Efficacy and Safety of Long-Term Romiplostim Use for Refractory Aplastic Anemia

Introduction: Aplastic anemia (AA) is a life-threatening bone marrow failure syndrome characterized by pancytopenia and hypocellular bone marrow caused by the destruction of hematopoietic stem cells by lymphocytes. About one-third of patients with severe AA who cannot undergo allogeneic hematopoietic stem cell transplantation from a matched sibling donor are refractory to single or repeated immunosuppressive therapy courses.

Romiplostim (ROMI), a thrombopoietin receptor agonist, signals and activates intracellular transcriptional pathways via the thrombopoietin receptor, resulting in stimulation of hematopoietic stem and progenitor cells. Our previous research, a phase II/III, multicenter, open-label interventional study, showed that ROMI induced the recovery of at least one lineage of blood cells in >80% of patients with refractory AA. However, data on the long-term efficacy and safety of ROMI in refractory AA beyond 52 weeks are scarce. Additionally, the pretreatment baseline factors of patients who achieve hematological response during treatment and maintain response after discontinuing ROMI are unclear. To address these issues, we report the results at the end of the extension phase (June 2020) of the aforementioned phase II/III study.

Methods: We conducted a long-term follow-up analysis of the efficacy and safety of ROMI 10 μg/kg administered subcutaneously once weekly for 4 weeks (Weeks 1-4), followed by 1-step titration to 5, 10, 15, and 20 μg/kg once weekly up to 52 weeks (Weeks 5-52) depending on platelet response. The extension study was started from Week 56 after a 4-week suspension period. The patients continued to receive the same dose of ROMI they received on Week 52 until its commercially available date for the treatment of AA in the study country or the end of June 2020 (end of the extension phase), whichever occurred first.

Results: Of the 31 patients enrolled in the phase II/III study, 27 completed the 53-week assessment. Twenty-five hematological responders (any cell lineage) and 2 non-responders entered the extension phase. ROMI was administered for 2 years in 23 patients, 3 years in 7 patients, and 3.5 years in 6 patients in this extension study. The median dose of ROMI was 20 μg/kg at Week 53, which was reduced to 15 μg/kg at 2 years, and 7.5 μg/kg at 3.5 years (Figure 1). Of the 2 non-responders, 1 patient showed platelet response at 2 years, which was sustained thereafter, while the other failed to respond by the end of the extension study at 103 weeks. Of the patients who failed to achieve the platelet (n=7) and erythrocyte (n=6) responses at 1 year, 3 (43%) and 1 (17%) showed responses at 2 years; the mean platelet count increased from 38.3 to 76.7 ×10⁹/L in the 3 platelet responders, and the hemoglobin level increased from 8.0 to 9.2 g/dL in the erythrocyte responder (Figure 2). Of the 23 patients who needed blood transfusions at baseline, 4 and 2 of them still required erythrocyte and platelet transfusions at 1 year, and 4 and 5 of them did so at 2 years, respectively. Five patients remained in response after discontinuing ROMI lasting 29-111 weeks even after discontinuing treatment. These 5 patients had relatively high baseline reticulocyte counts (45.8-93.8 ×10⁹/L, median 57.5 ×10⁹/L) compared with the remaining 22 patients (2.7-114.7 ×10⁹/L, median 46.5 ×10⁹/L).

The most common adverse drug reactions included headache (3 cases, 9.7%) and muscle spasms (2 cases, 6.5%); cytogenetic abnormality (-7) led to discontinuation of the study drug in 1 case. Two patients presented with chromosomal abnormalities of unknown significance, including 46,XX,t(11;17) at Week 108 and 46,XX,add(10) at Week 134. No transformation to acute myeloid leukemia or myelodysplastic syndromes occurred.

Conclusions: The up to 3.5-year follow-up study of ROMI administration in adult patients with refractory AA demonstrated its safety and efficacy during the extension period. The dose of ROMI was on a downward trend during the long-term follow-up. Nearly half the patients who did not achieve platelet or erythrocyte responses to ROMI at Week 52 eventually achieved responses by continuing the administration until the end of the study, demonstrating the efficacy of prolonged ROMI administration. High reticulocyte counts at ROMI initiation may predict achievement of response after discontinuing ROMI. Further studies with larger sample sizes should confirm these findings.

Mitani:Janssen Pharmaceutical K.K.: Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; Fujimoto Pharmaceutical Corp.: Speakers Bureau; Sanofi K.K.: Speakers Bureau; SymBio Pharmaceuticals Ltd.: Speakers Bureau; Amgen K.K.: Speakers Bureau; CSL Behring K.K.: Speakers Bureau; AstraZeneca K.K.: Speakers Bureau; Daiichi Sankyo Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Speakers Bureau; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding, Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Ono Pharmaceutical Co., Ltd.: Speakers Bureau; Alexion Pharmaceuticals, Inc.: Speakers Bureau; Bristol-Myers Squibb K.K.: Consultancy, Speakers Bureau; Kyowa Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Speakers Bureau; Novartis Pharma K.K.: Consultancy, Speakers Bureau; MSD K.K.: Speakers Bureau; Nippon Shinyaku Co., Ltd.: Research Funding, Speakers Bureau. Tomiyama:Chugai Pharmaceutical Co., Ltd.: Honoraria; UCB Japan Co. Ltd.: Honoraria; SobiTM Japan: Consultancy; Kyowa Kirin Co., Ltd.: Honoraria, Speakers Bureau; MEDICAL & BIOLOGICAL LABORATORIES CO., LTD.: Consultancy; Kissei Pharmaceutical Co., Ltd.: Consultancy; Novartis Pharma K.K.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sysmex Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Miyazaki:Kyowa Kirin Co., Ltd.: Research Funding, Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Daiichi Sankyo Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; MSD K.K.: Research Funding; Novartis Pharma K.K.: Speakers Bureau; Novo Nordisk Pharma Ltd.: Speakers Bureau; KM Biologics Co., Ltd.: Speakers Bureau; Nihon Pharmaceutical Co., Ltd.: Speakers Bureau; CSL Behring K.K.: Speakers Bureau. Usuki:Alexion Pharmaceuticals, Inc.: Consultancy, Research Funding, Speakers Bureau; SymBio Pharmaceuticals Ltd.: Consultancy, Research Funding; Nippon Shinyaku Co., Ltd.: Consultancy, Research Funding, Speakers Bureau; Otsuka Pharmaceutical Co., Ltd.: Consultancy, Research Funding, Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Consultancy, Research Funding, Speakers Bureau; Sanofi K.K.: Consultancy, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Consultancy, Research Funding, Speakers Bureau; Kyowa Kirin Co., Ltd.: Consultancy, Research Funding, Speakers Bureau; Astellas Pharma Inc.: Consultancy, Research Funding, Speakers Bureau; Alnylam Japan K.K.: Consultancy; Amgen K.K.: Research Funding; Apellis Pharmaceuticals, Inc.: Research Funding; Novartis Pharma K.K.: Research Funding, Speakers Bureau; AbbVie G.K.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Research Funding; Bristol-Myers Squibb K.K.: Research Funding, Speakers Bureau; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; MSD K.K.: Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Research Funding; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Incyte Biosciences Japan G.K.: Research Funding; Celgene K.K.: Research Funding, Speakers Bureau; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Mundipharma K.K.: Research Funding; Eisai Co., Ltd.: Research Funding, Speakers Bureau; Synbio Technologies LLC: Research Funding; PharmaEssentia Japan K.K.: Speakers Bureau; Yakult Honsha Co., Ltd.: Research Funding, Speakers Bureau. Uoshima:Bristol-Myers Squibb K.K.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria. Kosugi:BMS: Honoraria; Celgene KK: Honoraria; Chugai Pharmaceutical: Honoraria; Janssen: Honoraria; Japan Blood Products Organization: Honoraria; Kyowa-Kirin KK: Honoraria; MSD: Honoraria; Novartis Pharma KK: Honoraria; Ono Pharmaceutical: Honoraria; Sanofi: Honoraria; Takeda: Honoraria. Matsumura:Chugai Pharmaceutical Co., Ltd.: Research Funding; Kyowa Kirin Co., Ltd: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Daiichi Sankyo Co., Ltd.: Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding; Pfizer Japan Inc.: Research Funding, Speakers Bureau; SymBio Pharmaceuticals Ltd.: Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Research Funding; Mitsubishi Tanabe Pharma Corp.: Research Funding; Novartis Pharma KK: Research Funding, Speakers Bureau; Nippon Shinyaku Co., Ltd.: Research Funding; Eisai Co., Ltd: Research Funding; Asahi Kasei Pharma Corp.: Research Funding; AbbVie G.K.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K: Research Funding, Speakers Bureau; Taiho Pharmaceutical Co., Ltd.: Research Funding; Bristol-Myers Squibb K.K.: Speakers Bureau; Shionogi & Co., Ltd: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Consultancy, Research Funding, Speakers Bureau. Kizaki:Kyowa Kirin Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd.: Research Funding; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Research Funding; AbbVie G.K.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Speakers Bureau; Bristol-Myers Squibb K.K.: Speakers Bureau; Novartis Pharma K.K.: Speakers Bureau. Sawa:GSK plc.: Honoraria; Daiichi Sankyo Co., Ltd.: Honoraria; AstraZeneca K.K.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; SymBio Pharmaceuticals Ltd.: Honoraria; CSL Behring K.K.: Honoraria; AbbVie G.K.: Honoraria; Mundipharma K.K.: Honoraria; Shire plc: Honoraria; Mochida Pharmaceutical Co., Ltd.: Honoraria; Celgene K.K.: Honoraria; Sanofi K.K.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Eisai Co., Ltd.: Honoraria; Novartis Pharma K.K.: Honoraria; Asahi Kasei Pharma Corp.: Honoraria; Bristol-Myers Squibb K.K.: Honoraria; MSD K.K.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Pfizer Japan Inc.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria. Hidaka:Chugai Pharmaceutical Co., Ltd.: Honoraria; JCR Pharmaceuticals Co., Ltd.: Honoraria. Ichikawa:Meijiseika: Honoraria; AstraZeneca: Research Funding; Beigene: Research Funding. Yonemura:Alexion Pharmaceuticals, Inc.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Novartis Pharma K.K.: Honoraria. Murotani:Kyowa Kirin Co., Ltd.: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria; AstraZeneca K.K.: Honoraria; Taiho Pharmaceutical Co., Ltd.: Honoraria; MSD K.K.: Honoraria; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Yakult Pharmaceutical Industry Co., Ltd.: Honoraria. Shimizu:Kyowa Kirin Co., Ltd.: Current Employment. Matsuda:Kyowa Kirin Co., Ltd.: Consultancy; Alexion Pharmaceuticals, Inc.: Honoraria; Nippon Shinyaku Co., Ltd.: Honoraria; Novartis Pharma K.K.: Honoraria. Ozawa:Takara Bio Inc.: Consultancy; Human Life CORD Japan Inc.: Consultancy, Honoraria; Terumo Corporation: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Mitsubishi Tanabe Pharma Corp.: Honoraria; AbbVie G.K.: Honoraria; Novartis Pharma K.K.: Honoraria; Japan Agency for Medical Research and Development: Research Funding. Nakao:Novartis Pharma K.K.: Honoraria; SymBio Pharmaceuticals Ltd.: Consultancy; Alexion Pharmaceuticals, Inc.: Research Funding; Kyowa Kirin Co., Ltd.: Honoraria.