FDA Approves Luspatercept-aamt for First-Line Treatment of Anemia in Adults With Lower-Risk Myelodysplastic Syndromes

The FDA has granted approval to luspatercept-aamt (Reblozyl) as a first-line treatment for anemia in adults without previous administration of an erythropoiesis-stimulating agent (ESA) who have very low- to intermediate-risk myelodysplastic syndrome (MDS) and who may require regular red blood cell (RBC) transfusions. Luspatercept-aamt is a first-in-class therapy that was found to promote late-stage red blood cell maturation in clinical testing.

“For patients with lower-risk MDS, current standard therapies, including ESAs, have provided limited benefit in controlling anemia with only 1 in 3 patients responding for a duration of 6-18 months,” said lead investigator Guillermo Garcia-Manero, MD, chief of the Section of Myelodysplastic Syndromes at The University of Texas MD Anderson Cancer Center, in a press release. “Results from the COMMANDS study showed nearly twice as many patients treated with Reblozyl achieved transfusion independence of at least 12 weeks and concurrent hemoglobin increase compared to epoetin alfa. [The] approval represents an important advancement for patients with lower-risk MDS.”

The approval for the expanded indication of luspatercept-aamt in the first-line setting was based on interim results from the pivotal, open-label, randomized, phase 3 COMMANDS trial (NCT03682536). As of the cutoff date of August 31, 2022, a total of 356 patients were randomized, with 178 administered luspatercept-aamt versus 178 who received epoetin alfa.

The median age of patients in the trial was 74 years (interquartile range [IQR], 69-80), and 56% were male. The median transfusion burden in the 8 weeks before baseline was 3 units per 8 weeks (IQR, 2-4). Further, median endogenous serum erythropoietin at baseline was 84.5 U/L (IQR, 40.9-179.1), and median Hg concentration at baseline was 7.8 g/dL (IQR, 7-8). Of 355 evaluable patients, 73% had ring sideroblasts.

Luspatercept-aamt was administered subcutaneously once every 3 weeks, at a starting dose of 1.0 mg/kg, which could be increased to 1.33 mg/kg and then to 1.7 mg/kg maximum. Epoetin alfa was also administered subcutaneously once weekly, at a starting dose of 450 IU/kg, which could be increased to 787.5 IU/kg and then to 1050 IU/kg maximum. Patients were permitted to receive best supportive care in the form of transfusions, antivirals, antibiotics, and antifungals.

In the trial, luspatercept-aamt produced superior efficacy of concurrent RBC transfusion independence (RBC-TI) and hemoglobin (Hb) increase versus epoetin alfa, regardless of ring sideroblast status. The trial investigators said the results highlight the ability of luspatercept-aamt to treat chronic anemia earlier in a wider range of patients.

Key secondary endpoints in the trail included erythroid response (HI-E) of at least 8 weeks from weeks 1-24, RBC-TI ≥12 weeks, and RBC-TI for 24 weeks. At the time of the planned interim analysis on October 31, 2022, 147 evaluable patients were administered luspatercept-aamt and 154 evaluable patients were administered epoetin alfa, with median treatment durations of 41.6 and 27 weeks, respectively.

The results showed that 58.5% (n = 86) of patients administered luspatercept achieved the primary end point of RBC-TI of at least 12 weeks compared with 31.2% (n = 48) of patients administered epoetin alfa, with a mean Hb increase of at least 1.5 g/dL within the first 24 weeks (P <.0001). An HI-E increase of at least 8 weeks was observed in 74.1% (n=109) of patients in the luspatercept-aamt cohort compared with 51.3% (n=79) of patients in the epoetin alfa cohort (p<0.0001).

During the first 24 weeks of treatment, 47.6% (n=70) of patients in the luspatercept-aamt cohort achieved RBC-TI of at least 24 weeks compared with 29.2% (n=45) of patients in the epoetin alfa cohort (p=0.0012).

Further, 66.7% (n=98) of patients in the luspatercept-aamt cohort achieved RBC-TI of at least 12 weeks compared with 46.1% (n=71) of patients in the epoetin alfa cohort (p=0.0003).

Patients in the luspatercept-aamt cohort showed durable responses of nearly 2.5 years of median RBC-TI ≥12 weeks (126.6 weeks, week 1 to end of treatment). The most common (>10%) adverse events in the trial were diarrhea, fatigue, hypertension, peripheral edema, nausea, and dyspnea.

“The majority of patients with MDS experience chronic anemia and require RBC transfusions,” said Tracey Iraca, executive director, MDS Foundation, in a press release. “The approval of Reblozyl in the first-line treatment of anemia for patients with lower-risk MDS represents a crucial step in making transfusion independence possible for more patients.”

In November 2019, the FDA approved luspatercept-aamt for the treatment of anemia in adult patients with β-thalassemia who require regular RBC transfusions. In April 2020, the FDA approved luspatercept-aamt for the treatment of anemia failing an ESA and requiring 2 or more RBC units over 8 weeks in adults with very low- to intermediate-risk MDS with ring sideroblasts or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.

Reference

US FDA approves Bristol Myers Squibb's Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes who may require transfusions. News release. Bristol Myers Squibb. August 28, 2023. Accessed August 29, 2023.