Drug Reduces Need for Transfusions in Some Patients With Myelodysplastic Syndromes

By Gene Emery

January 10, 2020

(Reuters Health) - Therapy every 3 weeks with the drug luspatercept dramatically reduced the need for blood transfusions in a subset of patients with lower-risk myelodysplastic syndromes (MDS), according to results from the MEDALIST study reported in the Jan. 9 New England Journal of Medicine.

Of the 153 volunteers randomly assigned to receive the drug for 24 weeks, 38% achieved transfusion independence for 8 weeks or longer. The rate was 13% for the 76 patients assigned to the placebo group (P<0.001)

A similar pattern was seen when the trial stretched out to 48 weeks.

The findings apply to about 15% of MDS patients, specifically those with ring sideroblasts, said chief author Dr. Pierre Fenaux, director of the department of hematology and immunology at Hospital Saint-Louis in Paris, in email to Reuters Health.

The study was financed by Acceleron Pharma and Celgene, now a wholly-owned subsidiary of Bristol-Myers Squibb. BMS has asked the U.S. Food and Drug Administration to approve the drug, sold under the brand name Reblozyl, to treat anemia in adults who require red blood cell transfusions for their very low- to intermediate-risk MDS and who have ring sideroblasts. Acceleron employees approved the final report of the study's findings.

"The results from this study are exciting, as providing a well-tolerated treatment option that improves anemia and reduces transfusion burden can increase the quality of life and decrease complications such as iron overload in these patients," Dr. Meagan Jacoby, an assistant professor of medicine in the division of oncology at Washington University Medical School in St. Louis, Missouri, told Reuters Health in an email. She was not involved in the study.

"The MEDALIST trial may also pave the way for the first newly approved drug for MDS in over a decade," she said.

Luspatercept is already approved for adults with beta thalassemia who regularly need red cell transfusions.

The price of the drug depends on a person's weight. At the doses used in the study, the treatment would cost $187,000 to $327,000 per year for a 170-pound patient, according to data on goodrx.com. In contrast, conventional therapy with darbepoetin alfa costs about $122,000 per year and therapy with epogen alfa, another erythropoiesis-stimulating agent (ESA), would cost about $55,000 per year for a weekly 60,000-unit treatment.

Luspatercept was not compared to such conventional therapy. All of the patients either had disease that was refractory to such ESAs, were judged to be unlikely to respond to such agents, or had stopped using them because of their side effects. All had been receiving regular red-cell transfusions.

MDS affects 60,000 to 170,000 Americans, with 12,000 to 20,000 new cases each year. It is actually a group of closely-related but diverse blood cancers that originate in the bone marrow and prevent the marrow from making blood stem cells. Average survival time ranges from 5 months to 6 years, depending on severity.

The study was done on MDS patients who have ring sideroblasts, which are abnormal red blood cell precursors found in the bone marrow conspicuous for the granules of iron that form a ring around the nucleus. The marrow cells tend to have a mutation of the SF3B1 gene. It's the premature death of those cells before they multiply that luspatercept seems to inhibit. The result: more red blood cells.

Only about 15% of MDS patients have ring sideroblasts, so the new results are only expected to apply to that group, said Dr. Fenaux.

To meet the primary endpoint, a patient needed to be transfusion independent for 8 weeks, or longer during weeks 1 through 24.

Volunteers who were getting the fewest number of transfusions to begin with tended to do better on the drug. Eighty percent of patients who were getting fewer than 4 units every eight weeks had transfusion independence for at least 8 weeks. The rates were 37% among patients getting 4 to just under 6 units every 8 weeks, and 9% for those who had been getting at least 6 units every 8 weeks. (Placebo rates in these categories were 40%, 4% and 3%, respectively.)

When it came to being transfusion independent for 12 weeks, or longer for 48 weeks, which was a secondary endpoint, 33% of luspatercept recipients fell into that category versus 12% of placebo recipients.

Similarly, 28% of the luspatercept recipients were transfusion independent for 16 weeks versus 7% in the placebo group.

One volunteer went 30.6 weeks without needing a transfusion. In the placebo group, the longest time was 13.6 weeks.

The most common side effects seen at rates higher than in the placebo group were fatigue (seen in 27% of volunteers), diarrhea (22%), asthenia (20%), and nausea (20%). Headache, back pain, dyspnea and cough each occurred in at least 15% of patients.

The most common grade 3 side effects were fatigue (5%), asthenia (3%), and back pain (2%). Rates of 1% were seen for grade 3 nausea, headache, dyspnea, and bronchitis.

Few of the problems led to discontinuation of treatment.

Dr. Fenaux characterized the side effects as "very limited, like those of ESAs."

"We will obviously follow those patients with maintenance treatment to evaluate response duration," he wrote. "Treatment may be considered in higher risk patients, but probably in combination with other drug(s) rather than a single agent."

The study was done at 65 centers in 11 countries.

SOURCE: https://bit.ly/2QowUvx The New England Journal of Medicine, online January 8, 2020.