I am not going to give the patient an HMA as a first-line treatment if they have LR-MDS.

My approach in the past...I would have tried an ESA, and the chance of response [would be] 10% to 15%. If the patient didn’t respond after 3 or 4 months, then I would try something else. This has been my approach [until] the COMMANDS trial. There were some data with epoetin-α; this trial [EPOANE3021] is from Europe.⁴ In Europe, they cannot use drugs until they have randomized phase 3 trials. This trial was only published in 2018, but we've been using ESAs for probably 3 decades for MDS in the United States. It delays the time to transfusions.... For darbepoetin-α, the improvement over placebo was around one-third.² So generally, around 30% to 40% will respond to ESA when they are anemic with LR-MDS. [With the older and] the newer drugs, [those with] the higher EPO level, above 200 U/L, none of those patients responded. But in reality, I would say it's probably 10% to 15%. It's not 0%.

REFERENCES:

1. Park S, Kelaidi C, Meunier M, Casadevall N, Gerds AT, Platzbecker U. The prognostic value of serum erythropoietin in patients with lower-risk myelodysplastic syndromes: a review of the literature and expert opinion. Ann Hematol. 2020;99(1):7-19. doi:10.1007/s00277-019-03799-4

2. Platzbecker U, Symeonidis A, Oliva EN, et al. A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes. Leukemia. 2017;31(9):1944-1950. doi:10.1038/leu.2017.192

3. 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

4. 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