Expert Point of View: Mrinal Patnaik, MBBS, and David P. Steensma, MD

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Mrinal S. Patnaik, MBBS, Associate Professor of Internal Medicine and Oncology and a consultant in hematology at the Mayo Clinic, Rochester, commented on the MEDALIST trial for The ASCO Post. “Given its unique mode of action, relative ease of administration, and excellent tolerability, luspatercept is an exciting modality to treat anemia in patients with myelodysplastic syndromes (MDS).”

Dr. Patnaik noted the significant morbidity and mortality among patients with lower-risk MDS and transfusion-dependent anemia. Erythropoietin-stimulating agents are a key treatment modality in these patients, but they are effective in a select group, he noted.

Published studies have shown that low transfusion dependence, a morphologic diagnosis of refractory anemia or refractory anemia with ring sideroblasts, the use of a fixed-dose vs weight-based erythropoietin regimen, a shorter time from diagnosis to starting treatment, and a lower serum erythropoietin level are predictive of response to erythropoietin-stimulating agents. In these patients, the response rate is approximately 50%, and the median duration of response is about 12 to 18 months.

Recurrent anemia after failure of an erythropoietin-stimulating agent or patients who are nonresponsive to or ineligible for erythropoietin-stimulating agents is often difficult to treat, with limited options being androgens, lenalidomide, or hypomethylating agents—drugs that are associated with side effects, including worsening cytopenias, he pointed out.

‘Revolutionizing’ Management of Anemia

“THE ADVENT of agents such as luspatercept and sotatercept, which bind to select transforming growth factor-І superfamily ligands such as GDF11 to reduce aberrant Smad2/3 signaling—thus enhancing the late stages of erythropoiesis—has revolutionized the management of anemia in MDS,” Dr. Patnaik said. “In the MEDALIST trial, 37.9% of patients on the luspatercept arm achieved the primary endpoint of red blood cell transfusion independence for 8 weeks, vs 13.2% in the placebo arm (P < .0001), and 28% achieved red blood cell transfusion independence for 12 weeks. These numbers are very hard to achieve with alternative strategies…. Future evaluations in additional MDS subtypes and other myeloid neoplasms, such as MDS/myeloproliferative neoplasm overlap syndromes, will be needed for broader applicability,” he added.

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David P. Steensma, MD, Associate Professor of Medicine at Harvard Medical School and Institute Physician at Dana-Farber Cancer Institute in Boston, moderated a press briefing about the MEDALIST trial at the ASH meeting.

Dr. Steensma said that the responses seen in the placebo arm “highlight a challenge in formally measuring clinical responses in MDS, given that the disease course and transfusion needs fluctuate. There is a proposed revision to the International Working Group response criteria that should help clarify this. Currently, it’s a challenge in some patients to assess true responses to a trial therapy.”

Potentially Useful Agent in MDS

However, Dr. Steensma agreed that luspatercept has the potential to become a useful agent in MDS, a malignancy for which little progress has been made in recent years. “Luspatercept is clearly an active drug, and its safety profile seems quite benign. This will be useful for those with ring sideroblasts, who constitute about 25% of patients overall but who are clearly overrepresented among the clinic population receiving transfusions, since they have quite significant anemia,” he said. “We’ll have to watch for cost-effectiveness, but it will help to have this new addition to our MDS treatment armamentarium.”

He added that luspatercept could become the first drug to be approved in MDS in 12 years.

DISCLOSURE: Dr. Patnaik’s institution has received funding from Stem Line Therapeutics. Dr. Steensma’s institution has received research funding from Celgene, Aprea, and H3 Biomedicine. Dr. Patnaik has received funds for data safety monitoring committee service from Onconova and Janssen.

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Luspatercept May Reduce the Need for Transfusion in Lower-Risk Myelodysplastic Syndromes

IN THE RANDOMIZED, double-blind, phase III MEDALIST trial, the experimental drug luspatercept significantly reduced the need for frequent red blood cell transfusions in patients with lower-risk myelodysplastic syndromes (MDS) and ring sideroblasts. With luspatercept, 37.8% of patients remained...