Special Populations in MDS: Practical Considerations in the Management of Disease-related Anemia

Dr. Alan F. List
Alan F. List, MD
President & CEO
H. Lee Moffitt Cancer Center
Professor, Department of Oncologic Sciences
College of Medicine, University of South Florida
Tampa, Florida

Please note: On April 3, 2020, the Food and Drug Administration approved luspatercept for the treatment of anemia failing an erythropoiesis stimulating agent and requiring 2 or more red blood cell (RBC) units over 8 weeks in adult patients with very low- to intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T). View the full listing here.

In an interview with Managing MDS, Dr. Alan List, an internationally recognized oncologist from Moffitt Cancer Center in Tampa, provided insights on lower-risk MDS and the challenges clinicians face when treating this patient population. In this interview, Dr. List discusses important trials showing promise when treating patients who are transfusion dependent.

What are some of the key challenges associated with lower-risk MDS?

Lower-risk myelodysplastic syndromes (MDS) can be defined as the very good-, good-, and intermediate-risk categories of the Revised International Prognostic Scoring System (IPSS-R).1 Many people with lower-risk MDS do not need treatment when diagnosed, and we consider treatment when there is a symptomatic cytopenia. The most common cytopenia is anemia, which may be present in 80% to 85% of patients at diagnosis.2 Symptomatic patients may experience fatigue and dyspnea that can limit activities and impact their daily life. We generally first consider treatment with erythropoietin stimulating agents (ESAs) including epoetin alfa or darbepoetin. These recombinant erythropoietins can be very effective, particularly for people who have a low or no need for transfusions, and who have a low serum erythropoietin level. Unfortunately, once a patient becomes transfusion dependent, the probability of response to ESAs drops dramatically, and patients who have appropriately elevated erythropoietin levels have a low probability response.

What options are available for lower-risk MDS patients who received ESAs but are now unresponsive and transfusion dependent?

The only Food and Drug Administration (FDA)-approved treatments are the azanucleosides, and specifically azacitidine would be the option for patients with lower-risk disease. Azacitidine treatment was associated with a 40.5% rate of red blood cell transfusion independence (RBC-TI) and 77.3% clinical benefit rate in ESA‐refractory low-risk MDS patients who were ESA refractory in a recent meta-analysis.3 Lenalidomide, while not FDA approved in this setting, can restore effective erythropoiesis in 25% to 35% of patients without chromosome 5q deletion (del(5q)), while in patients with del(5q), approximately two-thirds of patients will become transfusion independent again—so for that specific subtype of MDS, lenalidomide is very effective.4

What recent studies have been conducted to address these unmet needs?

We have known for years that there is constitutive activation of transforming growth factor (TGF)-beta signaling in MDS, leading to suppression of erythroid maturation,5 so one promising approach targets the TGF-beta signaling pathway. This approach has been evaluated with sotatercept, an activin receptor type IIA/IgG-Fc fusion protein, and luspatercept, an activin receptor type IIB/IgG1-Fc recombinant fusion protein.

Sotatercept was studied in the United States in a phase I/II study in lower-risk, non-del(5q) MDS patients with transfusion-dependent anemia who had not received prior treatment with hypomethylating agents or lenalidomide. In that population, sotatercept was well tolerated and active in terms of patients achieving hematological improvement (HI-E, or hematologic improvement-erythroid).6

Luspatercept was studied in Europe in the phase I/II PACE-MDS study, which also yielded very encouraging results in the same population of patients. Of note, luspatercept yielded a high frequency of transfusion reduction or RBC-TI in patients with MDS with ringed sideroblasts, 52%, versus 30% for other subtypes.7

The development of sotatercept has moved into other diseases, while luspatercept was taken forward into the MEDALIST trial, a double-blind, randomized, placebo-controlled phase 3 study that was reported at the 2018 American Society of Hematology (ASH) annual meeting.8

Could you describe the results of the MEDALIST trial?

The phase 3 MEDALIST trial8 included lower-risk patients with MDS with ring sideroblasts, meaning they had 15% or greater ring sideroblasts in the bone marrow, or they had at least 5% ring sideroblasts plus a specific gene mutation involving SF3B1, which is strongly associated with ring sideroblasts and sideroblastic anemia.9 Patients were excluded if they had del(5q) MDS or had previously received treatment with lenalidomide or hypomethylating agents. Patients had failed ESA treatment or had a low probability of response (serum erythropoietin level >200 U/L).

Patients were randomized 2:1 to receive luspatercept (N=153) or placebo (N=76) every 21 days as a subcutaneous injection. Luspatercept was begun at a dose of 1 mg/kg every 3 weeks, and could be dose-escalated to as a high as 1.75 mg/kg every 3 weeks. Response was assessed after 24 weeks of therapy and then every 6 months thereafter. Patients were followed for 3 years or longer for progression of disease as well as overall survival. Primary endpoint is rate of RBC transfusion independence (RBC-TI) ≥8 weeks during the first 24 weeks of treatment. These patients were relatively heavily transfusion dependent; in fact, 43% of patients on both arms of the study were receiving 6 units or more every 8 weeks, and the median pretransfusion hemoglobin was low at 7.6 g/dL.

The primary endpoint in MEDALIST, which was RBC-TI for 8 weeks or longer, was achieved in 37.9% of patients with luspatercept, versus only 13.2% of patients in the placebo (P <.0001). Notably, patients in the placebo group who were categorized as responders all had a low transfusion burden and reached the primary endpoint as a result of change in transfusion pattern alone, so these were not clinically meaningful responses. In subgroup analyses, the magnitude of transfusion burden significantly impacted response, with a lower transfusion burden having a higher probability of achieving transfusion independence, as did a higher platelet count.

For the most part, these were fairly durable responses—at one year, approximately 40% of luspatercept-treated patients were still transfusion-free, so that is very encouraging. The change in hemoglobin in those people who achieved transfusion independence was a median of 2.55 g/dL compared to pretransfusion hemoglobin levels, whereas there was no significant change in the placebo patients or the non-responders. The proportion of patients who achieved HI-E, defined as a reduction in transfusion burden of >4 units/8 weeks during weeks 1 to 24 of the study, was 52.9% with luspatercept compared to 11.8% for placebo, and if you look at these endpoints over a 48-week period, the numbers are a bit higher, so overall about 58.8% achieved HI-E compared to 17% on placebo.

Luspatercept was very well tolerated in this study. The most common adverse events were fatigue, diarrhea, asthenia, and nausea. Treatment-emergent adverse effects on the trial were balanced between the luspatercept and placebo arms, and serious adverse events occurred at a similar frequency in those groups. The proportion of patients with at least one grade 3-4 treatment-emergent adverse event was 42.5% for luspatercept and 44.7% for placebo.

Overall, MEDALIST was a very positive study showing that luspatercept is quite active in patients with transfusion dependent MDS with ring sideroblasts. We know that TGF-beta signaling is active and plays a very important role in suppressing terminal erythroid maturation. Luspatercept serves to neutralize several of these important ligands such as GDF8, GDF11, and the activin B ligand to improve late-stage erythroid maturation.

How could luspatercept fit into clinical practice for patients with lower-risk MDS?

I think the luspatercept data is very powerful and encouraging. Hopefully, we will see an FDA approval, and it is possible luspatercept could be in the hands of practitioners by early next year. Recently, a supplemental biologics license application (sBLA) was submitted to the FDA for treatment of adults with lower-risk MDS-associated anemia with ring sideroblasts, and for adult patients with beta-thalassemia-associated anemia who require RBC transfusions.10

If approved, the label will be similar to the protocol design, so health care providers can start to consider luspatercept in patients who have MDS with ring sideroblasts and transfusion dependent, lower-risk disease, as first-line therapy if they have low probability of response to an ESA, or as second-line therapy if they have received an ESA and did not respond.

Of note, luspatercept is now going forward in another phase 3 trial, COMMANDS,11 which essentially includes all lower-risk, transfusion-dependent MDS patients other than those with del(5q). This includes patients with or without ring sideroblasts, and those who have not received an ESA in the past. The randomization is luspatercept compared to epoetin alfa given weekly. That study is currently recruiting and has an estimated primary completion date of April 2021.

Is there any other current research with the potential to change practice in lower-risk MDS?

Imetelstat is an interesting agent that has some exciting results that were presented at ASH this past year.12 This is a telomerase inhibitor that targets cells with short telomere lengths and active telomerase, which are characteristics found in some MDS patients. The results presented at ASH were from IMerge, an ongoing global study of imetelstat in ESA-refractory, RBC transfusion-dependent patients with lower-risk MDS. Among 38 patients who received imetelstat 7.5 mg/kg given intravenously every 4 weeks, the 8-week rate of RBC-TI was 37%, with a median duration of 10 months.

The median interval to onset of transfusion independence was about 8 weeks, so it was a fairly fast-acting drug, and several of the patients had sustained transfusion dependence for a year or longer. There were some adverse events with imetelstat, and looking at the treatment-emergent adverse events, about 50% of patients had a dose reduction and 68% had treatment delays because of adverse events. The ones that were most common were neutropenia and thrombocytopenia, followed by grade 3 reversible liver function test elevations, so it has a different profile of adverse events than what we see with luspatercept.

Also at the 2018 ASH meeting, we saw new data for tomaralimab (OPN-305), a toll-like receptor 2 (TLR-2) antibody evaluated in heavily pre-treated, transfusion-dependent lower-risk MDS patients who failed prior hypomethylating agent treatment.13 The primary endpoint was major response, defined as transfusion independence for two consecutive cycles, and minor response was defined as a 50% reduction in transfusion need. The overall response rate was 23.5%, or 12 of 47 patients. If patients did not respond to monotherapy, they added azacitidine, and of those 28 where they added it back, 46% responded, or 13 of 28 patients.

Another agent with relatively recent data in lower-risk MDS is rigosertib, a multikinase inhibitor that was evaluated in a single-arm phase 2 study reported at the 2017 ASH meeting.14 One continuous rigosertib dosing cohort was closed early due to a higher rate of urothelial adverse events. There was a transfusion independence rate of 44% (15 of 34) for patients who received rigosertib for 2 out of 3 weeks at a 560 mg BID dose, according to the published abstract. Of 62 evaluable patients who received intermittent dosing for at least 8 consecutive weeks, 20, or 32%, achieved TI for a median of 18 weeks.

How do you feel the treatment of lower-risk MDS patients will be impacted in the near future?

I think some of these treatments that are in development may find a role in lower-risk MDS at some point in time. I am hopeful we are going to see an approval for luspatercept in the next year, and I think it certainly will have an impact in patients with non-del(5q) patients with ring sideroblasts who are transfusion dependent, and in patients who are transfusion dependent for whom we expect that ESAs are not going to be effective. We know this agent can help a majority of patients, it’s well tolerated, and it is given as an injection every 3 weeks, which is more convenient for the patient compared to azacitidine that has to be given for 5 to 7 days in a row every month.


  1. Greenberg PL, Tuechler H, Schanz J, et al. Revised International Prognostic Scoring System for Myelodysplastic Syndromes. Blood. 2012;120(12):2454-2465. doi:10.1182/blood-2012-03-420489
  2. Steensma DP, Bennett JM. The Myelodysplastic Syndromes: Diagnosis and Treatment. Mayo Clin Proc. 2006;81(1):104-130. doi:10.4065/81.1.104
  3. Komrokji R, Swern AS, Grinblatt D, et al. Azacitidine in Lower‐Risk Myelodysplastic Syndromes: A Meta‐Analysis of Data from Prospective Studies. Oncologist. 2018;23(2):159-170. doi:10.1634/theoncologist.2017-0215
  4. List A, Dewald G, Bennett J, et al. Lenalidomide in the Myelodysplastic Syndrome with Chromosome 5q Deletion. N Engl J Med. 2006;355(14):1456-1465. doi:10.1056/NEJMoa061292
  5. Zhou L, Nguyen AN, Sohal D, et al. Inhibition of the TGF-β receptor I kinase promotes hematopoiesis in MDS. Blood. 2008;112(8):3434-3443. doi:10.1182/blood-2008-02-139824
  6. Komrokji R, Garcia-Manero G, Ades L, et al. Sotatercept with long-term extension for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes: a phase 2, dose-ranging trial. Lancet Haematol. 2018;5(2):e63-e72. doi:10.1016/S2352-3026(18)30002-4
  7. Platzbecker U, Germing U, Götze KS, et al. Luspatercept for the treatment of anaemia in patients with lower-risk myelodysplastic syndromes (PACE-MDS): a multicentre, open-label phase 2 dose-finding study with long-term extension study. Lancet Oncol. 2017;18(10):1338-1347. doi:10.1016/S1470-2045(17)30615-0
  8. Fenaux P, Platzbecker U, Mufti GJ, et al. The Medalist Trial: Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of Luspatercept to Treat Anemia in Patients with Very Low-, Low-, or Intermediate-Risk Myelodysplastic Syndromes (MDS) with Ring Sideroblasts (RS) Who Require Red Blood Cell (RBC) Transfusions. Blood. 2018;132(Suppl 1):1. doi:10.1182/blood-2018-99-110805
  9. Malcovati L, Karimi M, Papaemmanuil E, et al. SF3B1 mutation identifies a distinct subset of myelodysplastic syndrome with ring sideroblasts. Blood. 2015;126(2):233-241. doi:10.1182/blood-2015-03-633537
  10. Columbus G. FDA Approval Sought for Luspatercept for Anemias. OncLive. https://www.onclive.com/web-exclusives/fda-approval-sought-for-luspatercept-for-anemias. Accessed April 13, 2019.
  11. Efficacy and Safety Study of Luspatercept (ACE-536) Versus Epoetin Alfa for the Treatment of Anemia Due to IPSS-R Very Low, Low or Intermediate Risk Myelodysplastic Syndromes (MDS) in ESA Naïve Subjects Who Require Red Blood Cell Transfusions. https://clinicaltrials.gov/ct2/show/NCT03682536. Accessed April 13, 2019.
  12. Steensma DP, Platzbecker U, Eygen KV, et al. Imetelstat Treatment Leads to Durable Transfusion Independence (TI) in RBC Transfusion-Dependent (TD), Non-Del(5q) Lower Risk MDS Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Who Are Lenalidomide (LEN) and HMA Naive. Blood. 2018;132(Suppl 1):463-463. doi:10.1182/blood-2018-99-114877
  13. Garcia-Manero G, Jabbour EJ, Konopleva MY, et al. A Clinical Study of Tomaralimab (OPN-305), a Toll-like Receptor 2 (TLR-2) Antibody, in Heavily Pre-Treated Transfusion Dependent Patients with Lower Risk Myelodysplastic Syndromes (MDS) That Have Received and Failed on Prior Hypomethylating Agent (HMA) Therapy. Blood. 2018;132(Suppl 1):798-798. doi:10.1182/blood-2018-99-119805
  14. Raza A, Al-Kali A, Tibes R, et al. Rigosertib Oral in Transfusion Dependent Lower Risk Myelodysplastic Syndromes (LR-MDS): Optimization of Dose and Rate of Transfusion Independence (TI) or Transfusion Reduction (TR) in a Single-Arm Phase 2 Study. Blood. 2017;130(Suppl 1):1689-1689.