Luspatercept Promising Against Anemia in MDS

The results of a recent phase 2 trial demonstrate promising results of luspatercept in improving anemia in non–transfusion-dependent (NTD) patients with lower-risk myelodysplastic syndromes (LR-MDS). The study, published in International Journal of Hematology, was conducted across 16 clinical sites in Japan and included 21 patients, most 65 years and older, with symptomatic anemia and hemoglobin levels below 10.0 g/dL. The study evaluated the efficacy, safety, and pharmacokinetics of luspatercept in this patient population. ¹

The findings of the study show that "luspatercept resulted in statistically and clinically significant improvements in hemoglobin levels and may help delay the need for transfusions in NTD patients with LR-MDS."

Luspatercept, an erythroid maturation agent, promotes late-stage erythroblast expansion and differentiation, enhancing red blood cell production.² The study defined the primary end point as the percentage of patients achieving a hematological improvement-erythroid response, characterized by an increase in hemoglobin of at least 1.5 g/dL sustained for 8 weeks without requiring red blood cell transfusions during the first 24 weeks of treatment.

The study’s results show that at 24 weeks, 47.6% of patients achieved a hematological improvement-erythroid response, significantly surpassing the prespecified threshold of 10.0% (95% CI, 25.7%-70.2%; P < .0001). By 48 weeks, this rate increased to 57.1% (95% CI, 34.0%-78.2%), with 81.0% of participants remaining transfusion independent throughout treatment. Patients carrying the SF3B1 mutation, who were positive for ring sideroblasts, or who had max baseline erythropoietin (EPO) levels of 200 U/L demonstrated the highest response rates at 70.0%, 69.2%, and 57.1%, respectively. The median duration of hematological improvement-erythroid response was 35.4 (95% CI, 21.1-61.0) weeks.

In this analysis, the median half-life of luspatercept was 14.08 days, supporting the medication's administration once every 3 weeks. | Image Credit: © Sviatlana-stock.adobe.com

Luspatercept's efficacy was consistent across patient subgroups, including those with ring sideroblasts and SF3B1 mutations. These findings align with prior research, such as the MEDALIST (NCT02631070) and COMMANDS (NCT03682536) trials, which highlighted luspatercept's benefits in transfusion-dependent populations.^3,4 Collectively, these studies suggest that luspatercept may have a significant role in managing anemia across various populations of patients who have MDS.

"The [hematological improvement-erythroid] response in our trial was higher than the 14.7% response reported with darbepoetin-α in the ARCADE trial," the researchers highlighted, suggesting luspatercept as a viable alternative, especially for EPO-resistant cases.⁵

The safety profile of luspatercept was consistent with previous studies. Safety assessments show treatment-emergent adverse events (TEAEs) occurred in 33.3% of participants, with 14.3% experiencing grade 3 or 4 TEAEs. Hypertriglyceridemia, hyperuricemia, hypophosphatemia, and hypertension each occurred in 4.8% of patients each. The authors note there were no serious TEAEs, and no patients progressed to acute myeloid leukemia during the study.

A pharmacokinetics analysis revealed a median elimination half-life of 14.08 days, which is also consistent with earlier findings. This stability supports the administration of luspatercept once every 3 weeks. In this study, luspatercept was administered subcutaneously at a starting dosage of 1.0 mg/kg once every 3 weeks, with potential increases up to 1.75 mg/kg to maintain hemoglobin levels within a target range of 10 to 12 g/dL.

These findings are particularly relevant given the limited treatment options for NTD patients with LR-MDS. The ability to delay or prevent transfusion dependence is particularly significant for long-term outcomes in LR-MDS. Transfusion dependence is associated with reduced quality of life, increased risk of iron overload, and poorer overall survival.

"When begun early in the disease course, luspatercept may help to delay the need for [red blood cell] transfusions," the researchers note.

Although erythropoiesis-stimulating agents (ESAs) are the current standard of care for symptomatic anemia in patients who have LR-MDS with maximum serum erythropoietin of 500 U/L, primary resistance and loss of response to ESAs are common.⁶ Luspatercept, as an erythroid maturation agent, offers a novel mechanism of action that may provide an alternative for patients who do not respond adequately to ESAs.

Despite promising results, the study's small sample size and single-arm, open-label design may limit its generalizability. The ongoing ELEMENT trial (NCT05949684) will provide additional insights, particularly in comparing luspatercept with standard erythropoiesis-stimulating agents in similar patient populations.⁷

References

1. Kosugi H, Fujisaki T, Iwasaki H, et al. A phase 2 clinical trial of luspatercept in non-transfusion-dependent patients with myelodysplastic syndromes. Int J Hematol. Published online November 21, 2024. doi:10.1007/s12185-024-03872-3

2. Kubasch AS, Fenaux P, Platzbecker U. Development of luspatercept to treat ineffective erythropoiesis. Blood Adv. 2021;5(5):1565-1575. doi:10.1182/bloodadvances.2020002177

3. Platzbecker U, Della Porta MG, Santini V, et al. Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial. Lancet. 2023;402(10399):373-385. doi:10.1016/S0140-6736(23)00874-7

4. Fenaux P, Platzbecker U, Mufti GJ, et al. Luspatercept in patients with lower-risk myelodysplastic syndromes. N Engl J Med. 2020;382(2):140-151. doi:10.1056/NEJMoa1908892

5. Platzbecker U, Symeonidis A, Oliva EN, et al. A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes. Leukemia. 2017;31(9):1944-1950. doi:10.1038/leu.2017.192

6. Fenaux P, Haase D, Santini V, Sanz GF, Platzbecker U, Mey U; ESMO Guidelines Committee. Myelodysplastic syndromes: ESMO clinical practice guidelines for diagnosis, treatment, and follow-up. Ann Oncol. 2021;32(2):142-156. doi:10.1016/j.annonc.2020.11.002

7. ELEMENT-MDS: A study to compare the efficacy and safety of luspatercept in participants with myelodysplastic syndrome (MDS) and anemia not receiving blood transfusions (ELEMENT-MDS). ClinicalTrials.gov. 2023. Updated December 18, 2024. Accessed December 5, 2024. https://clinicaltrials.gov/study/NCT05949684