Efficacy and Safety of Romiplostim in Patients with Acquired Aplastic Anemia Ineligible or Refractory to Immunosuppressive Therapy: Interim Analysis of Phase 2/3 Clinical Trial

Abstract Introduction: Romiplostim is a thrombopoietin mimetic protein that increases platelet production. Romiplostim has already been approved in numerous countries for treatment of immune thrombocytopenia. We previously reported a clinical trial to identify the dosage of romiplostim in aplastic anemia (AA) patients with thrombocytopenia refractory to immunosuppressive therapy (IST). Platelet, erythroid, and neutrophil responses were achieved at high rates with the initial dose at 10 μg/kg in the previous studies (Lee JW et al, ASH2016, 2017). Based on these findings, we conducted a Phase 2/3 clinical study in Japan and Korea for the purpose of evaluating the efficacy and safety of romiplostim in patients with AA who were ineligible or refractory to IST. This abstract shows the efficacy and safety results as of cut-off date (17 Nov 2017), which will be updated with 1-year follow-up result on the ASH2018 annual meeting. Methods: This study was a multi-center, open-label, intra-individual dose adjustment study in adult AA patients in Japan and Korea (NCT02773290). Patients with AA who were ineligible or refractory to IST and having thrombocytopenia with platelet count equal to or less than 30×109/L were enrolled in this study. The dosage of romiplostim was set at the initial level of 10 μg/kg and fixed for the first 4 weeks. The dose was adjusted from 5 to 20 μg/kg according to dose adjustment procedure. Patients who did not achieve a platelet response after the treatment with 20 μg/kg during 8 consecutive weeks were withdrawn from the study. The primary endpoint was the proportion of patients achieving a hematological response (any of the platelet, erythroid, and neutrophil response) at Week 27. Each response was defined as Table1. The secondary endpoints included the proportion of patients achieving hematological response at Week 53; and the time from the first romiplostim administration to hematological response; and the proportion of patients with transfusion independence or decreased platelet transfusion requirement among patients receiving platelet transfusion within 8 weeks prior to the first romiplostim administration. The bone marrow and cytogenetic analyses were performed prior to enrollment and every 6 months after treatment. Results: Of 46 patients with screening, a total of 31 patients (24 Japanese patients, and 7 Korean patients) were enrolled in this study. The median age was 46.0 years old (range: 20-78 years old). All patients had received at least 1 AA treatment, most of which were antithymocyte globulin (71.0%) and cyclosporin (96.8%). As of cut-off date (17 Nov 2017), 28 patients completed assessment of Week 27, and 18 patients completed assessment of Week 53. Three patients discontinued before Week 27, and 1 patient discontinued after Week 27 but before Week 53. In total (31 patients), 26 patients (83.9% [95% CI; 66.3%, 94.5%]) achieved any hematological response at Week 27. Eight patients (25.8%) achieved tri-lineage hematological response at Week 27. The median days to reach any hematological response were 37.0 [95% CI; 36.0, 44.0] days. Of the patients who depended on platelet transfusion before romiplostim administration (15 patients), 12 patients (80.0%) achieved transfusion independence or showed a reduction of transfusion requirements until Week 53. The frequently reported adverse events (AEs) were nasopharyngitis (38.7%) followed by upper respiratory tract infection (22.6%); pyrexia (19.4%); headache (16.1%); and diarrhoea (12.9%). The frequently reported drug-related AEs were headache (12.9%) followed by muscle spasms (9.7%); and alanine aminotransferase increased, fibrin D dimer increased, malaise, and pain in extremity (each 6.5%). In bone marrow test, 2 patients showed abnormality in karyotypes after romiplostim dosing. Monosomy 7 was shown at Week16 in 1 patient who had been receiving granulocyte-colony stimulating factor prior to the start of romiplostim. This patient did not show the transformation into acute myeloblastic leukemia and/or myelodysplastic syndrome. The other patient showed the gains of chromosomes 3, 4, 14, 16, 17, 19 and 21 at Week 27, but did not show any abnormality at Week 53. None of patient discontinued the study because of AE or karyotype abnormality. Conclusion: These results demonstrate that romiplostim is quite effective and well-tolerated in adult patients with AA ineligible or refractory to IST. Disclosures Tomiyama: Sysmex Corporation: Consultancy; Kyowa Hakko Kirin Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Novartis Pharma Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lee:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding. Miyazaki:Kyowa Hakko Kirin Co., Ltd.: Honoraria, Research Funding; Novartis Pharma Co., Ltd.: Honoraria. Usuki:Novartis: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Takeda Pharmaceutical: Speakers Bureau; Janssen Pharmaceutical K.K: Research Funding; Pfizer Japan: Research Funding, Speakers Bureau; Boehringer-Ingelheim Japan: Research Funding; Sumitomo Dainippon Pharma: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Celgene Corporation: Research Funding, Speakers Bureau; SymBio Pharmaceuticals Limited.: Research Funding; Shire Japan: Research Funding; Sanofi K.K.: Research Funding; GlaxoSmithKline K.K.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Nippon Shinyaku: Speakers Bureau; Mochida Pharmaceutical: Speakers Bureau; MSD K.K.: Speakers Bureau. Kizaki:Nippon Shinyaku,: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Speakers Bureau. Sawa:Celgene Corporation: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis International AG: Honoraria; CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria; Mundipharma K.K.: Honoraria. Yonemura:Alexion Pharma: Honoraria, Research Funding. Keta:Kyowa Hakko Kirin Co., Ltd.: Employment. Matsuda:Novartis Pharma K. K.: Honoraria; GlaxoSmithKline K.K.: Honoraria; Chugai Pharmaceutical Co, Ltd.: Honoraria; Kyowa Hakko Kirin Co, Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Celgene Corporation: Honoraria; Alexion Pharmaceuticals, Inc.: Honoraria; Sanofi K.K.: Honoraria; Beckman Coulter K.K.: Honoraria. Mitani:Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau; Bristol-Myesr Squibb: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Chugai: Research Funding; Astellas: Research Funding; Sumitomo Dainippon: Research Funding; Novartis: Research Funding; Toyama Chemical: Research Funding. Nakao:Novartis: Honoraria; Kyowa Hakko Kirin Co., Ltd.: Honoraria; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria.