On April 3, 2020, luspatercept-aamt was approved in the treatment of anemia failing to respond to an erythropoiesis-stimulating agent and requiring 2 or more red blood cell (RBC) units over 8 weeks.^1,2 The treatment is geared toward adult patients with very low– to intermediate-risk myelodysplastic syndromes with ring sideroblasts (MDS-RS) or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T).

Luspatercept-aamt is not indicated for use as a substitute for RBC transfusions in patients who require immediate correction of anemia.

Supporting Efficacy Data

The current approval was based on findings in the double-blind, phase III MEDALIST trial (ClinicalTrials.gov identifier NCT02631070).³ In the trial, 229 patients with very low–, low-, or intermediate-risk MDS who had ring sideroblasts and required RBC transfusions (2 or more units over 8 weeks) were randomly assigned 2:1 to receive luspatercept-aamt (n = 153) or placebo (n = 76). The median age of study patients was 71 years; 63% were male, 69% were white.

Treatment was started at 1 mg/kg subcutaneously every 3 weeks; the dose could be increased after completion of the first two cycles if the patient had at least one RBC transfusion in the prior 6 weeks. Two dose level increases were allowed, to 1.33 mg/kg and to 1.75 mg/kg. The median durations of treatment were 49 weeks in the luspatercept-aamt group and 24 weeks in the placebo group. The primary efficacy endpoint in MDS-RS and MDS/MPN-RS-T was the proportion of patients who were RBC-transfusion independent (RBC-TI), defined as the absence of any RBC transfusion during any consecutive 8-week period between weeks 1 and 24.

RBC-TI for at least 8 weeks was achieved in 58 of 153 patients (37.9%) in the luspatercept-aamt group vs 10 of 76 patients (13.2%) in the placebo group (treatment difference = 24.6%, P < .0001). RBC-TI for at least 12 weeks during weeks 1 to 24 was achieved by 28.1% in the luspatercept-aamt group vs 7.9% (P = .0002). RBC-TI for at least 12 weeks during weeks 1 to 48 was achieved by 33.3% vs 11.8% (P = .0003).

How It Works

Luspatercept-aamt is a recombinant fusion protein that binds several endogenous transforming growth factor-β superfamily ligands, thus reducing Smad2/3 signaling. Luspatercept-aamt promoted erythroid maturation through differentiation of late-stage erythroid precursors (normoblasts) in mice. In models of β-thalassemia and MDS, luspatercept-aamt decreased abnormally elevated Smad2/3 signaling and improved hematology parameters associated with ineffective erythropoiesis in mice.

How It Is Used

The recommended starting dose of luspatercept-aamt in the current indication is 1 mg/kg once every 3 weeks via subcutaneous injection. Patient hemoglobin and transfusion history should be reviewed prior to each dose.

Prescribing information provides detailed instructions for dose titration, including increases to 1.33 mg/kg every 3 weeks and to 1.75 mg/kg every 3 weeks, based on hemoglobin response. Treatment should be discontinued if there is no reduction in RBC transfusion burden after at least three consecutive doses at 1.75 mg/kg.

Detailed instructions are provided for dose interruption and reduction if predose hemoglobin is at least 11.5 g/dL in the absence of transfusion or if there is an increase in hemoglobin > 2 g/dL within 3 weeks in the absence of transfusion. Depending on the current dose under these conditions, doses should be reduced to 1.0, 0.8, or 0.6 mg/kg. Treatment should be discontinued if there is an increase in hemoglobin > 2 g/dL within 3 weeks at a dose of 0.6 mg/kg.

Treatment should be discontinued for grade 3 or 4 hypersensitivity reactions. Treatment should be interrupted for other grade 3 or 4 adverse reactions and may be continued at the next lowest dose level upon resolution to no higher than grade 1 severity. Treatment should be discontinued if the dose delay is > 12 consecutive weeks.

Safety Profile

The most common adverse events of any grade (> 10%) observed in 242 patients with MDS-RS (n = 192) or other myeloid neoplasms (n = 50) who received luspatercept-aamt at the recommended dose and schedule included fatigue, musculoskeletal pain, dizziness, diarrhea, nausea, hypersensitivity reactions, hypertension, headache, upper respiratory tract infection, bronchitis, and urinary tract infection. The most common (> 2%) grade ≥ 3 adverse events included fatigue, hypertension, syncope, and musculoskeletal pain. Adverse events led to dose reduction in 7 patients (2.9%), to permanent treatment discontinuation in 11 patients (4.5%), and to death in 5 patients (2.1%). Laboratory abnormalities that changed from grade 0 or 1 at baseline to grade > 2 in at least 10% of patients included decreased creatinine clearance, increased total bilirubin, and increased alanine aminotransferase (ALT) levels.

In the MEDALIST trial, the most common adverse events of any grade (≥ 20%) in the luspatercept-aamt group were fatigue (41% vs 22% in placebo group) and musculoskeletal pain (20% vs 14%). The most common grade ≥ 3 adverse events were fatigue (7% vs 3%) and syncope/presyncope (3% vs 0%). Hypersensitivity reactions of any grade occurred in 10% vs 7% of patients, with one grade 3 event occurring in a patient in the luspatercept-aamt group.

Grade 2 to 4 laboratory abnormalities occurring through cycle 8 of treatment included decreased creatinine clearance in 27% vs 21%, elevated total bilirubin in 12% vs 5%, elevated ALT levels in 9% vs 7%, and elevated aspartate aminotransferase levels in 4% vs 0%.

Luspatercept-aamt has warnings/precautions for thrombosis/thromboembolism (increased risk in patients with beta-thalassemia), hypertension, and embryofetal toxicity. Across clinical studies of luspatercept-aamt, hypertension has been observed in 10.7% of patients. Blood pressure should be monitored during treatment. Patients should be advised not to breastfeed while receiving luspatercept-aamt. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves luspatercept-aamt for anemia in adults with MDS. Available at https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-luspatercept-aamt-anemia-adults-mds. Accessed April 21, 2020.

2. U.S. Food and Drug Administration: Highlights of prescribing information for Reblozyl (luspatercept-aamt) for injection, for subcutaneous use. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761136orig2lbl.pdf. Accessed April 21, 2020.

3. Fenaux P, Platzbecker U, Mufti GJ, et al: Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med 382:140-151, 2020.