Luspatercept Lessens RBC Transfusion Burden in MDS
Results from the COMMANDS trial led the FDA to approve luspatercept for the treatment of anemia without prior erythropoiesis-stimulating agent use in adult patients with very low- to intermediate-risk MDS who may require regular red blood cell transfusions.
Guillermo Garcia-Manero, MD,
Luspatercept-aamt (Reblozyl) significantly controlled anemia for patients with myelodysplastic syndrome (MDS) who had not yet received an erythropoiesis-stimulating agent (ESA) and were red blood cell (RBC) transfusion dependent, according to findings from the phase 3 COMMANDS trial (NCT03682536) presented at the 11th Annual Society of Hematologic Oncology (SOHO) meeting.1
In the open-label study, 58.5% of patients who received luspatercept remained RBC transfusion independent (TI) for 12 weeks or more with concurrent mean hemoglobin increase of 1.5 g/dL or more, this was compared with 31.2% of those receiving the ESA epoetin alfa who achieved this end point (P < .0001). The median duration of RBC-TI was 126.6 weeks with luspatercept compared with 77.0 weeks with epoetin alfa (HR, 0.456; 95% CI, 0.260-0.798). Based on findings from the COMMANDS trial, on August 28, 2023, the FDA approved luspatercept for the treatment of anemia without prior ESA use in adult patients with very low- to intermediate-risk MDS who may require regular RBC transfusions.2
"We believe luspatercept provides clinical benefit regardless of subgroup and baseline mutation burden, and, therefore, we believe this now becomes the standard of care for the majority of our patients with lower-risk disease with anemia who are transfusion dependent," Guillermo Garcia-Manero, MD, COMMANDS trial lead investigator and chief of the Section of Myelodysplastic Syndromes at The University of Texas MD Anderson Cancer Center in Houston, said while presenting the results at SOHO. "We are basically giving our patients an extra year of being transfusion-free, which I think is quite significant."
The COMMANDS trial randomized 178 patients to receive luspatercept and 178 to receive epoetin alfa. Luspatercept was administered at 1.0 mg/kg subcutaneously every 3 weeks with a titration up to 1.75 mg/kg. Epoetin alfa was given at 450 IU/kg every week with a titration allowed up to 1050 IU/kg. Patient characteristics were well-balanced between the arms, except for ring sideroblast (RS) status, Garcia-Manero noted. In the luspatercept arm, 73% of patients were RS+ compared with 71.9% in the epoetin alfa group. SF3B1 mutations were seen in 62.4% of those in the luspatercept arm and for 55.6% in the epoetin alfa group.
In the luspatercept arm, the median age was 74 years (range, 46.0-93.0). The baseline transfusion burden was a median of 3 (range, 1-10), with 64% of patients having a burden of <4 packed RBC units. ISS risk was primarily very low or low for 79.8% of patients. At baseline, the median hemoglobin level was 7.8 g/dL and the platelet count was a median of 230 x 109/L. The baseline absolute neutrophil count was 2.5 x 109/L.
The median time to first RBC transfusions was 168.0 days with luspatercept compared with 42.0 days with the ESA. In the luspatercept arm, at 8 weeks or beyond, 74.1% of patients achieved a hematologic improvement in erythroid (HI-E) compared with 51.3% in the epoetin alfa group (P < .0001). Without the concurrent improvement in hemoglobin, the RBC-TI rate at 12 weeks or more with luspatercept was 66.7% compared with 46.1% with epoetin alfa (P = .0002). RBC-TI for 24 weeks or more occurred in 47.6% of patients treated with luspatercept compared with 29.2% with epoetin alfa (P = .0006).
In an exploratory analysis, it was found that high baseline mutational burden significantly impacted response seen with epoetin alfa (P = .016). This was not observed in the luspatercept arm (P = .56). Moreover, those harboring mutations in SF3B1, SF3B1alpha, ASXL1, and TET2 were more likely to have benefit with luspatercept compared with epoetin alfa. "This is quite intriguing and needs to be explored further," Garcia-Manero said.
In the RS phenotypes, the median duration of RBC-TI in the RS+ subgroup was 120.9 weeks with luspatercept compared with 47.0 weeks with epoetin alfa (HR, 0.626; 95% CI, 0.361-1.085). In the RS- group, the median was not yet estimable with luspatercept compared with 95.1 weeks with epoetin alfa (HR, 0.492; 0.148-1.638). "In the group of patients with RS- disease, there was a significant trend toward improvement in duration of response in those treated with luspatercept compared with those treated with an ESA," said Garcia-Manero.
Treatment was discontinued by 44% of patients in the luspatercept group and by 60% in the epoetin alfa arm. The most common cause of treatment discontinuation was lack of efficacy, as seen in 28 patients in the luspatercept arm and 57 in the epoetin alfa group. Death was a secondary cause, with 11 patients in each arm, followed by progressive disease, which was 7 patients in each arm. Adverse events (AEs) led to treatment discontinuation for 8 of those in the luspatercept arm compared with 4 of those in the epoetin alfa group. The exposure to luspatercept was roughly 2 times longer compared with epoetin alfa, Garcia-Manero noted, providing a longer reporting period for AEs.
The most common treatment-emergent AEs (TEAE) with luspatercept were fatigue (14.6%), diarrhea (14.6%), peripheral edema (12.9%), asthenia (12.4%), nausea (11.8%), dyspnea (11.8%), anemia (9.6%), thrombocytopenia (6.2%), and neutropenia (5.1%). The most common grade 3/4 TEAE with luspatercept was anemia (7.3%). A TEAE of any grade was experienced by 92.1% of patients in the luspatercept arm compared with 85.2% in the epoetin alfa arm.
"There is no signal in terms of safety that would differentiate luspatercept vs ESA in this first-line group of patients with lower-risk MDS," said Garcia-Manero. "This [study] is comparable with other studies of luspatercept."
Luspatercept received its first approval from the FDA in November 2019, as a treatment for patients with anemia caused by β-thalassemia. The label for the agent also carries other indications for the treatment of anemia in MDS and myeloproliferative neoplasms.
