Efficacy and Safety of Romiplostim in Patients with Aplastic Anemia Refractory to Immunosuppressive Therapy: 1-Year Interim Analysis of Phase 2 Clinical Trial

Objectives: Romiplostim (RMP) is a thrombopoietin mimetic protein that increases platelet production. RMP has already been approved in numerous countries for treatment of immune thrombocytopenia. However, the efficacy of RMP in aplastic anemia (AA) is still unclear. Therefore, we conducted this study to determine an optimal initial dose of RMP for the treatment of patients with AA refractory to immunosuppressive therapy (IST). We also evaluated the efficacy and safety of a 52-week treatment.

Methods: This study was a multicenter, randomized, open-label, parallel, comparative, dose-finding study in South Korea (NCT02094417). The subjects enrolled were patients with AA refractory to prior IST. The eligible patients were randomized to four treatment groups (1, 3, 6, or 10 μg/kg), and subcutaneously administered RMP once weekly for 8 weeks. After the 8-week treatment, the dose of RMP was adjusted from 1 to 20 μg/kg to maintain their platelet response. Patients who did not achieve a platelet response after the 8-week treatment with 20 μg/kg were withdrawn from the study. Platelet response was defined as 1) absolute increase of ≥20×10⁹/L above baseline or 2) increase ≥10×10⁹/L and by at least 100% from baseline. The bone marrow and cytogenetic analysis were performed prior to enrollment and every 6 months after treatment. The planned data collection was suspended after treatment week 52 in the middle of the trial. Total treatment period is 156 weeks (3 years).

Results: A total of 35 subjects were randomized into one of four treatment groups. The platelet count, hemoglobin concentration and absolute neutrophil count at baseline were similar between all treatment groups. The median age and time since last therapy with anti-thymocyte globlin (ATG) were 49 (28-76) years and 92 (7-267) months, respectively. Thirty-three patients completed the initial 8-week treatment while 18 completed the 52-week treatment. The primary endpoint, which was the platelet response rate after 8 weeks was 0% (0/7 subjects), 0% (0/7 subjects), 33.3% (3/9 subjects) and 70.0% (7/10 subjects) at 1, 3, 6 and 10 µg/kg, respectively, and it was dose-dependent.

By treatment week 8, the platelet, erythroid and neutrophil responses to 10 µg/kg at any time were 100.0% (10/10 subjects), 30.0% (3/10 subjects), and 60.0% (6/10 subjects), respectively. The bi-lineage responses at 10 µg/kg were the highest among all treatment groups.

By treatment week 52, 33.3% (11/33 subjects) achieved the tri-lineage response at least once, and 45.5% (15/33 subjects) went off their platelet transfusion at least once.

No dose-dependent adverse events (AEs) or dose-dependent drug-related AEs occurred during the 52-week treatment. Common AEs were upper respiratory tract infection, fatigue, transfusion reaction, myalgia, and dyspepsia. None of the patients developed clonal evolution or cytogenetic abnormalities. Finally, no neutralizing antibody was detected in any patient during the 52-week treatment.

Conclusion: These results demonstrate that RMP was effective and safe for patients with AA that was refractory to IST by 1 year. Based on the efficacy and safety results of the initial 8-week treatment, we recommend 10 μg/kg as an optimal initial dose for AA. Further clinical studies of RMP to confirm its efficacy in patients with AA are currently ongoing (NCT02773290).