FDA Approves Frontline Luspatercept for Anemia Related to Low-Risk MDS

The News

Luspatercept-aamt (Reblozyl) has been approved by the FDA for use in patients with lower-risk myelodysplastic syndrome (MDS) with anemia in the first line, according to a press release from the regulatory agency.¹

Expert Perspective

“[Luspatercept] is great for our patients with low-risk MDS who may not need chemotherapy or hypomethylating agent or transplant, but [whose] quality of life is impacted negatively because of the anemia. With luspatercept we will be able to [improve] hemoglobin, avoid anemia, fatigue, shortness of breath, and the reduction in quality of life,” Naval G. Daver, MD, associate professor in the Department of Leukemia at MD Anderson Cancer Center, said in a conversation with CancerNetwork^®.

Supporting Data

Results from the phase 3 COMMANDS trial (NCT03682536) were presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.² The trial analyzed the use of luspatercept vs epoetin alfa in patients who were erythropoiesis-stimulating agent (ESA)–naïve.

A total of 58.5% of patients achieved transfusion independence at 12 weeks in the luspatercept group compared with 31.2% in the epoetin alfa group (P <.0001).

"With luspatercept we will be able to [improve] hemoglobin, avoid anemia, fatigue, shortness of breath, and the reduction in quality of life," according to Naval G. Daver, MD, on the approval of luspatercept in the lower-risk MDS.

The median time to first RBC transfusion was 168.0 weeks in the luspatercept arm and 42.0 weeks in the epoetin alfa arm. The rate of hematologic-erythroid response at 8 weeks or more was 74.1% vs 51.3% (P <.0001), transfusion independence at 24 weeks was 47.6% vs 29.2% (P = .0006), and transfusion independence at 12 weeks was 66.7% vs 46.1% (P = .0002) in the luspatercept and epoetin alfa groups, respectively.

The median duration of transfusion independence at 12 weeks was 126.6 weeks (95% CI, 108.3-not eligible [NE]) in the luspatercept group and 77.0 weeks (95% CI, 39.0-NE) in the epoetin alfa group (hazard ratio [HR], 0.456; 95% CI, 0.260-0.798).

In patients who were ring sideroblast positive, the median duration of transfusion independence at 12 weeks was 120.9 weeks (95% CI, 76.4-NE) in the luspatercept group vs 47.0 (95% CI, 36.6-NE) in the epoetin alfa group (HR, 0.626; 95% CI, 0.361-1.085). For those who were ring sideroblast negative, the median duration of transfusion independence was NE (95% CI, 46.0-NE) in the luspatercept group and 95.1 weeks (95% CI, 35.3-NE) in the epoetin alfa group (HR, 0.492-0.148-1.638).

FDA/Pharma Perspective

“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,” Guillermo Garcia-Manero, MD, lead investigator and Chief of the Section of Myelodysplastic Syndromes at The University of Texas MD Anderson Cancer Center, said in the press release.¹ “Results from the COMMANDS study showed nearly twice as many patients treated with [luspatercept] achieved transfusion independence of at least 12 weeks and concurrent hemoglobin increase compared to epoetin alfa. Today’s approval represents an important advancement for patients with lower-risk MDS.”

Safety Information

Treatment discontinuation occurred in 43.8% of patients in the luspatercept group for reasons including lack of efficacy (15.7%), death (6.2%), adverse effects (AEs; 4.5%), or disease progression (3.9%). In the epoetin alfa arm, 59.7% of patients discontinued treatment because of lack of efficacy (32.4%), death (6.3%), disease progression (4.0%), or AEs (2.3%).

Common any-grade AEs included diarrhea, fatigue, hypertension, peripheral edema, nausea, and dyspnea. Grade 3/4 hematologic-related treatment-emergent AEs included anemia (7.3% vs 6.8%), thrombocytopenia (3.9% vs 0.6%), and neutropenia (3.9% vs 5.7%) in the luspatercept and epoetin alfa groups, respectively. The most common grade 3/4 TEAEs of interest in each respective arm were dyspnea (3.9% vs 1.1%), thromboembolic event (2.8% vs 0.6%), and diarrhea (1.1% vs 0.6%), respectively.

COMMANDS Trial Design

Patients were randomly assigned 1:1 to either the luspatercept group (n = 178), where they were given 1.0 mg/kg subcutaneously every 3 weeks with titration up to 1.75 mg/kg, or the epoetin alfa group (n = 178), in which they received 450 IU/kg subcutaneously weekly with titration up to 1050 IU/kg.

Patients had their responses assessed at day 169 and then every 24 weeks after. Treatment was halted due to a lack of clinical benefit or disease progression by International Working Group criteria. Patients were monitored for other malignancies, additional therapies, and survival for up to 5 years from the first dose or 3 years from the last dose.

Patients were eligible for treatment if they were 18 years or older, had a Revised International Prognostic Scoring System of very low-, low-, or intermediate-risk MDS with 5% or fewer blasts in the bone marrow. Additionally, patients needed to have had red blood cell (RBC) transfusions, endogenous serum erythropoiesis of 500 U/L or less, or be ESA naïve.

The primary end point was RBC-transfusion independence with a concurrent mean hemoglobin increase of 1.5 mg/dL or more. Secondary end points included hematologic-erythroid response at 8 weeks or more, RBC transfusion independence for 24 weeks, and RBC transfusion independence for longer than 12 weeks.

The median duration of treatment was 41.6 weeks in the luspatercept arm vs 27.0 weeks in the epoetin alfa arm. Additionally, 71.3% vs 67.0% of patients completed treatment at 24 weeks, 45.5% vs 32.4% completed treatment at 48 weeks, and 56.2% vs 40.3% were still on treatment at data cutoff in each respective arm.

Additionally, 70.2 vs 74.4% of patients in the luspatercept and epoetin alfa arms received 1 dose escalation or more, with the median time to first dose escalation of 45.0 weeks and 43.0 weeks, respectively.

Between the luspatercept and epoetin alfa groups, the median ages were 74.0 years vs 75.0 years, 39.9% vs 48.9% were female, the median time since MDS diagnosis was 8.02 months vs 5.17 months, and the median baseline transfusion burden was 3.0 packed RBC units vs 3.0 packed RBC units, respectively.

Investigators also highlighted the SF3B1 mutation status, in those with a mutation (62.4% vs 55.6%), no mutations (36.5% vs 40.4%), and missing mutations (1.1% vs 3.9%) in the experimental and control arms, respectively.

References

1. U.S. FDA approves Bristol Myers Squibb’s Reblozyl® (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes (MDS) who may require transfusions. News release. Bristol Myers Squibb. August 28, 2023. Accessed August 29, 2023. https://bit.ly/3qH7YEQ
2. Garcia-Manero G, Platzbecker U, Santini V, et al. Efficacy and safety results from the COMMANDS trial: A phase 3 study evaluating luspatercept vs epoetin alfa in erythropoiesis-stimulating agent (ESA)‑naive transfusion-dependent (TD) patients (pts) with lower‑risk myelodysplastic syndromes (LR-MDS). J Clin Oncol. 2023;41(suppl 16):7003. doi:10.1200/JCO.2023.41.16_suppl.7003