Efficacy and safety of romiplostim in refractory aplastic anaemia: a Phase II/III, multicentre, open-label study

Jun Ho Jang, Yoshiaki Tomiyama, Koji Miyazaki, Koji Nagafuji, Kensuke Usuki, Nobuhiko Uoshima, Tomoaki Fujisaki, Hiroshi Kosugi, Itaru Matsumura, Ko Sasaki, Masahiro Kizaki, Masashi Sawa, Michihiro Hidaka, Naoki Kobayashi, Satoshi Ichikawa, Yuji Yonemura, Kouki Enokitani, Akira Matsuda, Keiya Ozawa, Kinuko Mitani, Jong Wook Lee, Shinji Nakao, Jun Ho Jang, Yoshiaki Tomiyama, Koji Miyazaki, Koji Nagafuji, Kensuke Usuki, Nobuhiko Uoshima, Tomoaki Fujisaki, Hiroshi Kosugi, Itaru Matsumura, Ko Sasaki, Masahiro Kizaki, Masashi Sawa, Michihiro Hidaka, Naoki Kobayashi, Satoshi Ichikawa, Yuji Yonemura, Kouki Enokitani, Akira Matsuda, Keiya Ozawa, Kinuko Mitani, Jong Wook Lee, Shinji Nakao

Abstract

A previous dose-finding study has suggested that romiplostim is effective in patients with refractory aplastic anaemia (AA) and 10 µg/kg once weekly was recommended as a starting dose. In this Phase II/III, multicentre, open-label study, romiplostim was administered subcutaneously at a fixed dose of 10 µg/kg once weekly for 4 weeks (weeks 1-4) followed by weekly doses (5, 10, 15 and 20 µg/kg) titrated by platelet response for up to 52 weeks (weeks 5-52). A total of 31 patients with AA who were refractory to immunosuppressive therapy (IST) and thrombocytopenia (platelet count of ≤30 × 109 /l) were enrolled. The primary efficacy endpoint of the proportion of patients achieving any haematological (platelet, neutrophil and erythrocyte) response at week 27 was 84% [95% confidence interval (CI) 66-95%]. Trilineage response was 39% (95% CI 22-58%) at week 53. The most common treatment-related adverse events (AEs) were headache and muscle spasms (each 13%). All AEs were mild or moderate except for three patients with Grade 3 hepatic AEs; no AEs necessitated romiplostim discontinuation. Two patients developed cytogenetic abnormalities, of whom one returned to normal karyotype at last follow-up. High-dose romiplostim is effective and well tolerated in the treatment of patients with AA refractory to IST.

Keywords: aplastic anaemia; bone marrow failure; haematopoiesis; thrombopoietin.

Conflict of interest statement

Yoshiaki Tomiyama honoraria from Novartis Pharma K.K., Chugai Pharmaceutical Co., Ltd. and Kyowa Kirin Co., Ltd.; and advisory committee member for Novartis Pharma K.K. Koji Miyazaki honoraria from Kyowa Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Pfizer Japan, Inc., Novartis Pharma K.K., Novo Nordisk Pharma Ltd., KM Biologics, Nihon Pharmaceutical Co., Ltd. and CSL Behring K.K.; and research funding from Kyowa Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Pfizer Japan Inc., Daiichi Sankyo Co., Ltd., Astellas Pharma Inc., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd. and MSD K.K. Kensuke Usuki research funding from Astellas Pharma Inc., Alexion Pharmaceuticals, AbbVie GK, Gilead, SymBio Pharmaceuticals Ltd., Daiichi Sankyo Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Chugai Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Novartis Pharma K.K., Bristol‐Myers Squibb Company, Ono Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Celgene Corporation, Takeda Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Mundipharma K.K., Astellas‐Amgen‐Biopharma KK, Apellis Pharmaceuticals Inc, Nippon Shinyaku Co., Ltd., Kyowa Kirin Co., Ltd. and Pfizer Japan Inc.; and speakers bureaus for Novartis Pharma K.K., Alexion Pharmaceuticals, Eisai Co., Ltd., Ono Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., MSD K.K., Otsuka Pharmaceutical Co., Ltd., SymBio Pharmaceuticals Ltd., Celgene Corporation, Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., PharmaEssentia Corp., Bristol‐Myers Squibb Company and Yakult Honsha Co. Ltd. Hiroshi Kosugi honoraria from Chugai Pharmaceutical Co., Ltd., Celgene Corporation, Novartis Pharma K.K., Bioverativ Japan, MSD K.K., Takeda Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Japan Blood Products Organization, Bristol‐Myers Squibb Company and Ono Pharmaceutical Co., Ltd. Itaru Matsumura research funding from Kyowa Kirin Co., Ltd. Masahiro Kizaki research funding and speakers bureau from Bristol‐Myers Squibb Company, Celgene Corporation and Nippon Shinyaku Co., Ltd.; and speakers bureaus from Bristol‐Myers Squibb Company, Celgene Corporation, Nippon Shinyaku Co., Ltd. and Novartis Pharma K.K. Masashi Sawa honoraria from Celgene Corporation, Takeda Pharmaceutical Co., Ltd., Bristol‐Myers Squibb Company, Novartis International AG, Chugai Pharmaceutical Co., Ltd. and Mundipharma K.K. Michihiro Hidaka research funding from Chugai Pharmaceutical Co., Ltd. Yuji Yonemura honoraria Alexion Pharmaceuticals, Novartis Pharma K.K., Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd. and Japan Blood Products Organization; and research funding from Alexion Pharmaceuticals. Kouki Enokitani employed by Kyowa Kirin Co., Ltd. A.M. honoraria from GlaxoSmithKline K.K., Novartis Pharma K.K., Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Nippon Shinyaku Co., Ltd., Celgene Corporation, Alexion Pharmaceuticals, Sanofi K.K., Beckman Coulter, Inc., Siemens Healthineers and Shire Japan; research funding from Chugai Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Novartis Pharma K.K., Astellas Pharma Inc., Asahi Kasei Pharma Corporation, Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., MSD K.K., Daiichi Sankyo Co., Ltd., AbbVie GK, HUYA Bioscience International, Kyowa Kirin Co., Ltd., Taiho Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Daiichi Sankyo Co., Ltd., Sanofi K.K., Pfizer Japan, Inc., Teijin Pharma, Ltd. and Takeda Pharmaceutical Co., Ltd.; and speakers bureaus for Kyowa Kirin Co., Ltd., Bristol‐Myers Squibb Company and Celgene Corporation. Kinuko Mitani consulting fees Kyowa Kirin Co., Ltd.; on speakers bureaus for Kyowa Kirin Co., Ltd., Bristol‐Myers Squibb Company and Celgene Corporation; and research funding from Kyowa Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Sumitomo Dainippon Pharma Co., Ltd., Taiho Pharmaceutical Co., Ltd., Nippon Shinyaku Co., Ltd., Daiichi Sankyo Co., Ltd., Sanofi K.K., Pfizer Japan Inc., Teijin Pharma Ltd. and Takeda Pharmaceutical Co., Ltd. Jong Wook Lee honoraria, consulting fees and research support (to Seoul St. Mary’s Hospital) from Alexion Pharmaceuticals; and advisory board member for Alexion Pharmaceuticals. Shinji Nakao honoraria from Novartis Pharma K.K., Kyowa Kirin Co., Ltd. and Alexion Pharmaceuticals. Jun Ho Jang, Koji Nagafuji, Nobuhiko Uoshima, Tomoaki Fujisaki, Ko Sasaki, Naoki Kobayashi, Satoshi Ichikawa and Keiya Ozawa have no competing interests.

© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.

Figures

Fig 1
Fig 1
Romiplostim doses given to the patients each week.
Fig 2
Fig 2
Haematological responses to romiplostim at weeks 27 and 53. Venn diagrams show the numbers of patients with single, bilineage and trilineage responses at (A) week 27 and (B) week 53 for the full analysis set (N = 31).
Fig 3
Fig 3
Change in haematological parameters with romiplostim. Data are given as mean (± SD) during treatment with romiplostim (5–20 µg/kg) for 52 weeks: (A) platelet count, (B) haemoglobin concentration and (C) neutrophil count (N = 31).

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