5 days ago
Luspatercept May Prolong Life in Low-Risk MDS
A new analysis from the COMMANDS trial of erythroid maturation agent luspatercept in patients with lower-risk myelodysplastic syndromes (MDS) shows not only sustained, longer-term benefits over epoetin alfa in providing significantly greater independence from transfusions but also, importantly, a promising trend in reducing disease progression and even improving survival.
'We're starting to see a very significant trend in terms of lower rate of transformation and an improvement in survival for patients treated with luspatercept vs epoetin alfa, and I believe this is the first example of this phenomenon ever reported in low risk MDS,' said first author Guillermo Garcia-Manero, MD, of the University of Texas MD Anderson Cancer Center, in Houston, in presenting the findings at American Society of Clinical Oncology (ASCO) 2025 in Chicago.
In previously reported primary results, the phase 3, global COMMANDS trial showed luspatercept to be the first therapy to have superiority over erythropoiesis-stimulating agents (ESAs) in transfusion-dependent lower-risk MDS.
The findings were especially important, as ESAs had for decades represented the first-line treatment for patients with lower-risk MDS. They were described as leading the way to a 'paradigm shift,' with luspatercept subsequently approved in the first-line and second-line treatment of patients with anemia and low-risk MDS.
For the new analysis, Garcia-Manero and colleagues reported the first results regarding longer-term duration of responses, safety, and survival of patients treated for more than 2.5 years.
In the study, patients in the luspatercept group (n = 182) received 1.0-1.75 mg/kg subcutaneously every 3 weeks, while those in the epoetin alfa arm (n = 181) received 50-1050 IU/kg, with a maximum dose of 80,000 IU, subcutaneously every week, for at least 24 weeks in both groups.
In the new analysis, with a median follow-up of 30.6 months in the luspatercept arm and 28.8 months in the epoetin alfa arm, patients treated with luspatercept vs epoetin alfa had a slower rate of disease progression, with just 2.2% vs 5.6% progressing to higher-risk MDS (hazard ratio [HR], 0.388).
While the difference was not significant ( P = .1003), 'what we see is a phenomenon that is emerging that is quite significant in that there is indeed a slower rate of progression in the luspatercept arm vs the epoetin alfa,' Garcia-Manero explained.
Of note, however, there was no significant difference between the groups in terms of progression to acute myeloid leukemia (4.9% vs 4.4%).
Long-Term Treatment Response
In terms of long-term treatment response outcomes, red blood cell transfusion independence of at least 12 weeks was achieved by 76.4% (139/182) of patients on luspatercept vs 55.8% (101/181) of those on epoetin alfa (odds ratio [OR], 2.8; P < .0001).
The median cumulative duration of transfusion independence through the end of treatment was 150.0 weeks for luspatercept and 95.1 weeks for epoetin alfa (HR, 0.52; P = .0011).
'The results basically show that patients receiving luspatercept are responding for almost a year longer vs the epoetin alfa,' Garcia-Manero noted.
Overall Survival
Median overall survival in the intention-to-treat population for luspatercept was not reached, while the rate was 46.7 months for epoetin alfa (HR, 0.86).
A regression analysis showed six deaths among 68 patients (8.8%) in the luspatercept arm vs 15 deaths among 55 patients (27.3%) in the epoetin alfa arm (HR, 0.330; P = .02).
Importantly, the survival curves begin to separate at 36 months — while the 3-year overall survival rates were 63.8% with luspatercept and 62.2% with epoetin alfa, by 5 years, the overall survival rates were 54.0% and 41.8%, respectively, in favor of luspatercept.
'This is very encouraging data suggesting that those patients treated on the luspatercept arm appear to have a longer longevity that those patients in the epoetin alfa arm,' Garcia-Manero said.
Furthermore, subgroup analysis of overall survival based on patient characteristics, including transfusion burden, ring sideroblast activity, and baseline serum erythropoietin (EPO) levels, showed survival favoring luspatercept in all groups.
'I think the data this [subanalysis] data is quite important because there have been some questions in terms of what should be the first-line agent to use in a patient with lower risk disease with a [higher] EPO level,' Garcia-Manero said.
'So if we're looking now looking at an intervention that may be changing the natural history of the disease, I think this is quite significant,' he said.
Mechanisms?
In terms of the mechanisms that might underlie improvements in survival, Garcia-Manero noted that 'there is emerging data that, for instance, [luspatercept] may modulate not only TGF [transforming growth factor] beta but some other innate immunity pathways that are very important for the behavior of the stem cell in MDS,' he explained.
'Furthermore, the [improved overall survival] may not be just mediated by the need for fewer transfusions or higher hemoglobin levels, but there may be actually some biology behind how these drugs work that could be changing natural history of patients with low-risk MDS,' Garcia-Manero said.
Findings Are 'Surprising'
Commenting on the study, Pamela Sung, MD, PhD, an assistant professor in the Departments of Medicine and Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, who co-moderated the ASCO session, underscored that the results were not anticipated.
'These findings are a surprise, as there has not been a previous study in low-risk MDS that has shown a potential survival benefit,' Sung said in an interview.
'The reason for this improvement is still under investigation as there were no differences between the groups for transformation to AML' — which may have logically explained differences in survival.
Of note, 'there was a clear split of the survival curves beginning at 3 years, which is encouraging that these results will hold with longer follow-up,' she added. The findings underscore that 'luspatercept has sustained responses in terms of RBC transfusion independence,' Sung said.
'Preliminary evidence suggests potential disease-modifying activity and survival benefit in low-risk MDS.'
Speaking from the audience, Steven Vogl, MD, an oncologist based in the Bronx, New York, speculated on the potential role of subsequent therapies used after failing on epoetin alfa as increasing deaths in that group.
'If patients fail erythropoietin, they may get more transfusions, and/or more treatment or therapies that can cause, for instance, iron overload,' he noted. 'And [that therapy], which was delayed in the luspatercept group, could have had toxicity and made patients weaker, potentially leading to [higher rates of] death in the epoetin alfa group.'
He added that while the cause of death can sometimes be hard to pin down in such studies, 'toxicity isn't so hard.'
Garcia-Manero responded, 'I totally agree. The mission for us is to start understanding this a little bit better,' he said. 'I don't think it is as simple as [the luspatercept group] just having fewer transfusions, but I may be wrong. The analysis is ongoing.'
The study was sponsored by Celgene and Acceleron Pharma.
