Luspatercept Broadens Lower-Risk MDS Treatment Landscape

Guillermo Garcia-Manero, MD

Luspatercept-aamt (Reblozyl) is a novel addition to the transfusion-dependent, lower-risk myelodysplastic syndrome (MDS)–associated anemia armamentarium, particularly for patients with ring sideroblastic disease, according to Guillermo Garcia-Manero, MD.

The phase 3 COMMANDS trial (NCT03682536) investigated luspatercept vs the erythropoiesis stimulating agent (ESA) epoetin alfa in ESA-naïve patients with transfusion-dependent, lower-risk MDS with anemia. The primary end point of this trial was red blood cell transfusion independence for at least 12 weeks with a concurrent mean hemoglobin increase of at least 1.5 g/dL within the first 24 weeks. In total, 58.5% of patients in the luspatercept arm achieved the primary end point vs 31.2% in the epoetin alfa arm (P < .0001), regardless of ring sideroblast status.1 The interim COMMANDS data supported the August 2023 FDA approval of frontline luspatercept for patients in this population.²

“This compound will be important in the community because now have in the front line a good drug for the treatment of patients with anemia,” Garcia-Manero said in an interview with OncLive® during the 2023 SOHO Annual Meeting.

In the interview, Garcia-Manero discussed key efficacy and safety findings from the COMMANDS trial; the significance of the FDA approval of luspatercept in patients with lower-risk MDS; and considerations for bringing this agent into clinical practice.

Garcia-Manero is a professor in the Department of Leukemia, chief of the Section of Myelodysplastic Syndromes, deputy chair of Translational Research, and fellowship program director in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, where he is also chair of the Faculty Senate.

OncLive: What are the implications of the FDA approval of luspatercept in patients with lower-risk MDS?

Garcia-Manero: [This approval is] significant because anemia and transfusion independency are major problems for patients with low-risk MDS. For as long as I remember, we only had 1 class of first-line agents, ESAs. They are great drugs that helped patients for many years, but we needed better compounds.

We developed luspatercept, [which received its] first indication in 2020 in the second-line setting in patients with ring sideroblastic anemia. Those data formed the basis for the randomized COMMANDS trial, published in Lancet Oncology in June 2023, where we randomly assigned [previously untreated], transfusion-dependent patients with low-risk MDS to either luspatercept or an ESA, in this case, epoetin alfa. The results are clear. [In the] intention-to-treat [ITT] population, responses [with luspatercept] were doubled, at 58.5% [vs] 31.2% [with epoetin alfa]. The duration of response [DOR] was 126.6 weeks [with luspatercept] with an excellent safety profile. We are excited.

What patient population did COMMANDS enroll?

This is a multicenter, multi-country trial. There were 178 patients enrolled in each arm, comparing luspatercept vs epoetin alfa. It was well balanced. There were more patients with ring sideroblastic anemia enrolled in the study; [73.0% and 71.9% of patients] were ring sideroblastic positive [in the luspatercept and epoetin alfa arms, respectively]. We don’t know why that happened. However, the data we have published [that were] presented at [the 2023 ASCO Annual Meeting and the 2023 EHA Congress] are on an ITT basis.

There is some question about the activity of this compound vs epoetin alfa in the ring sideroblastic–negative phenotype. The reality is that if you look at the data, the DOR is also longer in the ring sideroblastic–negative subset of patients. That, together with the schedule, toxicity profile, and so forth, [shows that] most patients with this disease will be treated with luspatercept, although one could argue [whether there is a drawback to] using an ESA in ring sideroblastic–negative disease in the front line as opposed to luspatercept, and the answer is no.

What safety considerations with luspatercept are important to note?

[Safety] is important because in low-risk MDS, where we’re trying to mitigate anemia, we don’t want to cause other problems, such as thrombocytopenia, neutropenia, infections, bleeding, and so forth. The COMMANDS trial, where we compared epoetin alfa vs luspatercept, showed a similar safety profile between those compounds, nothing that the community will not know, and there were no major differences between both drugs. There was no increased rate of transformation to high-risk MDS or acute leukemia.

Overall, [both are] well tolerated compounds. It’s important to reflect on the fact that in the United States, at least, we never had randomized studies for the approval of ESAs. The COMMANDS data also teach us about how those drugs behave in this context and the types of toxicities we see with those drugs. In general, these are easy, well-tolerated compounds.

How quickly may luspatercept be adopted in clinical practice, and will this agent become the standard of care for patients with lower-risk MDS?

It’s a new drug. The reality is, it’s already been approved for a couple of years in another indication, so the community is familiar with the drug already. However, on the other hand, we have had ESAs for a long time, and they’re part of our daily practice. It will be interesting to see how [the field will] shift from ESAs to luspatercept.

What is your main message for colleagues regarding advances in the MDS treatment paradigm?

[The presentations from SOHO show] quite a bit of progress. [In the] first line, [we have] luspatercept. [In the] second line, [we may have] the imetelstat compound. [There is also] the development of oral hypomethylating agents [HMAs] and better data with transplant. Furthermore, we are waiting [the results of] one of the last randomized trials in high-risk [MDS] with venetoclax [Venclexta] in combination with azacitidine [Vidaza]. If that is positive, we’re starting to check all the boxes. People are starting to talk about early intervention and maybe starting to [ask]: Can we cure some patients with this disease? We still have a problem of [disease progression in the] second line after HMAs, but we’ll get there.

References

1. Garcia-Manero G, Platzbecker U, Santini V, et al. Luspatercept versus epoetin alfa for treatment of anemia in patients with erythropoiesis-stimulating agent-naive lower-risk myelodysplastic syndromes requiring red blood cell transfusions: data from the phase 3 COMMANDS study. Presented at: 2023 SOHO Annual Meeting; September 6-9, 2023; Houston, TX.
2. 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. Accessed September 21, 2023. 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