KEY TAKEAWAYS
- The phase 3 COMMANDS trial compared the effectiveness and safety of luspatercept and epoetin alfa in treating anemia in ESA-naive LR-MDS patients.
- The study’s primary endpoint was to measure the percentage of patients achieving 12-week RBC transfusion independence with a concurrent 1.5 g/dL hemoglobin increase during weeks 1–24. Secondary objectives included assessing HI-E for 8 weeks and RBC-TI for 24 and 12 weeks during weeks 1–24.
Patients with low-risk myelodysplastic syndromes (LR-MDS) who need red blood cell (RBC) transfusions often face chronic anemia, increased morbidity, iron overload, and reduced overall survival. The current standard treatment using erythropoiesis-stimulating agents (ESAs) is not ideal because many patients (pts) are ineligible or have limited and temporary responses. There is a significant need for an effective treatment for anemia in LR-MDS. Luspatercept has been approved in the US and EU to address anemia in LR-MDS after ESA treatment failure, and up to this point, it has not been directly compared to ESAs in pts who are ESA-naive.
The phase 3, open-label, randomized COMMANDS trial aimed to present interim data on the effectiveness and safety of luspatercept compared to epoetin alfa in ESA-naive pts with LR-MDS.
Eligible pts were at least 18 years old, had serum erythropoietin (sEPO) levels below 500 U/L, and required RBC transfusions. Patients received subcutaneous luspatercept (1.0–1.75 mg/kg; every 3 weeks) or epoetin alfa (450–1050 IU/kg; weekly) for a minimum of 24 weeks. Patients were categorized based on their baseline RBC transfusion burden (<4 vs. ≥4 RBC units every 8 weeks), baseline sEPO levels (≤200 vs. >200 U/L), and Revised International Prognostic Scoring System (IPSS-R) status (RS+, RS−). The primary objective was the percentage of patients who achieved RBC transfusion independence (RBC-TI) for at least 12 weeks with a concurrent mean hemoglobin increase of at least 1.5 g/dL during weeks 1–24. Secondary endpoints included hematologic improvement-erythroid (HI-E) for at least 8 weeks, RBC-TI for at least 24 weeks, and RBC-TI for at least 12 weeks during weeks 1–24. The study also involved subgroup analyses, the impact of mutations in MDS-associated genes on the response, and safety.
A total of 178 pts were randomly assigned to receive luspatercept, and 178 received epoetin alfa (as of August 31, 2022). The median treatment durations were 41.6 and 27.0 weeks, respectively. Baseline characteristics were comparable among the two cohorts. The primary endpoint was achieved by 86 out of 147 (58.5%) luspatercept-treated patients and 48 out of 154 (31.2%) epoetin alfa-treated patients (P<0.0001). The achievement of the primary endpoint favored luspatercept or was similar to epoetin alfa across all subgroups.
Luspatercept treatment also favored the achievement of HI-E for at least 8 weeks, RBC-TI for at least 24 weeks, and RBC-TI for at least 12 weeks during weeks 1–24. The median duration of RBC-TI for at least 12 weeks (from week 1 until the end of treatment) was longer with luspatercept compared to epoetin alfa treatment overall (126.6 and 77.0 weeks, respectively) and for clinically relevant subgroups, encompassing RS+ and RS−.
Patients with mutations in SF3B1, SF3B1α, ASXL1, TET2, DNMT3A, EZH2, IDH2, and U2AF1 also showed a favorable response to luspatercept compared to epoetin alfa. Luspatercept-treated patients had a higher likelihood of experiencing clinical benefit, regardless of their overall mutational burden.
A total of 164 (92.1%) luspatercept-treated patients and 150 (85.2%) epoetin alfa-treated patients reported treatment-emergent adverse events (TEAEs) of any grade, with 8 (4.5%) and 4 (2.3%) patients discontinuing treatment due to TEAEs. The most common TEAEs (of any grade) with luspatercept were fatigue (14.6%), diarrhea (14.6%), and hypertension (12.9%), while those with epoetin alfa were asthenia (14.2%), diarrhea (11.4%), and anemia (9.7%). Most TEAEs in luspatercept-treated pts were mild to moderate, non-serious, and generally did not lead to treatment discontinuation. Four (2.2%) luspatercept-treated pts and 5 (2.8%) epoetin alfa-treated pts progressed to acute myeloid leukemia (AML), with overall death rates being similar between the two treatment arms (32 [18.0%] vs. 32 [18.2%], respectively).
Luspatercept demonstrated its superiority over epoetin alfa, showing clinically meaningful improvements in RBC-TI and HI-E rates in ESA-naive LR-MDS patients who require transfusions. Luspatercept also displayed more favorable outcomes than epoetin alfa across a range of known MDS mutations. The safety profile of luspatercept was consistent with previous reports. Moreover, no new safety concerns were identified. Luspatercept holds the potential to reshape the current landscape, setting a fresh benchmark in the treatment approach for ESA-naive pts with transfusion-dependent LR-MDS.
Clinical Trial: https://classic.clinicaltrials.gov/ct2/show/NCT03682536
Porta, M.G.D., Platzbecker, U., Santini, V., Zeidan, A.M., Fenaux, P., Komrokji, R.S., Shortt, J., Valcárcel, D., Jonášová, A., Dimicoli-Salazar, S., Tiong, I.S., Lin, C., Li, J., Zhang, J., Giuseppi, A.C., Kreitz, S., Pozharskaya, V., Keeperman, K.L., Rose, S., Shetty, J.K., Hayati, S., Vodala, S., Degulys, A., Paolini, S., Cluzeau, T., Garcia-Manero, G. LUSPATERCEPT VERSUS EPOETIN ALFA FOR TREATMENT (TX) OF ANEMIA IN ESA-NAIVE LOWER-RISK MYELODYSPLASTIC SYNDROMES (LR-MDS) PATIENTS (PTS) REQUIRING RBC TRANSFUSIONS: DATA FROM THE PHASE 3 COMMANDS STUDY. EHA Library. Della Porta M. 06/08/2023; 387802; S102
