Long-term follow-up of patients with aplastic anemia enrolled in two phase 2/3 trials of immunosuppressive therapy plus romiplostim as a first-line treatment: Final report for up to 5 years

Abstract Background Results from two phase 2/3 clinical trials evaluating the safety and efficacy of immunosuppressive therapy (IST) plus romiplostim (ROMI) for IST-naïve patients with aplastic anemia (AA) have been previously reported: the 531-003 trial [rabbit anti-thymocyte globulin (ATG) plus cyclosporin (CsA) plus ROMI; NCT03957694] and the 531-004 trial [CsA plus ROMI; NCT04095936]). Although information on the long-term treatment outcomes is essential due to the chronic life-threatening nature of the disease, the long-term follow-up data on effectiveness and safety of ROMI treatment have been lacking after completion of 27 or 53 weeks in the two studies. Therefore, we conducted a multicenter prospective observational study up to 5 years after administration of romiplostim (531-005 study [NCT04870346]). We previously presented the results of a 2-year interim analysis for the 531-005 trial (Hosokawa et al. ASH 2024). Herein we report the final analysis result of the 531-005 study in the context of efficacy and safety of ROMI. Methods Patients who participated in the 531-003 and 531-004 trials and gave written informed consent to participate in this study were registered. After completion of each of the previous trials, treatment (including ROMI and CsA) was continued or discontinued at the discretion of individual physicians. Data were collected at least once every 6 months. The study period was from December 2019 to June 30, 2025. The primary endpoint was the hematological response (overall response rate [ORR]) up to 5 years after IST plus ROMI treatment in the 531-003 and 531-004 trials. Results Thirty-six patients were enrolled (531-003 trial, n = 15; 531-004 trial, n = 21). The median observation period was 4.1 years (range, 0.1-5.0 years): 4.5 years (range, 4.2-5.0 years) in the 531-003 trial, and 3.5 years (range 0.1-4.5 years) in the 531-004 trial. ORR at up to 5 years was 77.1% (95% confidence interval [CI], 59.9%–89.6%), and complete response (CR) and partial response (PR) rates were 40.0% and 37.1%, respectively. In the 531-003 and 531-004 trials, ORRs were 86.7% (95% CI, 59.5%–98.3%) and 70.0% ((95% CI, 45.7%–88.1%), respectively, and CR/PR rates were 53.3%/33.3% and 30.0%/40.0%, respectively. We previously reported the ORR at 2 years was 78.8%; 93.3% in the 531-003 trial and 66.7% in the 531-004 trial, revealing a sustained response with no clear difference compared to that at 2 years. The transfusion dependency rates for platelets and red blood cells were 83.3% and 94.4%, respectively, at baseline, improving to 9.4% and 13.9%, respectively, at the final observation point. Hematologic parameters (e.g. platelet count, hemoglobin concentration, neutrophil count, and reticulocyte count) remained stable throughout the observation period. New chromosomal abnormalities or transformation to acute myeloid leukemia (AML)/ myelodysplastic syndromes (MDS) have not been observed from week 27 until the final observation point. The survival rate at 5 years was 88.6% (95% CI, 72.5%-95.6%): 4 deaths were confirmed during the observation period (3 pneumonia,1 unknown). Of the 13 responders at the 27-week in the 531-003 trial, 11 patients discontinued ROMI during 531- 005 study period. Among the 11 patients who discontinued ROMI (response status at ROMI discontinuation: 7 CR and 4 PR), 6 patients sustained response CR/PR until the last observation point. Regarding relations between sustained CR/PR and response status at ROMI discontinuation, 71% (5 of 7) of patients who discontinued ROMI at CR state sustained response, whereas 25% (1 of 4) of patients discontinued ROMI at PR state sustained response. Of note, five patients with sustained CR/PR had been observed without ROMI and CsA,and achieved treatment-free remission. Summary/ConclusionA long-term follow-up study was conducted following the IST plus ROMI trials (531-003 trial and 531-004 trial) in IST-naïve adult patients with AA. The response rate at the final observation point was sustained and comparable to that at two years, and new chromosomal abnormalities or transformation to AML/MDS were not observed throughout the follow-up period in this study. In addition, a subset of patients achieved treatment-free remission with successful discontinuing of both ROMI and CsA. IST plus ROMI can be recommended as a first-line treatment option for IST-naïve patients with AA who are not eligible for transplantation