Real-World Study Confirms Long-Term Efficacy, Safety of Darbepoetin Alfa for Anemia in MDS

A 10-year post-marketing surveillance study of darbepoetin alfa (NESP, Japan; Aranesp, US) in nearly 1900 Japanese patients with MDS-related anemia has confirmed the long-term safety and effectiveness of the erythropoiesis-stimulating agent across a broad real-world population, with no new safety or effectiveness concerns identified compared with prior clinical trials, according to findings published in the International Journal of Hematology.

The study followed patients for up to 5 years after initiating darbepoetin alfa, demonstrating meaningful improvements in hemoglobin levels, sustained reductions in red blood cell transfusion burden, and erythroid response rates comparable to those seen in the registration trial that supported the drug's approval in Japan. The data also confirmed that poor prognostic factors for survival align closely with established MDS risk stratification criteria, including IPSS risk category, age, chromosomal abnormalities, and pre-treatment platelet count.

Study Background and Design

Darbepoetin alfa received approval in Japan in 2014 for MDS-related anemia at a starting dose of 240 µg subcutaneously once weekly. The approval was supported by a small clinical trial of only 52 patients, leaving the long-term real-world picture incomplete. This post-marketing surveillance study (UMIN000056049), conducted between February 2015 and October 2024 across 460 sites in Japan, was designed to close that gap. After exclusions, the final safety and effectiveness analysis populations comprised 1834 and 1821 patients, respectively, with 5-year observation following treatment initiation.

Patient Characteristics

The study population reflected a typical real-world MDS population, with a median age of 79.0 years and 68.4% of patients aged 75 or older. The majority were male (61.9%). IPSS risk categories were Low in 39.3%, Intermediate-1 in 45.1%, Intermediate-2 in 7.7%, and High in 2.8% of patients. Most patients (63.9%) had prior MDS treatment history, with red blood cell transfusion the most common (50.7%). Chromosomal abnormalities were present in 36.1%.

Efficacy

Mean hemoglobin concentrations rose from a baseline of 7.6 g/dL to 8.3-8.9 g/dL during the first 48 weeks and continued to increase to 9.0-9.6 g/dL between weeks 52 and 260, reflecting durable improvement with long-term treatment. Among 909 transfusion-dependent patients, the proportion achieving transfusion independence increased progressively, reaching a peak of 40.9% at years 4 to 5. Among 911 transfusion-independent patients at baseline, approximately 60% maintained transfusion avoidance throughout the observation period.

Overall erythroid response rates were consistent with the registration trial. A minor response or greater was achieved by 65.2% of patients (vs 66.7% in the approval trial), and a major response—defined as transfusion independence for at least 56 consecutive days with an Hb increase of ≥1.0 g/dL from baseline—was achieved by 30.4% (vs 33.3%). The median time to achieving a minor response or greater was 2 days, and 16 days for a major response. Pre-treatment EPO concentration was predictive of response, with patients having EPO levels below 200 mIU/mL achieving the highest minor response or greater and major response rates (74.0% and 36.1%, respectively).

Five-year OS and LFS rates demonstrated a statistically significant gradient across IPSS risk categories (P <.0001). In the IPSS Low group, 5-year OS and LFS were 49.5% and 48.8%, respectively; Intermediate-1, 31.1% and 30.2%; Intermediate-2, 11.9% and 10.4%; and High-risk, 0% for both. Median OS was 57.86 months for Low, 33.43 months for Intermediate-1, 11.37 months for Intermediate-2, and 13.48 months for High-risk patients.

Chromosomal abnormalities were associated with significantly shorter survival compared with normal karyotype (median OS: 26.93 vs 45.49 months; P <.0001). Among karyotypic subgroups, del(20q) and -Y were associated with more favorable 5-year OS/LFS rates, while chromosome 7 abnormalities and complex karyotypes carried the worst outcomes (3.4%/2.6% and 7.0%/7.3%, respectively).

Achieving higher peak post-treatment Hb concentrations was associated with better survival. Patients reaching a peak Hb of ≥10 g/dL had a 5-year OS of 47.8%, compared with 18.5% for those with peak Hb below 8 g/dL (P <.0001). Patients without any erythroid response had significantly shorter median OS (16.48 months) and LFS (15.20 months) compared with major responders (45.30 and 44.44 months, respectively; P <.0001).

Safety

Adverse events were reported in 75.1% of patients and serious adverse events in 63.9%. The most common adverse events (≥5%) were pneumonia (16.6%), transformation to AML (9.0%), MDS progression (7.5%), cardiac failure (5.6%), and sepsis (5.3%). Adverse drug reactions were reported in 22.6% of patients, which was lower than the 34.6% rate reported at the time of approval. Fatal ADRs occurred in 7.7% of patients, with death (2.0%) and transformation to AML (1.6%) most common. Authors attributed fatal adverse drug reactions to underlying disease, advanced age, infection susceptibility, and comorbidities rather than to darbepoetin alfa specifically. No new safety signals were identified.

Prognostic Factor Analysis and Conclusions

Multivariable analyses identified 5 independent poor prognostic factors for both death and transformation to AML: higher IPSS risk, older age, chromosomal abnormalities, lower pretreatment platelet count, and a history or comorbidity of malignant tumors—consistent with broadly recognized MDS prognostic variables.

The authors conclude that the long-term real-world safety and effectiveness of darbepoetin alfa in MDS-related anemia are consistent with registration trial findings, and that achieving an erythroid response and maintaining higher hemoglobin concentrations remain clinically meaningful treatment goals.

REFERENCE

Morita Y, Tsuji Y, Yasukawa T, Mitani K. Darbepoetin alfa for the treatment of anemia in myelodysplastic syndromes: a post-marketing surveillance study in Japan. Int J Hematol. Published online May 18, 2026. doi:10.1007/s12185-026-04227-w