COMMANDS Trial Demonstrates Benefit Across Mutations in RS-Positive LR-MDS

Yazan Madanat, MD

Associate Professor of Internal Medicine

Division of Hematology and Oncology

UT Southwestern Medical Center

Dallas, TX

KEY TAKEAWAYS FROM YAZAN MADANAT, MD

• The COMMANDS (NCT03682536) trial investigators selected a patient population where ESAs (erythropoiesis-stimulating agents) are known to be effective.
• Luspatercept (Reblozyl) met the primary end point of superior transfusion independence.
• The trend favoring luspatercept was seen in patients with nearly all common mutations, primarily benefiting those with ring sideroblasts (RS).

Targeted Oncology: Could you describe the patient population of the COMMANDS trial in low-risk myelodysplastic syndrome (LR-MDS)?

Yazan Madanat, MD: COMMANDS is a phase 3 clinical trial with a 1:1 randomization for using luspatercept or epoetin alfa weekly for patients who are 18 years of age or older with very low–, low-, or intermediate-risk MDS by the Revised International Prognosis Scoring System [R-IPSS]. The blasts had to be less than 5% in the bone marrow, but all the patients needed to have at least 2 units of blood transfusions in an 8-week period. That’s about 1 unit a month, so the patient [at baseline is] coming once a month and getting a unit of [red blood cells (RBCs)]. They capped the number of units to 6, because historically, luspatercept and ESA therapy do not work very well for patients with an extremely high transfusion burden. The endogenous serum EPO [erythropoietin] level had to be less than 500 U/L because patients with a higher EPO level should not be receiving ESA therapy, and they had to be ESA naive. The interim analysis [had a] cutoff of August 31, 2022.

Looking at the baseline characteristics…73% of patients receiving luspatercept were RS positive, and 72% of the epoetin alfa arm were RS positive. So [nearly] three quarters of patients on the COMMANDS study were in the RS-positive group. If we look at the mutations in SF3B1, those were about 63% on [the experimental] arm and 58% on the [comparator] arm.

The baseline characteristics of patients were classic for patients who have MDS with a median age of 74 for the whole population. The majority of patients had low-risk R-IPSS score. The serum EPO level was less than 100 U/L for the majority of patients, with a median of 84 U/L for the whole cohort. Eighty percent of patients [also] had a serum EPO level less than 200 U/L, and those with an EPO level of 200 to 500 U/L were about 20%. The majority of patients had less than 4 [RBC] units in an 8-week period, which are the patients [with what] we call low transfusion burden in general, needing 2 to 3 units in 2 months. Sixty percent of patients had a hemoglobin less than 8 g/dL at presentation, and most patients had normal platelet counts.

What were the efficacy outcomes of this study?

Coming to the RBC transfusion independence, if we look at the luspatercept vs the epoetin alfa in a 12-week period, it was statistically significant [P = .0002] for the primary end point, which was…an increase of hemoglobin of 1.5 g/dL or more with transfusion independence for 12 weeks. Both of these combined were the primary end point for the study. There was increase in RBC transfusion independence in the first 24 weeks, as well as an erythroid response [improvement].

Looking at the primary end point responder status by common genetic mutations, most of the mutations favor luspatercept including ASXL1, which historically is a bad actor in MDS, as well as SF3V1, TET2, and U2AF1 mutations. The only mutation that had a trend towards favoring epoetin alfa is the CBL mutation, which is quite uncommon in patients with MDS, and only 7 patients had it out of 170 in this trial.

How did the tolerability of luspatercept compare with that of epoetin alfa?

Looking at adverse events [AEs], fatigue tends to be one of the more common AEs from luspatercept at 15% vs 7% with epoetin alfa. However, grades 3 to 4 fatigue were 1% in each [arm], so most of the fatigue was grade 1 to 2, without a lot of grade 3 fatigue. Looking at gastrointestinal AEs, it was the same. If you look at grade 3 toxicities, the only one that stands out for me is the dyspnea, which is unexplained with luspatercept. We see it sometimes in about 5% of patients, where it can be problematic without any pulmonary embolism or thrombosis. Again, it is not a common thing, [at grade 3 or 4] in 4% of patients compared with 1% with epoetin alfa. Hypertension is also another more common AE with luspatercept in 13% of patients [vs 7% with epoetin alfa], so I advise all of my patients to check their blood pressure closely after they start. We're watching for a lot of those other AEs as well.

_Reference:

_{1. Platzbecker U, Della Porta MG, Santini V, et al. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial. Lancet. 2023;402(10399):373-385. doi:10.1016/S0140-6736(23)00874-7}