P777: efficacy and safety of romiplostim combined with cyclosporine a as a first-line treatment in patients with aplastic anemia: a phase 2/3 clinical trial.

Topic: 12. Bone marrow failure syndromes incl. PNH - Clinical Background: Romiplostim (Rom), a thrombopoietin receptor agonist (TPO-RA), has been shown to promote tri-lineage hematopoiesis in patients with acquired aplastic anemia (AA) refractory to immunosuppressive therapy (IST) or eltrombopag, another TPO-RA. Its effectiveness in combination therapy with cyclosporine (CsA) as a first-line treatment, however, remains unknown. Aims: IST is the mainstay of AA treatment. However, given tolerability of the key IST drug anti-thymocyte globulin (ATG), there are still unmet needs to develop effective therapeutics without ATG. To approach this issue, we conducted a phase 2/3 study to evaluate the efficacy and safety of Rom combined with CsA. Methods: A multi-national, open-label, phase 2/3 study with dose adjustment of Rom in combination with CsA was conducted with adult AA patients who were previously untreated with IST and transfusion dependent at institutes in Japan and Korea (NCT 04095936). Rom was started on day 1 at 10 µg/kg and subsequently given weekly for the first 4 weeks. The dose was adjusted from 5 to 20 µg/kg from Week 5. Treatment was continued until Week 26, when terminated. The primary endpoint was the hematological response rate (HRR) at Week 27 based on the response assessment criteria (Table 1). The secondary endpoints included the HRR at Week 14; the time to hematological response; and the proportion of patients achieving transfusion independence or reduced requirement. The morphologic and cytogenetic analyses of bone marrow cells were performed prior to the enrollment and at Week 27. Results: Thirty-one patients were screened, of which 24 (9 Japanese and 15 Korean; 7 platelet or red blood cell (RBC) transfusion dependent non-severe AA [NSAA], 13 severe AA [SAA], and 4 very severe AA [VSAA]) were enrolled. Two patients discontinued Rom before Week 26 due to adverse events (AEs) and the investigator’s decision. The median age was 52.0 years (range, 19-80). The HRR at Week 27 was 41.7% (10/24), of which 3 and 7 achieved CR and PR, respectively, with 57.1 % in NSAA, 46.2% in SAA, and 0 % in VSAA subjects. The HRR at Week14 was 29.2%. The median day to achieve the first hematological response was 92.0 (range, 31-133). Of 19 patients depending on platelet transfusion at baseline, 14 (73.7%) had decreased platelet transfusion requirements and 8 (42.1%) achieved platelet transfusion independence at Week 27. In addition, of 22 patients who depended on RBC transfusion at baseline, 15 (68.2%) had decreased RBC transfusion requirements and 9 (40.9%) achieved RBC transfusion independence at Week 27. The most frequently reported AE was nausea, observed in 7 subjects (29.2%). The drug-related AEs were nausea, abnormal liver function test, abnormal coagulation test, and dizziness, occurring in 1 (4.2%) of the 24 subjects. Of 22 patients who underwent bone marrow examination at Week 27, increased reticulin was observed in two patients (9.1%). Newly acquired chromosomal abnormalities not involving chromosome 7 were reported in 4 (16.7%) during the study, among whom transformation into MDS was observed in 1 (4.2%). Transformation into AML was not recorded. Summary/Conclusion: This is the first study of Rom combined with CsA in patients with acquired AA requiring transfusions who were previously untreated with IST. This ATG-free doublet regimen produced high HRR at Week 27 (41.7%), with manageable AEs, and could therefore serve as a new first-line treatment option in patients with AA depending on the severity and tolerability of ATG.Keywords: Thrombopoietin (TPO), Aplastic anemia, Bone marrow failure