Combination Therapy With Luspatercept and ESA Showed Promise in Participants With Difficult-to-Treat RS-Negative MDS

In the phase 1 Combala study, the combination of luspatercept and erythropoiesis-stimulating agents (ESAs) achieved meaningful erythroid responses in a challenging population of participants with ring sideroblast (RS)–negative lower-risk myelodysplastic syndrome (MDS) who had previously not responded to ESA therapy. This regimen may provide a new option for patients who do not respond to ESA therapy, balancing efficacy and safety.

“What treatment can we offer to lower-risk, RS-negative MDS patients who have failed ESA therapy?” stated Lionel Ades, MD, PhD, Hôpital Saint Louis, Paris, France, in his presentation. Ades and colleagues examined the safety and efficacy of combining luspatercept with ESA in participants with RS-negative MDS refractory to ESA treatment in the phase 1/2 Combala trial (NCT05181735).¹

This phase 1/2 trial included 24 participants across 10 French centers with low or intermediate-1 risk MDS in the International Prognostic Scoring System. All participants received escalating doses of luspatercept (0.8, 1.33, and 1.75 mg/kg subcutaneously every 21 days) combined with weekly epoetin alfa (30,000–60,000 IU). Participants had a median age of 77.7 years and were predominantly transfusion dependent.

The combination therapy of luspatercept and epoetin alfa demonstrated a favorable safety profile. Dose-limiting toxicities were not observed. Forty-five adverse events, including 16 serious events (grade >2), were reported, but none were associated with the treatment. Thirty percent of the participants presented with an erythroid response at week 25 and a median response duration of 9.2 months.

Ades et al identified the regimen of luspatercept 1.75 mg/kg every 21 days plus epoetin alfa 60,000 IU weekly as the recommended dose, which is currently being compared with luspatercept monotherapy in the ongoing randomized phase 2 part of the same Combala trial.

In conclusion, the combination of luspatercept and epoetin alfa offers a potential breakthrough for patients with non-RS MDS, who historically have limited options after ESA treatment failure. If validated in the ongoing phase 2 trial, this dual therapy approach could redefine the therapeutic strategy for patients with difficult-to-treat RS-negative MDS.

REFERENCES

Ades S, Cluzeau T, Comont T, et al. Combining ESA and luspatercept in non-RS MDS patients having failed ESA – results of the phase 1-2 part a of the GFM Combola Study. Abstract #351. Presented at the ASH Annual Meeting; December 7-10, 2024; San Diego, California.