New Approach Leads to Transfusion Independence in Low-risk MDS

The investigational agent lustpatercept significantly lessens anemia severity and reduces or eliminates the need for transfusions in patients with low-risk myelodysplastic syndromes (MDS), a new phase 3 study has found.

The encouraging results support the prospect of a new, well-tolerated drug for MDS patients, who currently have few alternatives.

Chronic anemia is a critical issue in MDS patients, most of whom are elderly when diagnosed. In those patients’ bone marrow cells, signaling on the SMAD2/3 regulatory pathway is elevated, which inhibits maturation of red blood cells. Many MDS patients eventually require regular transfusions and face anemia-related complications such as heart disease, fractures and reduced survival.

“Over two-thirds of patients with myelodysplastic syndromes have some type of anemia,” says study co-author Mikkael Sekeres, MD, Cleveland Clinic Cancer Center’s Vice Chair for Clinical Research and Director of the Leukemia Program. “The most common initial therapy for those patients is to use an erythropoietin-stimulating agent such as recombinant humanized erythropoietin or darbepoetin. These agents work in about 20-40% of patients and, on average, for about a year. Once they stop working there are limited options available.”

Luspatercept is a recombinant fusion protein that aids erythroid maturation by reducing SMAD2/3 signaling. It was approved in 2019 for the treatment of anemia in adult patients with beta thalassemia, and also has shown promise in lower-risk MDS. A phase 2 study showed that 38% of luspatercept-treated patients had transfusion independence for 8 weeks or longer.

Recognizing the need for additional therapeutic approaches, Dr. Sekeres and his colleagues sought to further explore the potential of luspatercept among MDS patients.

Study details and key findings

Patients in this double-blind, placebo-controlled, phase 3 trial known as MEDALIST, which took place at Cleveland Clinic Cancer Center and 64 other institutions in 11 countries, were randomly assigned (2:1) to receive either luspatercept (n=153) or placebo (n=76), administered subcutaneously every three weeks for 24 weeks. Luspatercept was given at a dose of 1.0 mg-1.75 mg per kilogram of body weight.

Eligible patients included those with very-low-risk, low-risk, or intermediate-risk MDS with ring sideroblasts who had been receiving regular red blood cell transfusions. Additional criteria were that patients’ disease was refractory to, or unlikely to respond to, erythropoiesis-stimulating agents, or that they had discontinued these agents due to an adverse event.

Patients’ median age was 71 years (range 26-95), and 63% were men. In terms of their disease, 10% of the enrolled patients had MDS defined as very low risk, 72% low risk, and 17% intermediate risk.

The primary endpoint was transfusion independence for eight weeks or longer during weeks 1-24 of the trial, according to Dr. Sekeres. The key secondary objective was transfusion independence for 12 weeks or longer.

“Patients who received luspatercept were significantly more likely to achieve transfusion independence compared to those in the placebo group (38% vs. 13%),” says Dr. Sekeres, who is the primary investigator of the National MDS Natural History Study and chair of the expert panel preparing the American Society of Hematology’s clinical practice guidelines for treating older adults with acute myeloid leukemia. “The duration of transfusion independence lasted a median of about 31 weeks, with some people going a couple of years and longer without requiring a transfusion.”

Patients who were treated with luspatercept were more likely to reach the key secondary endpoint than those who received the placebo (28% vs. 8% for weeks 1-24, and 33% vs. 12% for weeks 1-48).

Fatigue (27%), diarrhea (22%), asthenia (20%), nausea (20%) and dizziness (20%) were the most commonly reported luspatercept-associated adverse events. Sixty-five patients (42%) in the luspatercept group had grade 3 or 4 adverse events compared to 34 (45%) in the placebo arm. Forty-eight patients (31%) who were treated with luspatercept had at least one serious adverse event versus 23 (30%) of those who received placebo.

In the luspatercept treatment arm, dose reductions due to adverse events occurred in seven patients (5%). Thirteen patients (8%) in the luspatercept group and six (8%) treated with placebo discontinued the regimen as a result of adverse events.

“Patients with lower-risk myelodysplastic syndromes with ring sideroblasts for whom erythropoiesis-stimulating agents are not effective or are not an option have limited treatment options available beyond continued transfusions,” the study authors concluded. “Luspatercept significantly reduced the transfusion burden in a substantial proportion of these patients and was associated with mainly low-grade toxic effects.”

A new hope for MDS

These findings suggest luspatercept can be added to the MDS arsenal, offering patients with few options a new approach.

“We haven’t had a drug approved specifically for MDS in 14 years,” Dr. Sekeres says. “It’s been a desert of treatment options for our patients and, typically, once our patients have exhausted erythropoiesis-stimulating agents, we move on to treat them with drugs that have a lot of side effects and limited efficacy because we don’t have many tools in our toolbox.

“[Luspatercept] would give us a really a nice option for another drug that has very few side effects,” he says. “While I would love a drug that works in 100% of my patients, the cold hard reality of treatments for MDS is that drugs tend to work for 20-40% of patients. This drug is closer to 40%, with a strong safety profile, making it a significant development for this patient population.”

Dr. Sekeres is designing a phase 1/2 study led by Cleveland Clinic Cancer Center that will evaluate the combination of luspatercept and another MDS drug to treat MDS-associated anemia.