Key Points:

• The randomized phase 3 COMMANDS trial compares the efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent–naive patients with transfusion-dependent, lower-risk myelodysplastic syndromes.
• Interim results showed that luspatercept increased hemoglobin levels and enabled nearly twice as many patients to avoid red blood cell transfusion during the first 24 weeks of the study when compared with epoetin alfa.
• Luspatercept benefits were particularly pronounced in patients with ringed sideroblasts or SF3B1 mutations.

Results of the phase 3 COMMANDS trial support the use of luspatercept in patients with transfusion-dependent, lower-risk myelodysplastic syndromes (MDS) as a well-tolerated, more effective alternative to epoetin alfa for the first-line management of anemia (Abstract 7003). The trial easily met the primary endpoint—at least a 12-week duration of red blood cell (RBC) transfusion independence in tandem with a mean hemoglobin increase ≥ 1.5 g/dL within the first 24 weeks of the study—as well as all secondary endpoints.

Among the 301 erythropoiesis-stimulating agent (ESA)–naive patients evaluated for efficacy in a prespecified interim analysis, 58.5% of patients who received luspatercept versus 31.2% of patients who received epoetin alfa achieved the primary endpoint (P < .0001). Other measures of hematologic improvement and transfusion independence also heavily favored luspatercept as opposed to epoetin alfa (Figure 1). Of note, the median time to the first RBC transfusion was 168 days for patients treated with luspatercept versus 42 days for patients treated with epoetin alfa. In addition, among the subset of patients who attained at least 12 weeks of RBC transfusion independence, the median duration of response was nearly 1 year longer with luspatercept versus epoetin alfa, at 2.43 years versus 1.48 years, respectively.

Figure 1. COMMANDS Secondary Endpoints: Luspatercept Superior to Epoetin Alfa

“Transfusions are a significant burden to our patients based on the time spent in transfusion units, the potential for infectious complications, iron accumulation, transfusion reactions that can be quite severe, and eventually failure to respond to the transfusions. In addition, transfusions have a significant economic impact,” commented Guillermo Garcia-Manero, MD, of The University of Texas MD Anderson Cancer Center, and the principal investigator of the COMMANDS trial.

“The COMMANDS results could transform how we approach the treatment of anemia in patients with lower-risk MDS. They suggest that luspatercept could represent the standard of care as first-line therapy for a significant fraction of patients with anemia and lower-risk disease,” Dr. Garcia-Manero said.

“The COMMANDS results could transform how we approach the treatment of anemia in patients with lower-risk MDS. They suggest that luspatercept could represent the standard of care as first-line therapy for a significant fraction of patients with anemia and lower-risk disease.” – Dr. Guillermo Garcia-Manero

Discussant Anand Ashwin Patel, MD, of the University of Chicago, agreed based on his assessment of the COMMANDS data.

“I believe that the findings of this trial establish luspatercept as the standard of care for ESA-naive, lower-risk MDS patients [who] do not have del(5q) with transfusion-dependent anemia,” he said.

Luspatercept Development

Luspatercept’s mechanism of action is thought to be completely independent from that of epoetin alfa, which is a recombinant human erythropoietin. Whereas epoetin alfa acts during early-stage erythropoiesis, luspatercept stimulates late-stage erythroblast differentiation and maturation in the bone marrow by binding to select ligands within the TGF-β superfamily to inhibit aberrant Smad2/3 signaling.

Luspatercept is already approved for use in patients with transfusion-dependent, lower-risk MDS with ringed sideroblasts or myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, but only after failure of an ESA. The COMMANDS trial specifically focused on first-line use of luspatercept in patients with transfusion-dependent, lower-risk MDS with or without ringed sideroblasts and with < 5% bone marrow blasts. To be eligible for the study, patients had to be ESA naive, have a serum epoetin level < 500 U/L, and require 2 to 6 RBC units over an 8-week period for ≥ 8 weeks immediately prior to treatment randomization.

Additional COMMANDS Data

Besides meeting the primary study endpoint in the overall population, nearly all patient subgroups showed an enhanced response to luspatercept versus epoetin alfa, particularly the subgroups with ringed sideroblasts or SF3B1 mutations (Figure 2).

Figure 2. COMMANDS: Achievement of Primary Endpoint in Different Patient Subgroups

“I think the open question in the management of lower-risk MDS with anemia pertaining to the COMMANDS trial is what the right therapy is for patients without ringed sideroblasts, as the epoetin alfa arm had slightly higher rates of achieving the primary endpoint within that subset,” Dr. Patel commented.

Treatment-emergent adverse events (AEs) did occur slightly more often among patients treated with luspatercept versus epoetin alfa (92.1% vs 85.2%). However, it is important to note that patients treated with luspatercept remained on the therapy much longer than those treated with epoetin alfa (median of 41.6 vs 27.0 weeks).

Dr. Patel described the toxicity profile of luspatercept as “quite reassuring,” given that heme-related grade 3/4 AEs and various grade 3/4 AEs of interest arose in no more than 8% of patients and occurred at rates similar to those observed with epoetin alfa. Moreover, only 8 of the 78 patients who discontinued luspatercept did so due to AEs. The rates of progression to high-risk MDS (2.8% vs 4.0%), progression to acute myeloid leukemia (2.2% vs 2.8%), and overall mortality (18.0% vs 18.2%) were also comparable between the luspatercept and epoetin alfa arms.

Implications for Clinical Use

With luspatercept poised to become a new first-line standard of care for transfusion-dependent, lower-risk MDS, questions emerge regarding how to sequence the growing number of agents available to treat anemia.

“For example, what is the right therapy for patients with del(5q) syndrome where lenalidomide is ineffective or there is progression of disease on lenalidomide? How do the data from the phase 3 IMerge trial of imetelstat fit into the treatment landscape of lower-risk MDS if luspatercept will be the preferred initial agent for a subset of patients with lower-risk MDS?” Dr. Patel asked.

— Kara Nyberg, PhD