Expansion of Luspatercept Indication Underscores Evolving Treatment Landscape for Low-Risk MDS

Although luspatercept-aamt (Reblozyl) is now indicated for the first-line treatment of anemia in all patients with low-risk myelodysplastic syndrome (MDS), further data could help inform treatment decisions for certain subgroups of patients, such as those without SF3B1 mutations, according to Benjamin Tomlinson, MD.

On August 28, 2023, the FDA approved luspatercept for the treatment of anemia without prior erythropoiesis-stimulating agent use in patients with very low- to intermediate-risk MDS who may require regular red blood cell (RBC) transfusions. The regulatory decision was supported by data from the phase 3 COMMANDS trial (NCT03682536).^1,2

Tomlinson shared his insights on luspatercept and other updates in MDS during a presentation at an OncLive^® State of the Science Summit™ on hematologic malignancies.

In an interview with OncLive, Tomlinson discussed the impact of the COMMANDS data and the integration of luspatercept into the frontline setting of low-risk MDS; highlighted other key studies in the low-risk MDS space; and detailed anticipated data for venetoclax (Venclexta) plus azacitidine (Vidaza) in patients with high-risk MDS. Tomlinson is the program director of Hematology and Oncology at University Hospitals, Cleveland Medical Center, and an assistant professor at the Case Western Reserve University School of Medicine in Ohio.

OncLive: What were some of the key topics you highlighted in your presentation on MDS?

Tomlinson: I discussed the results of the COMMANDS trial that led to the broader approval of luspatercept for [anemia in patients with] low-risk MDS. I discussed clinical data for an off-label use of eltrombopag [Promacta] that were encouraging, showing that it did not increase the risk for AML or progression of MDS, and was effective at improving platelet counts in [patients with] lower-risk MDS with severe thrombocytopenia.

Finally, I noted that the FDA approved ivosidenib [Tibsovo] for [adult patients with relapsed/refractory MDS with a susceptible IDH1 mutation]. Admittedly, the clinical data for that [approval from the phase 1 AG120-C-001 trial (NCT02074839)] were limited to a small number of patients. However, the outcomes in those [patients] were extremely impressive, including a handful of patients with remissions documented over 5 years in length, which is historically not something we typically see with that disease.

What key data were seen in the COMMANDS study?

It's important to note that COMMANDS was designed to be in an all-comers [population] of patients with MDS with some degree of transfusion dependence to assess the need for luspatercept. Notably, [61%] of the patients in that trial did have MDS with mutated SF3B1, or what was previously identified as MDS with ringed sideroblasts prior to the 2022 World Health Organization and International Consensus Classification updates. The data [for luspatercept] in the subset of patients [harboring SF3B1 mutations] were very strong.

There are still some questions regarding whether this trial [addressed] the use of luspatercept vs erythropoietin alfa for [patients with] all forms of lower-risk MDS, as response outcomes in those other subsets [of patients with non-mutated SF3B1 or ring sideroblasts–negative disease] didn't seem to be as beneficial. Yet, based on the study design, the FDA did grant approval for [first-line] luspatercept for [the treatment of anemia in patients with] all forms of lower-risk MDS.

What key data were seen with eltrombopag in the phase 2 EQoL-MDS trial (NCT02912208) for low-risk MDS and severe thrombocytopenia?

The most critical pieces of data [included] the rates of improvement of thrombocytopenia [demonstrated by increased platelet responses for eltrombopag vs placebo (42.3% vs 11.1%)]. Importantly, they also measured clinically significant bleeding events, and that was reduced with the use of eltrombopag [incidence rate ratio, 0.54; 95% CI, 0.38-0.75; P = .0002].³

Finally, what makes us as practitioners nervous with any myeloid growth factor in the setting of MDS is if it increases the risk of progression, and this was not observed. [AML evolution and/or disease progression occurred in 17% of patients in both the eltrombopag and placebo arms]. Overall, the data for EQoL-MDS would suggest that eltrombopag is both safe and effective for managing severe thrombocytopenia in [patients with low-risk MDS].

Are there data from any ongoing studies in MDS that you’re eager to see?

Venetoclax [plus azacitidine] has a breakthrough [therapy designation from the FDA] in [previously untreated, intermediate-, high-, and very high–risk MDS], but there is still the ongoing phase 3 VERONA study [NCT04401748]. We are awaiting those results, and [that trial] is comparing standard-of-care azacytidine [plus placebo] vs venetoclax given on days 1 through 14 in combination with azacytidine. We hope that this [study] may also prove the benefit of venetoclax in the MDS space and change the standard of care for higher-risk MDS.

References

1. 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 April 29, 2024.
2. Garcia-Manero G, Platzbecker U, Santini V et al. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive patients with transfusion-dependent lower-risk myelodysplastic syndromes: full analysis of the COMMANDS trial. Blood. 2023;142(suppl 1):193. doi:10.1182/blood-2023-178596
3. Oliva EN, Riva M, Niscola P, et al. Eltrombopag for low-risk myelodysplastic syndromes with thrombocytopenia: interim results of a phase II, randomized, placebo-controlled clinical trial (EQOL-MDS). J Clin Oncol. 2023;41(28):4486-4496. doi:10.1200/JCO.22.02699