Good Response Rate for New Anemia Drug in Patients with Myelodysplastic Syndromes

FDA approval may come in 2019

The majority of patients with myelodysplastic syndromes (MDS) have anemia and are often first treated with erythropoiesis-stimulating agents (ESAs).

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Only about 20 to 40 percent of MDS patients, however, respond to ESAs, and that response lasts for an average of only one year. Once those drugs stop working, MDS patients typically must receive red blood cell (RBC) transfusions.

Thus, there is a tremendous need for drugs for lower-risk MDS patients with anemia in whom ESAs either don’t work or have stopped working.

With this in mind, a team of international researchers recently conducted a phase 3 randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of the drug luspatercept in patients with very low-, low-, or Intermediate-risk MDS with ring sideroblasts. Ring sideroblasts are erythroblasts with iron deposits.

“There have been two earlier phase studies, one with luspatercept and one with its sister compound sotatercept, and we participated in one of those earlier studies,” said Mikkael Sekeres, MD, Hematology and Medical Oncology, Cleveland Clinic. He was a participating clinician in this new phase 3 study and recently presented the results at the 60th American Society of Hematology Annual Meeting.

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“In those earlier studies, we saw a response rate in patients with lower risk MDS that was between 40 and 50 percent,” says Dr. Sekeres. “In patients with lower risk MDS with ring sideroblasts, we saw an even higher response rate that approached 60 percent.”

Patients taking Luspatercept improved

In the phase 3 study, investigators randomized 229 international patients with lower-risk MDS who had ring sideroblasts to receive either luspatercept or a placebo. The researchers used a 2-1 allocation to randomize the patients.

“The patients were typical of those that we see in clinic with MDS in that their median age was 71 and they were dependent on red blood cell transfusions,” says Dr. Sekeres.

Of the 153 patients receiving luspatercept, 58 (37.9 percent) achieved the primary endpoint of red blood cell transfusion independence (RBC-TI) for ≥ 8 weeks compared with 10 of 76 patients (13.2 percent) receiving the placebo (odds ratio [OR] 5.1, P < 0.0001). Of those receiving luspatercept, 43 of 153 (28.1 percent) achieved the key secondary endpoint of RBC-TI for ≥ 12 weeks (weeks 1-24) compared with 6 of 76 (7.9 percent) receiving placebo (OR 5.1, P = 0.0002).

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Overall, patients receiving luspatercept were more likely to achieve a hematologic improvement-erythroid (mHI-E) response, which is defined as a reduction in transfusion of ≥ 4 RBC units/8 weeks or a mean hemoglobin increase of ≥ 1.5 g/dL/8 weeks in the absence of transfusions, compared with patients receiving placebo (52.9 percent vs 11.8 percent during weeks 1-24; P < 0.0001).

Targeted to patients with mutation

Earlier studies had shown that luspatercept was well tolerated by patients with most side effects deemed mild to moderate.

“This study shows that luspatercept is another potential therapy for lower-risk MDS patients with anemia that’s extremely well tolerated,” says Dr. Sekeres. “It will go before FDA for possible approval in 2019.”

He also pointed out that MDS patient with ring sideroblasts almost uniformly have an SF3B1 mutation — 90 percent of the patients in the phase 3 study had this mutation— and therefore if the FDA approves luspatercept, it would be targeted for parents with this specific mutation.