MedicalResearch.com Interview with:
Dr. Alan List MD
President and Chief Executive Officer
Moffitt Cancer Center
MedicalResearch.com: What is the background for this study?
Response: In patients with lower risk Myelodysplastic Syndromes (MDS), which accounts for the vast majority of patients with MDS overall, the most common symptomatic cytopenia is anemia. These patients, overtime, become dependent upon red blood cell transfusions and with that, they face a risk of iron loading as well as complications that occur with it. The standard first line therapy that we consider for these patients is erythropoietin-stimulating agents (ESAs). Patients who are transfusion dependent have a low response rate to ESAs, and responses are of short duration. There limited effective limited treatment options for those patients unresponsive or lose response to ESAs.
For years, we’ve known that the transforming growth factor (TGF)-β pathway play an important pathogenetic role in suppressing red cell maturation and cell survival.
Luspatercept is an agent that acts as an erythroid maturation agent by inhibiting the TGF-β signaling pathway by neutralizing a select group of TGF-β superfamily ligands.
MedicalResearch.com: What are the main findings?
Response: This was a randomized phase III, placebo-controlled study in patients with lower risk . Myelodysplastic Syndromes and ring sideroblasts that were transfusion dependent. The primary endpoint for the study was transfusion independence for 8 weeks or longer and overall, 37.9% of patients achieved that endpoint with luspatercept treatment compared to 13.2% in the placebo arm. These results were durable, with about 40% of those patients remaining transfusion free at one year. Additionally, there was a robust rise in hemoglobin – a median of 2.55 grams per deciliter reaching as high as 4.1 grams per deciliter in luspatercept patients achieving RBC transfusion independence.
A key secondary endpoint was erythroid hematologic improvement, which was defined by a 4 unit or greater reduction in red blood cell transfusion needs over 8 weeks, or a 1.5 gram per deciliter rise in hemoglobin for those patients with a lower transfusion burden. Overall, erythroid improvement was achieved in 52.9% in patients on the luspatercept arm, compared 11.8% receiving placebo. The safety profile of luspatercept was also quite favorable with no significant differences in treatment-emergent AEs.
MedicalResearch.com: What should readers take away from your report?
Response: This study tells us that we have a new, potentially effective strategy for people with lower-risk Myelodysplastic Syndromes with ring sideroblasts who are transfusion dependent. We’ve observed that luspatercept has potentially long-lasting responses in these patients with a favorable safety profile. We also found that serum ferritin levels declined in luspatercept-treated patients over time, whereas they continued to rise on the placebo arm. This has the potential to not only impact the quality of life for these patients but also decrease the risk of iron loading over time.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: One of the encouraging parts of this study was that among the two most important determinants of response to ESAs – i.e., transfusion load and serum erythropoietin level – patients who responded to luspatercept responded across all levels of serum erythropoietin, suggesting that this agent may whave greater activity in the upfront setting compared to ESA treatment. That is the subject of the next phase three COMMANDS trial.
Disclosures: – I chaired the steering committee for the study.
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
Pierre Fenaux, MD, PhD1, Uwe Platzbecker, MD2, Ghulam J. Mufti3*, Guillermo Garcia-Manero, MD4, Rena Buckstein, MD, FRCPC5, Valeria Santini6, María Díez-Campelo7*, Carlo Finelli, MD8*, Mario Cazzola9, Osman Ilhan, MD10*, Mikkael A. Sekeres, MD, MS11, José F. Falantes12*, Beatriz Arrizabalaga, MD. PhD13*, Flavia Salvi14*, Valentina Giai14*, Paresh Vyas, MRCP FRCP FRCPath15, David Bowen, MD16, Dominik Selleslag, MD17*, Amy E. DeZern, MD18, Joseph G. Jurcic, MD19, Ulrich Germing, MD20*, Katharina S. Götze, MD21, Bruno Quesnel22, Odile Beyne-Rauzy23*, Thomas Cluzeau, MD, PhD24*, Maria Teresa Voso25, Dominiek Mazure26*, Edo Vellenga27, Peter L Greenberg, M.D.28, Eva Hellstrom Lindberg, MD, PhD29, Amer M. Zeidan, MBBS, MHS30*, Abderrahmane Laadem, MD31, Aziz Benzohra32*, Jennie Zhang31*, Anita Rampersad31*, Peter G. Linde33, Matthew L. Sherman33, Rami S. Komrokji, MD34 and Alan F. List, MD34
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