Luspatercept Provides Effective First-Line Alternative to ESAs in Lower-Risk MDS

Sunil Iyer, MD

The incorporation of luspatercept-aamt (Reblozyl) into the frontline treatment armamentarium for patients with lower-risk myelodysplastic syndrome (MDS) with anemia marks a pivotal advancement in the management of disease-related anemia, allowing for more individualized treatment decision-making, according to Sunil Iyer, MD.

On August 28, 2023, the FDA expanded the indication for luspatercept to include patients with low- to intermediate-risk MDS who are naive to erythropoiesis-stimulating agents (ESAs) and may require consistent red blood cell (RBC) transfusions. This regulatory decision was supported by interim findings from the phase 3 COMMANDS trial (NCT03682536), which met its primary end point of RBC transfusion independence (RBC-TI) with subcutaneous luspatercept vs epoetin alfa. Data showed that 58.5% (n = 86) of patients in the intention-to-treat population treated with luspatercept achieved RBC-TI of at least 12 weeks vs 31.2% (n = 48) of those given epoetin alfa, with a mean hemoglobin (Hb) increase of at least 1.5 g/dL within the first 24 weeks (P <.0001). 

“We have a lot more tools than we had before,” said Iyer following his participation in an OncLive® State of the Science Summit™on hematologic malignancies. “For patients with low-risk MDS and anemia, [we used to] start with ESAs for most patients, and you could consider luspatercept if [patients were to progress]. With the approval of luspatercept, we have [an alternative] for patients for whom we know that ESAs may not be as effective, and who may achieve better and more durable response by using luspatercept first.”

In an interview with OncLive, Iyer, who is an assistant professor of medicine at Columbia University Irving Medical Center in New York City, New York, highlighted the mechanism of action, efficacy, and safety data with luspatercept in the frontline treatment of anemia in patients with lower-risk MDS, as well as the clinical implications of the regulatory decision and its potential impact on treatment decision-making in this setting. Iyer expanded further on key research efforts and advancements in higher-risk MDS in a related interview.

OncLive: Please describe the mechanism of action of luspatercept. How does it allow for the agent to mitigate disease-related anemia in MDS?

Iyer: Traditionally, the medication class we’ve used for patients with lower-risk MDS with anemia who required transfusions were ESAs. [In MDS], you do see cytopenia, as well as ineffective erythropoiesis; this happens through signaling from a cytokine family called transforming growth factor-beta [TGFβ]. There are many of these ligands, such as activin and myostatin, that bind to a receptor on the RBC surface called the activin receptor. This leads to ineffective erythropoiesis because it is difficult for the RBCs to mature. Luspatercept is not a chemotherapy and it’s not an immunotherapy; it is a molecule that looks like the extracellular domain of the activin receptor. It acts as somewhat of a decoy, binding to all the TGFβ ligands that would normally bind to the RBC surface. Because they’re not binding to the receptor, [we see a] reduction in somatosensory signaling, and the RBCs are able to mature.

Please expand on the trial design of COMMANDS, as well as the patient population enrolled onto the study.

In 2020, luspatercept was approved [by the FDA under] a different indication. [The indication was] for [patients with] low-risk MDS with 15% or more ring sideroblasts [RS] or at least 5% RS in the presence of an SF3B1mutation who were disease refractory to an ESA. What’s unique about the COMMANDS study is that it tested luspatercept vs ESAs in patients with lower-risk MDS and anemia requiring transfusions who have not yet been treated with ESAs. This was a frontline study of luspatercept vs ESAs [rather than following] ESAs.

COMMANDS was a global, phase 3, open-label, randomized trial [that enrolled] adults with very low– to intermediate-risk [disease] by the Revised International Prognostic Scoring System. Patients had to have 5% or fewer blasts in the bone marrow, and they must have required RBC transfusions, defined as 2 to 6 units of packed RBCs for a minimum of 8 weeks right before randomization. The endogenous serum erythropoietin level had to be under 500 units per liter. This is because we know ESAs don’t work as well when the level is over 500, so this would have been an unfair comparison. These patients were all naive to ESAs.

What key efficacy findings were reported from the COMMANDS trial?

Patients were randomly assigned 1:1 to luspatercept vs epoetin alfa. Responses were assessed during the course [of treatment]. The primary outcome of the study was 12-week RBC-TI. This was met in 60.4% of patients getting luspatercept [at the time of the primary analysis], and only 34.8% of patients getting ESAs—so, luspatercept was superior. If you were to break [results] down by baseline transfusion burden, baseline serum erythropoietin level below or above 200, or SF3B1 mutational status, luspatercept was superior in all groups.

The one subgroup where there is something to think about is RS status. In the RS-positive group, [outcomes were] significantly superior, with 65% of patients [achieving RBC-TI] vs 29% of those in the ESA group. [However], numbers were comparable in the RS-negative group. Not shown in the presentation was that the duration of response [appears to be] longer with luspatercept [ vs ESAs in the RS-negative group], so it can be considered superior [to ESAs] in that sense.

What did the trial reveal about the safety profile of luspatercept in MDS?

Both drugs were quite safe. Many know the safety profile of ESAs and [types of] patients who tolerate them well. Sometimes there’s some fatigue, hypertension, peripheral edema, and a small thromboembolic risk. With luspatercept, [we also saw] fatigue and gastrointestinal adverse effects. There were many cases of COVID-19 in both groups; we don’t think this has to do directly with the other medications, but rather, the ongoing pandemic. There was weakness in both groups, but [we have to keep in mind that] these are transfusion-dependent, anemic patients. It’s hard to definitively say what’s due to a drug and what’s due to the condition being treated.

How has the approval of luspatercept impacted treatment decision-making and outcomes in this setting?

Luspatercept was superior to ESAs with regard to attaining 12-week RBC-TI in the frontline...In [this setting], we can now use either luspatercept or ESAs. [The choice between these options] might depend on the clinician or on the patient. For example, if the patient has lower serum erythropoietin level, you may want to try the ESA first knowing the safety profile. Then, you can always use luspatercept if ESAs don’t work. [However], if a patient has a higher serum erythropoietin level and you want to administer luspatercept first, [you can, as] it’s now approved for that indication.

Reference

US FDA approves Bristol Myers Squibb's Reblozyl (luspatercept-aamt) as first-line treatment of anemia in adults with lower-risk myelodysplastic syndromes who may require transfusions. News release. Bristol Myers Squibb. August 28, 2023. March 20, 2024. https://news.bms.com/news/details/2023/U.S.-FDA-Approves-Bristol-Myers-Squibbs-Reblozyl-luspatercept-aamt-as-First-Line-Treatment-of-Anemia-in-Adults-with-Lower-Risk-Myelodysplastic-Syndromes-MDS-Who-May-Require-Transfusions/default.aspx