Luspatercept Provides Frontline Alternative to ESAs For Lower-Risk MDS and Anemia

September 21, 2023

Commentary

Article

Uwe Platzbecker, MD, discusses the efficacy and safety data from the COMMANDS trial that supported the approval, and the next steps planned for luspatercept’s investigation in patients with lower-risk MDS who are transfusion independent.

Uwe Platzbecker, MD

The recent FDA approval of luspatercept-aamt (Reblozyl) for patients with lower-risk myelodysplastic syndrome (MDS) with anemia provides an effective, if not superior, alternative to standard erythropoiesis-stimulating agents (ESAs), expanding a historically limited treatment armamentarium in the frontline setting, according to Uwe Platzbecker, MD.

On August 28, 2023, luspatercept received FDA approval for the treatment of anemia in patients with very low– to intermediate-risk MDSwho are ESA naïve and may require regular red blood cell (RBC) transfusions.¹ Findings from the phase 3 COMMANDS trial (NCT03682536) supported the regulatory decision.

RBC transfusion independence (RBC-TI) for at least 12 weeks with associated concurrent mean hemoglobin increase of at least 1.5 g/dL through weeks 1 to 24 was achieved by 58.5% (95% CI, 50.1%-66.6%) of those in the luspatercept arm (n = 147) vs 31.2% (95% CI, 24.0%-39.1%) with epoetin alfa (n = 154; common rate difference, 26.6%; 95% CI, 15.8%-37.4%; P < .0001).²

“[Luspatercept] is a game changer. For the first time, a novel drug has shown superiority compared with the first-line standard of care, epoetin alfa, in [patients with] lower-risk MDS,” said Platzbecker, who is the director of the Clinic and Polyclinic for Hematology, Cell Therapy and Hemostaseology at the Leipzig University Hospital, in Leipzig, Germany.

In an interview with OncLive®, Platzbecker discussed the efficacy and safety data from the COMMANDS trial that supported the approval and the next steps planned for luspatercept’s investigation in patients with lower-risk MDS who are transfusion independent.

OncLive: What unmet needs have historically existed for patients with MDS, and how might the approval of luspatercept address them?

Platzbecker: There are a couple of unmet medical needs. In general, there are 2 groups of patients [with unmet need]. The [first is patients with] so-called higher-risk MDS where the intention is to delay disease progression and to prevent leukemic evolution, which is not covered by the drugs currently available. In lower-risk MDS, where anemia and RBC transfusion dependency is the predominant phenotype, [the unmet need is] the prevention of transfusions or to get patients off transfusions if they are already transfusion dependent.

The armamentarium currently available for [patients with] lower-risk MDS, especially in the European Union, covers ESAs like epoetin alfa. [It also includes] luspatercept in a specific subset of patients with ring sideroblastic phenotype, who are not eligible or who are relapsed/refractory to a first-line therapy of epoetin alfa or other ESAs. That’s [all we have], apart from the small subset of del 5q patients where lenalidomide [Revlimid] is the standard of care. Especially in the first line, we only have ESAs for most patients, and we know that the minority of these patients respond and have a durable response. More agents are needed in [these lines].

Please describe the mechanism of action of luspatercept.

Luspatercept is a ligand trap. TGF-β cytokines, especially GDF8 or GDF11, are trapped by this drug. By doing so, the blockade on maturation and differentiation is released and terminal erythroid differentiation can take place in the bone marrow of patients with low-risk MDS, where the predominant feature is ineffective erythropoiesis. What these patients experience is an increase of reticular sites, hemoglobin levels, and RBC TI. This was the take-home message from the pivotal phase 2 study where patients had an erythroid irrespective of ring sideroblastic status, but those with the ring sideroblastic phenotype had a better response [vs] patients who were not ring sideroblastic.

What was the rationale for investigating this agent in patients with lower-risk MDS?

The rationale to develop the drug in the low-risk MDS group was based on the knowledge that there’s an altered signaling of TGF-β in the bone marrow and the bone marrow microenvironment. There was a mouse model, which nicely showed that luspatercept improves erythropoiesis. These preclinical data were [used to support subsequent] phase 2/3 programs.

Could you expand on the trial design of COMMANDS, as well as the patient population enrolled?

COMMANDS was a consecutive phase 3 trial based on the approval of luspatercept in ring sideroblastic patients [who progressed on] first-line ESA therapy. In the COMMANDS trial, a first-line approach was investigated. [The trial enrolled patients with] lower-risk MDS who were RBC transfusion dependent, naïve to luspatercept, and especially naïve to ESA therapy. These are the [patients for whom] we would try ESAs first.

The unique nature of the trial was that it not only [included] patients with the ring sideroblastic phenotype, but also those [without the] phenotype. Roughly two-thirds of the patients had a ring sideroblastic phenotype. The study was a head-to-head comparison to show the superiority of luspatercept [vs epoetin alfa] with regard to the primary end point [of] RBC TI for at least 12 weeks and an additional increment of hemoglobin levels by at least 1.5 g/dL. The study included a large number of patients with lower-risk MDS and was recently published in The Lancet.

What key efficacy findings were reported from the trial?

The results of the COMMANDS trial showed superiority [with luspatercept] with regard to the primary end point of TI. Also, the durability of TI was significantly longer in favor of luspatercept. This superiority in the entire population was primarily driven by patients with the ring sideroblastic phenotype. In the non–ring sideroblastic phenotype patients, response rates between epoetin alfa and luspatercept were [more] comparable, although the durability of response appeared to be significantly longer [in the luspatercept arm] compared with the epoetin alfa arm.

What should be known about the safety profile of luspatercept in this study?

The study showed the superiority of luspatercept vs ESA therapy, but not at the expense of any new safety signals. There was a signal with regard to fatigue and asthenia, which occurred in a higher proportion of patients in the luspatercept arm. [However, these toxicities] were not grade 3/4 for most cases. Beyond this, there were no new safety signals. Also, disease progression and other end points were not different with luspatercept.

Are there any next steps planned for research with luspatercept in low-risk MDS?

Research is ongoing with luspatercept. There is the recently started global phase 3 [ELEMENTS-MDS] trial [NCT05949684] examining luspatercept in a comparable patient population to the COMMANDS [study. It includes] patients [who have] lower-risk MDS [with or without] ring sideroblastic [phenotype], but this time, [the patients are] TI. It’s a head-to-head comparison of anemic patients with lower-risk MDS [treated with] luspatercept and epoetin alfa.

Editor’s Note: This interview was conducted prior to the FDA approval of luspatercept in patients with lower-risk MDS with anemia.