今日の臨床サポート

再生不良性貧血

著者: 中尾眞二 石川県赤十字血液センター

監修: 木崎昌弘 埼玉医科大学総合医療センター

著者校正済:2022/09/28
現在監修レビュー中
参考ガイドライン:
  1. 再生不良性貧血診療の参照ガイド令和1年改訂版
患者向け説明資料

概要・推奨   

  1. 輸血が不要なステージ2aまでの非重症再生不良性貧血のうち、血小板の減少が他の血球の減少に比べて優位な例に対してはシクロスポリン3.5㎎/㎏を8週間投与して網赤血球数や血小板数の増加の有無をみる(推奨度2)
  1. 2血球系統のみの減少が血小板減少を含む場合、血球減少の程度が再生不良性貧血の診断基準を満たさない場合でも、「前再生不良性貧血状態」を疑う必要がある。前再生不良性貧血状態を見逃した結果、重症化してから再生不良性貧血と診断され、治療に難渋することがしばしばある。このため、軽症再生不良性貧血と同様にシクロスポリン(保険適用外)の効果をみることが勧められる(推奨度2)
  1. シクロスポリンは2年以上投与すれば、HLA-DRB1*15:01保有例を除くほとんどの例で、再燃を来すことなく中止することが可能である。ただし、減量の過程で急速に悪化することがあるため、血小板の減少傾向がみられた場合には、次回受診時までの観察期間を短縮し、血小板減少がさらに進行する場合にはただちにシクロスポリンを増量する必要がある。
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  1. HLA-A*02:01を除くHLAクラスIアレルが欠失した白血球が検出される場合は、二次性の骨髄異形成症候群(MDS)を発症するリスクが低いこと、逆にHLA-A*02:01欠失白血球が検出される場合は、MDSに移行するリスクが高いことが最近の研究により示された。このため状況が許せば患者のHLAをタイピングし、再生不良性貧血において欠失する頻度が高いHLA-B*40:02HLA-A*02:06HLA-B*54:01HLA-A*02:06などが陽性の場合は、予後を予測するために、これらのアレル欠失血球の有無を調べることが勧められる(推奨度2)
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、 著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適応の査定において保険適応及び保険適応外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適応の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
中尾眞二 : 報酬額(シンバイオ),講演料(ノバルティス,協和キリン)[2022年]
監修:木崎昌弘 : 講演料(武田薬品工業,ヤンセンファーマ,小野薬品工業,ブリストル・マイヤーズスクイブ),研究費・助成金など(武田薬品工業),奨学(奨励)寄付など(協和キリン,旭化成ファーマ,第一三共,中外製薬,日本新薬,武田薬品工業)[2022年]

改訂のポイント:
  1. 最近の知見に基づき、以下の点を改訂した。
  1. 抗胸腺細胞グロブリン(ATG、サイモグロブリン®)とシクロスポリンの併用(ATG+シクロスポリン)療法にエルトロンボパグ(EPAG)を追加することの有用性が、最近の無作為比較試験で証明された。このため、2019年の参照ガイドの「輸血が必要な中等症以上の重症度を示す患者にATG+シクロスポリン併用療法を行う場合、原則としてEPAGを追加する」の推奨から、原則を削除し、この重症度の患者にはATG+シクロスポリン+EPAG療法を行う、に変更した。
  1. EPAGが無効または効果不十分であった難治性再生不良性貧血でも、最大用量(20μg/㎏)のROMIへの切り替えによって約70%に少なくとも1血球系統の改善が得られる。
  1. HLA欠失血球が検出される例は免疫抑制療法に反応して改善する確率が高く、二次性のMDSに移行するリスクも低い。ただし、欠失するHLAアレルがHLA-A*02:01であった場合は、免疫抑制療法に対する反応性は必ずしも高くはなく、MDSに移行するリスクが高いため、このアレルを持つ例では注意が必要である。

病態・疫学・診察

疾患情報  
  1. 再生不良性貧血は、末梢血でのすべての血球の減少(汎血球減少)と骨髄の細胞密度の低下(低形成)を特徴とする1つの症候群である。
  1. ヘモグロビン濃度:10.0g/dL未満、②好中球:1,500/μL未満、③血小板:10万/μL未満の3項目のうち、少なくとも2つを満たす。
  1. 再生不良性貧血の診断基準(平成28年度改訂):表<図表>
  1. 2項目だけを満たす場合、免疫病態による再生不良性貧血では血小板減少を必ず含んでいる。
  1. わが国の患者数は約1万1000人で、年間新患者発生数は100万人当たり6人前後である。
  1. 発病後間もない例であれば、約70%は抗胸腺細胞グロブリン(ATG)・シクロスポリン併用療法によって改善する。
  1. 40歳未満でヒト白血球抗原(HLA)一致適合同胞ドナーがいれば、骨髄移植が原則として第1選択の治療となる。
  1. 初診時の末梢血顆粒球には、全体の約40%にPIG-ABCOR/BCORL1DNMT3AASXL1などの遺伝子変異が検出される[1]PIG-ABCOR/BCORL1変異は、免疫抑制療法の反応率が高く、予後良好と相関する。DNMT3AASXL1などの存在は、MDS(myelodysplastic syndrome;骨髄異形成症候群)、AML(acute myeloid leukemia; 急性骨髄性白血病)への移行と相関する予後不良因子であるが、免疫抑制療法に対する反応性には影響を与えない。
  1. 再生不良性貧血は、指定難病であり、重症度基準Stage2以上の場合は、難病認定を申請し、それが認定されると診療費の自己負担分の一部が公費負担として助成される。([平成27年1月施行])
  1.  難病法に基づく医療費助成制度 
 
  1. 30歳以上の再生不良性貧血患者に対する血縁者間骨髄移植や、すべての年齢層の患者に対する非血縁者間移植においては、従来より用いられてきた200mg/kgのシクロホスファミド(CY)を基本薬とする前処置よりも、フルダラビン(Flu)と比較的少量のCYを基本薬とする前処置を用いることが勧められる(推奨度2)
  1. 200mg/kgのCYにATGを併用したレジメンは標準的な移植前処置レジメンとして頻用されてきたが、心毒性が強いことが問題であった。CYを100mg/kg(25mg/kg×4日、-5~-2日目)に減量し、同日にFlu(30mg/m2×4日)、サイモグロブリン2.5mg/kg/日を-3、-2日目、非血縁ドナーからの移植では-1日目に全身放射線照射2Gyを投与するレジメンが最近では多く用いられている[2]
  1. 追記:日本人では欧米と同じスケジュールでサイモグロブリンを投与すると、ドナーのT細胞排除が強く起こりすぎるため、移植後のウイルス感染・EBウイルスの再活性化や、混合キメラが起こりやすくなる可能性がある。このためATG投与は-5、-4日目などの前処置前半に投与したほうがよい可能性がある。
 
再生不良性貧血に対する移植前処置例

患者の年齢・状態や移植片の種類に応じてA~Dの前処置を使い分ける。代替ドナーからの移植の場合はday-1にTBI 2-4 Gyを追加する。臍帯血移植ではATGは用いないことが多い。rATG、ウサギATG;CY、シクロホスファミド;Flu、フルダラビン;MEL、メルファラン

 
  1. 免疫抑制療法としてのサイモグロブリンの投与量は2.5~3.75mg/kgと幅が広いが、2.5㎎と3.5㎎の間で奏効率に差がないことが示されている(推奨度2)
  1. 日本、韓国、中国(天津)で行われた前向きの臨床試験により、サイモグロブリン2.5㎎と3.5㎎の間で奏効率や生存率に差がないことが示された[3]
 
  1. 再生不良性貧血に対する同種造血幹細胞移植では末梢血幹細胞ではなく骨髄を用いるべきである(推奨度1)
  1. 再生不良性貧血に対する血縁ドナーからの移植に末梢血幹細胞を用いると、骨髄移植に比べて慢性移植片対宿主病の頻度が高くなるため生存率が低下する[4]。日本造血細胞移植学会に登録された106例の解析においても、末梢血幹細胞移植(PBSCT)を受けた37例の生存率(74.5%)は、骨髄移植を受けた患者69例の生存率(90%)に比べて低い傾向がみられた。非血縁ドナーからの移植では慢性移植片対宿主病の頻度は変わらないが、やはり末梢血幹細胞移植では骨髄移植に比べて生存率が劣っていた[5]。したがって、再生不良性貧血に対する同種移植においては末梢血幹細胞ではなく、骨髄を用いるべきである。
問診・診察のポイント  
  1. 薬剤の服用歴、感染症の徴候などがなかったかを確認する。

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文献 

Tetsuichi Yoshizato, Bogdan Dumitriu, Kohei Hosokawa, Hideki Makishima, Kenichi Yoshida, Danielle Townsley, Aiko Sato-Otsubo, Yusuke Sato, Delong Liu, Hiromichi Suzuki, Colin O Wu, Yuichi Shiraishi, Michael J Clemente, Keisuke Kataoka, Yusuke Shiozawa, Yusuke Okuno, Kenichi Chiba, Hiroko Tanaka, Yasunobu Nagata, Takamasa Katagiri, Ayana Kon, Masashi Sanada, Phillip Scheinberg, Satoru Miyano, Jaroslaw P Maciejewski, Shinji Nakao, Neal S Young, Seishi Ogawa
Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia.
N Engl J Med. 2015 Jul 2;373(1):35-47. doi: 10.1056/NEJMoa1414799.
Abstract/Text BACKGROUND: In patients with acquired aplastic anemia, destruction of hematopoietic cells by the immune system leads to pancytopenia. Patients have a response to immunosuppressive therapy, but myelodysplastic syndromes and acute myeloid leukemia develop in about 15% of the patients, usually many months to years after the diagnosis of aplastic anemia.
METHODS: We performed next-generation sequencing and array-based karyotyping using 668 blood samples obtained from 439 patients with aplastic anemia. We analyzed serial samples obtained from 82 patients.
RESULTS: Somatic mutations in myeloid cancer candidate genes were present in one third of the patients, in a limited number of genes and at low initial variant allele frequency. Clonal hematopoiesis was detected in 47% of the patients, most frequently as acquired mutations. The prevalence of the mutations increased with age, and mutations had an age-related signature. DNMT3A-mutated and ASXL1-mutated clones tended to increase in size over time; the size of BCOR- and BCORL1-mutated and PIGA-mutated clones decreased or remained stable. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and longer and a higher rate of overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes. However, clonal dynamics were highly variable and might not necessarily have predicted the response to therapy and long-term survival among individual patients.
CONCLUSIONS: Clonal hematopoiesis was prevalent in aplastic anemia. Some mutations were related to clinical outcomes. A highly biased set of mutations is evidence of Darwinian selection in the failed bone marrow environment. The pattern of somatic clones in individual patients over time was variable and frequently unpredictable. (Funded by Grant-in-Aid for Scientific Research and others.).

PMID 26132940
Andrea Bacigalupo, Gerard Socie', Edoardo Lanino, Arcangelo Prete, Franco Locatelli, Anna Locasciulli, Simone Cesaro, Avichai Shimoni, Judith Marsh, Mats Brune, Maria Teresa Van Lint, Rosi Oneto, Jacob Passweg, Severe Aplastic Anemia Working Party of the European Group for Blood and Marrow Transplantation
Fludarabine, cyclophosphamide, antithymocyte globulin, with or without low dose total body irradiation, for alternative donor transplants, in acquired severe aplastic anemia: a retrospective study from the EBMT-SAA Working Party.
Haematologica. 2010 Jun;95(6):976-82. doi: 10.3324/haematol.2009.018267. Epub 2010 May 21.
Abstract/Text BACKGROUND: We analyzed the outcome of 100 patients with acquired severe aplastic anemia undergoing an alternative donor transplant, after immune suppressive therapy had failed.
DESIGN AND METHODS: As a conditioning regimen, patients received either a combination of fludarabine, cyclophosphamide, and antithymocyte globulin (n=52, median age 13 years) or this combination with the addition of low dose (2 Gy) total body irradiation (n=48, median age 27 years).
RESULTS: With a median follow-up of 1665 and 765 days, the actuarial 5-year survival was 73% for the group that received fludarabine, cyclophosphamide, and antithymocyte globulin and 79% for the group given the conditioning regimen including total body irradiation. Acute graft-versus-host disease grade III-IV was seen in 18% and 7% of the groups, respectively. Graft failure was seen in 17 patients with an overall cumulative incidence of 17% in patients receiving conditioning with or without total body irradiation: 9 of these 17 patients survive in the long-term. The most significant predictor of survival was the interval between diagnosis and transplantation, with 5-year survival rates of 87% and 55% for patients grafted within 2 years of diagnosis and more than 2 years after diagnosis, respectively (P=0.0004). Major causes of death were graft failure (n=7), post-transplant-lymphoproliferative-disease (n=4) and graft-versus-host disease (n=4).
CONCLUSIONS: This study confirms positive results of alternative donor transplants in patients with severe aplastic anemia, the best outcomes being achieved in patients grafted within 2 years of diagnosis. Prevention of rejection and Epstein-Barr virus reactivation may further improve these results.

PMID 20494932
Atsushi Narita, Xiaofan Zhu, Hideki Muramatsu, Xiaojuan Chen, Ye Guo, Wenyu Yang, Jingliao Zhang, Fang Liu, Jun H Jang, Hoon Kook, Hawk Kim, Kensuke Usuki, Hirohito Yamazaki, Yoshiyuki Takahashi, Shinji Nakao, Jong Wook Lee, Seiji Kojima, Aplastic Anaemia Working Party of the Asia-Pacific Blood, Marrow Transplantation Group
Prospective randomized trial comparing two doses of rabbit anti-thymocyte globulin in patients with severe aplastic anaemia.
Br J Haematol. 2019 Oct;187(2):227-237. doi: 10.1111/bjh.16055. Epub 2019 Jun 17.
Abstract/Text The treatment of choice for patients with severe aplastic anaemia (SAA) includes immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and ciclosporin A. However, the optimal dose for rabbit ATG has yet to be established. We herein report the first prospective, randomized, multicentre study comparing two doses of rabbit ATG in patients with SAA. Patients with SAA who required initial IST in Japan (n = 89), China (n = 85) and Korea (n = 48) were enrolled between May 2012 and October 2017. A 1:1 block randomization was employed for two doses of rabbit ATG. In total, 222 patients were randomized, with 112 patients receiving 2·5 mg/kg and 110 receiving 3·5 mg/kg of rabbit ATG for 5 days. The primary endpoint was the haematological response at day 180. After 6 months, no significant difference in response rates was observed between the 2·5 and 3·5 mg/kg groups (49% vs. 48%, P = 0·894). Overall survival at 3 years was similar between the two groups [85% (95% confidence interval [CI], 76%-91%) vs. 91% (95% CI, 82%-96%); P = 0·107]. The current study revealed no significant differences in the efficacy and safety between the 2·5 and 3·5 mg/kg doses of rabbit ATG in patients with SAA. Trial registration: UMIN000011134.

© 2019 British Society for Haematology and John Wiley & Sons Ltd.
PMID 31206607
Mary Eapen, Jennifer Le Rademacher, Joseph H Antin, Richard E Champlin, Jeanette Carreras, Joseph Fay, Jakob R Passweg, Jakub Tolar, Mary M Horowitz, Judith C W Marsh, H Joachim Deeg
Effect of stem cell source on outcomes after unrelated donor transplantation in severe aplastic anemia.
Blood. 2011 Sep 1;118(9):2618-21. doi: 10.1182/blood-2011-05-354001. Epub 2011 Jun 15.
Abstract/Text Outcome after unrelated donor bone marrow (BM) transplantation for severe aplastic anemia (SAA) has improved, with survival rates now approximately 75%. Increasing use of peripheral blood stem and progenitor cells (PBPCs) instead of BM as a graft source prompted us to compare outcomes of PBPC and BM transplantation for SAA. We studied 296 patients receiving either BM (n = 225) or PBPC (n = 71) from unrelated donors matched at human leukocyte antigen-A, -B, -C, -DRB1. Hematopoietic recovery was similar after PBPC and BM transplantation. Grade 2 to 4 acute graft-versus-host disease risks were higher after transplantation of PBPC compared with BM (hazard ratio = 1.68, P = .02; 48% vs 31%). Chronic graft-versus-host disease risks were not significantly different after adjusting for age at transplantation (hazard ratio = 1.39, P = .14). Mortality risks, independent of age, were higher after PBPC compared with BM transplantation (hazard ratio = 1.62, P = .04; 76% vs 61%). These data indicate that BM is the preferred graft source for unrelated donor transplantation in SAA.

PMID 21677312
Takamasa Katagiri, Aiko Sato-Otsubo, Koichi Kashiwase, Satoko Morishima, Yusuke Sato, Yuka Mori, Motohiro Kato, Masashi Sanada, Yasuo Morishima, Kohei Hosokawa, Yumi Sasaki, Shigeki Ohtake, Seishi Ogawa, Shinji Nakao, Japan Marrow Donor Program
Frequent loss of HLA alleles associated with copy number-neutral 6pLOH in acquired aplastic anemia.
Blood. 2011 Dec 15;118(25):6601-9. doi: 10.1182/blood-2011-07-365189. Epub 2011 Sep 30.
Abstract/Text Idiopathic aplastic anemia (AA) is a common cause of acquired BM failure. Although autoimmunity to hematopoietic progenitors is thought to be responsible for its pathogenesis, little is known about the molecular basis of this autoimmunity. Here we show that a substantial proportion of AA patients harbor clonal hematopoiesis characterized by the presence of acquired copy number-neutral loss of heterozygosity (CNN-LOH) of the 6p arms (6pLOH). The 6pLOH commonly involved the HLA locus, leading to loss of one HLA haplotype. Loss of HLA-A expression from multiple lineages of leukocytes was confirmed by flow cytometry in all 6pLOH(+) cases. Surprisingly, the missing HLA-alleles in 6pLOH(+) clones were conspicuously biased to particular alleles, including HLA-A*02:01, A*02:06, A*31:01, and B*40:02. A large-scale epidemiologic study on the HLA alleles of patients with various hematologic diseases revealed that the 4 HLA alleles were over-represented in the germline of AA patients. These findings indicate that the 6pLOH(+) hematopoiesis found in AA represents "escapes" hematopoiesis from the autoimmunity, which is mediated by cytotoxic T cells that target the relevant auto-antigens presented on hematopoietic progenitors through these class I HLAs. Our results provide a novel insight into the genetic basis of the pathogenesis of AA.

PMID 21963603
Hiroyuki Maruyama, Takamasa Katagiri, Koichi Kashiwase, Takashi Shiina, Aiko Sato-Otsubo, Yoshitaka Zaimoku, Kana Maruyama, Kohei Hosokawa, Ken Ishiyama, Hirohito Yamazaki, Hidetoshi Inoko, Seishi Ogawa, Shinji Nakao
Clinical significance and origin of leukocytes that lack HLA-A allele expression in patients with acquired aplastic anemia.
Exp Hematol. 2016 Oct;44(10):931-939.e3. doi: 10.1016/j.exphem.2016.05.013. Epub 2016 May 29.
Abstract/Text To gain insight into the origin and clinical significance of leukocytes that lack human leukocyte antigen A (HLA-A) allele expression caused by a copy-number-neutral loss of heterozygosity in the short arm of chromosome 6 in patients with acquired aplastic anemia (AA), we used a high-sensitivity flow cytometry assay to investigate the presence of HLA-A allele-lacking leukocytes (HLA-LLs) in 144 AA patients. HLA-LLs, accounting for 0.2-99.8% of each leukocyte population, were detected in 18 of 71 (25.4%) newly diagnosed patients and in 25 of 73 (34.2%) previously treated patients. The lineage combination patterns of the HLA-LLs in the 43 HLA-LL(+) patients were granulocytes (Gs), monocytes (Ms), B cells (Bs), and T cells (Ts; GMBT) in 13 cases, GMB in 16 cases, GM in 11 cases, and B alone in three cases. The response rate to antithymocyte globulin plus cyclosporine therapy (100%) and the 2-year, failure-free survival rate (100%) in 8 newly diagnosed HLA-LL(+) patients were significantly higher than in 23 HLA-LL(-) patients (52.2% for both). These data suggest that HLA-LLs are a useful marker of the presence of immune pathophysiology in AA and that T-cell attacks against hematopoietic progenitor cells, rather than against hematopoietic stem cells, can trigger bone marrow failure in AA patients.

Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.
PMID 27250585
Kohei Hosokawa, Hiroki Mizumaki, Takeshi Yoroidaka, Hiroyuki Maruyama, Tatsuya Imi, Noriaki Tsuji, Ryota Urushihara, Mikoto Tanabe, Yoshitaka Zaimoku, Mai Anh Thi Nguyen, Dung Cao Tran, Ken Ishiyama, Hirohito Yamazaki, Takamasa Katagiri, Hiroyuki Takamatsu, Kazuyoshi Hosomichi, Atsushi Tajima, Fumihiro Azuma, Seishi Ogawa, Shinji Nakao
HLA class I allele-lacking leukocytes predict rare clonal evolution to MDS/AML in patients with acquired aplastic anemia.
Blood. 2021 Jun 24;137(25):3576-3580. doi: 10.1182/blood.2020010586.
Abstract/Text
PMID 33754630
Yoshitaka Zaimoku, Bhavisha A Patel, Sharon D Adams, Ruba Shalhoub, Emma M Groarke, Audrey Ai Chin Lee, Sachiko Kajigaya, Xingmin Feng, Olga Julia Rios, Holly Eager, Lemlem Alemu, Diego Quinones Raffo, Colin O Wu, Willy A Flegel, Neal S Young
HLA associations, somatic loss of HLA expression, and clinical outcomes in immune aplastic anemia.
Blood. 2021 Dec 30;138(26):2799-2809. doi: 10.1182/blood.2021012895.
Abstract/Text Immune aplastic anemia (AA) features somatic loss of HLA class I allele expression on bone marrow cells, consistent with a mechanism of escape from T-cell-mediated destruction of hematopoietic stem and progenitor cells. The clinical significance of HLA abnormalities has not been well characterized. We examined the somatic loss of HLA class I alleles and correlated HLA loss and mutation-associated HLA genotypes with clinical presentation and outcomes after immunosuppressive therapy in 544 AA patients. HLA class I allele loss was detected in 92 (22%) of the 412 patients tested, in whom there were 393 somatic HLA gene mutations and 40 instances of loss of heterozygosity. Most frequently affected was HLA-B*14:02, followed by HLA-A*02:01, HLA-B*40:02, HLA-B*08:01, and HLA-B*07:02. HLA-B*14:02, HLA-B*40:02, and HLA-B*07:02 were also overrepresented in AA. High-risk clonal evolution was correlated with HLA loss, HLA-B*14:02 genotype, and older age, which yielded a valid prediction model. In 2 patients, we traced monosomy 7 clonal evolution from preexisting clones harboring somatic mutations in HLA-A*02:01 and HLA-B*40:02. Loss of HLA-B*40:02 correlated with higher blood counts. HLA-B*07:02 and HLA-B*40:01 genotypes and their loss correlated with late-onset of AA. Our results suggest the presence of specific immune mechanisms of molecular pathogenesis with clinical implications. HLA genotyping and screening for HLA loss may be of value in the management of immune AA. This study was registered at clinicaltrials.gov as NCT00001964, NCT00061360, NCT00195624, NCT00260689, NCT00944749, NCT01193283, and NCT01623167.

© 2021 by The American Society of Hematology.
PMID 34724566
Chizuru Saito, Ken Ishiyama, Hirohito Yamazaki, Yoshitaka Zaimoku, Shinji Nakao
Hypomegakaryocytic thrombocytopenia (HMT): an immune-mediated bone marrow failure characterized by an increased number of PNH-phenotype cells and high plasma thrombopoietin levels.
Br J Haematol. 2016 Oct;175(2):246-251. doi: 10.1111/bjh.14210. Epub 2016 Jun 28.
Abstract/Text Patients with mild hypomegakaryocytic thrombocytopenia (HMT) that does not meet the diagnostic criteria for a definite disease entity may potentially progress to aplastic anaemia (AA) that is refractory to therapy. To clarify the clinical picture of HMT, we prospectively followed 25 HMT patients with white blood cell count >3·0 × 10(9) /l, haemoglobin level >100 g/l and platelet count of <100·0 × 10(9) /l in the absence of morphological and karyotypic abnormalities in the bone marrow. Glycosylphosphatidylinositol-anchored protein-deficient blood cells [paroxysmal nocturnal haemoglobinuria (PNH)-type cells] were detected in 7 of the 25 (28%) patients and elevated plasma thrombopoietin (TPO, also termed THPO) levels (>320 pg/ml) were observed in 11 (44%) patients. Five (four PNH+ and one PNH-) of six TPO(high) patients who were treated with ciclosporin (CsA) showed improvement. Among the 21 patients who were followed without treatment, thrombocytopenia progressed in four of ten TPO(low) patients and four of 11 TPO(high) patients. The 3-year failure-free survival rate of the CsA-treated TPO(high) patients (100%) was significantly higher than that of the untreated TPO(high) patients (20%). These results suggest that a significant population of HMT patients has an immune pathophysiology that is similar to AA and may be improved by early therapeutic intervention with CsA.

© 2016 John Wiley & Sons Ltd.
PMID 27351867
Chiharu Sugimori, Tatsuya Chuhjo, Xingmin Feng, Hirohito Yamazaki, Akiyoshi Takami, Masanao Teramura, Hideaki Mizoguchi, Mitsuhiro Omine, Shinji Nakao
Minor population of CD55-CD59- blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia.
Blood. 2006 Feb 15;107(4):1308-14. doi: 10.1182/blood-2005-06-2485. Epub 2005 Sep 22.
Abstract/Text We investigated the clinical significance of a minor population of paroxysmal nocturnal hemoglobinuria (PNH)-type blood cells in patients with acquired aplastic anemia (AA). We quantified CD55-CD59- granulocytes and red blood cells (RBCs) in peripheral blood from 122 patients with recently diagnosed AA and correlated numbers of PNH-type cells and responses to immunosuppressive therapy (IST). Flow cytometry detected 0.005% to 23.1% of GPI-AP- cells in 68% of patients with AA. Sixty-eight of 83 (91%) patients with an increased proportion of PNH-type cells (PNH+) responded to antithymocyte globulin (ATG) + cyclosporin (CsA) therapy, whereas 18 of 39 (48%) without such an increase (PNH-) responded. Failure-free survival rates were significantly higher (64%) among patients with PNH+ than patients with PNH- (12%) at 5 years, although overall survival rates were comparable between the groups. Numbers of PNH-type and normal-type cells increased in parallel among most patients with PNH+ who responded to IST, suggesting that these cells are equally sensitive to immune attack. These results indicate that a minor population of PNH-type cells represents a reliable marker of a positive IST response and a favorable prognosis among patients with AA. Furthermore, immune attack against hematopoietic stem cells that allows PNH clonal expansion might occur only at the onset of AA.

PMID 16179371
Chiharu Sugimori, Kanako Mochizuki, Zhirong Qi, Naomi Sugimori, Ken Ishiyama, Yukio Kondo, Hirohito Yamazaki, Akiyoshi Takami, Hirokazu Okumura, Shinji Nakao
Origin and fate of blood cells deficient in glycosylphosphatidylinositol-anchored protein among patients with bone marrow failure.
Br J Haematol. 2009 Oct;147(1):102-12. doi: 10.1111/j.1365-2141.2009.07822.x. Epub 2009 Jul 28.
Abstract/Text Peripheral blood from 489 recently diagnosed patients with aplastic anaemia (AA) and 316 with refractory anaemia (RA) of myelodysplastic syndrome was evaluated to characterize CD55(-)CD59(-) [paroxysmal nocturnal haemoglobinuria (PNH)]-type blood cells associated with bone marrow (BM) failure. PNH-type cells were detected in 57% and 20% of patients with AA and RA, respectively. The percentages of PNH-type granulocytes ranged from 0.003% to 94.2% and the distribution was log-normal with a median of 0.178%. Serial analyses of 75 patients with PNH-type cells over 5 years revealed that the percentage of PNH-type cells constantly increased in 13 (17%), persisted in 44 (59%), disappeared in the remaining 18 (24%) although even in the 'Disappearance' group, PNH-type granulocytes persisted for at least 6 months. A scattergram profile of PNH-type cells unique to each patient persisted regardless of the response to immunosuppressive therapy and only single PIGA mutations were detected in PNH-type granulocytes sorted from four patients. These findings suggest that the PNH-type cells in patients with BM failure are derived from single PIGA mutant haematopoietic stem cells even when their percentages are <1% and their fate depends on the proliferation and self-maintenance properties of the individual PIGA mutants.

PMID 19656154
Nobuhiro Nishio, Hiroshi Yagasaki, Yoshiyuki Takahashi, Hideki Muramatsu, Asahito Hama, Nao Yoshida, Kazuko Kudo, Seiji Kojima
Natural history of transfusion-independent non-severe aplastic anemia in children.
Int J Hematol. 2009 May;89(4):409-13. doi: 10.1007/s12185-009-0302-9. Epub 2009 Apr 3.
Abstract/Text Although the known clinical courses of non-severe aplastic anemia (NSAA) in children comprise spontaneous resolution, persistent NSAA, or progression to severe aplastic anemia (SAA), only a few published reports have indicated the outcome of transfusion-independent NSAA. We retrospectively evaluated the incidence and time of progression from transfusion-independent to transfusion-dependent NSAA or SAA. We reviewed the records of 70 children with acquired AA who were referred to our hospital between 1986 and 2006, and among them we found 22 patients who had transfusion-independent NSAA at diagnosis and were treated with supportive care alone until progression to transfusion-dependent AA. 22 patients were followed up for a median of 86 months (range, 11-198 months). The Kaplan-Meier estimates for progression-free survival were 62 +/- 12 and 22 +/- 13% at 60 and 120 months after diagnosis, respectively. None of the patients treated with supportive care alone improved hematologically. In conclusion, because the incidence of disease progression was high in patients with NSAA, a prospective randomized trial of early intervention with IST or observation alone until disease progression to SAA, followed by IST when the patients become transfusion-dependent is warranted.

PMID 19343478
Hirohito Yamazaki, Chiharu Sugimori, Tatsuya Chuhjo, Shinji Nakao
Cyclosporine therapy for acquired aplastic anemia: predictive factors for the response and long-term prognosis.
Int J Hematol. 2007 Apr;85(3):186-90. doi: 10.1532/IJH97.06156.
Abstract/Text Although cyclosporine (CsA) is a key drug in the treatment of acquired aplastic anemia (AA), the role of single-agent therapy with CsA remains unclear. To determine the efficacy of CsA in the treatment of AA, we treated 38 AA patients with CsA alone and followed up the patients for 6 months to 16 years. Twenty patients (53%) achieved either a partial or complete remission within 1 year of starting CsA therapy. Thirteen (81%) of 16 patients who showed an increase in the reticulocyte count of >20 x 10(9)/L within 2 months achieved remission, whereas the response rate was only 32% in patients who failed to show such an increase in the reticulocyte count. The actuarial overall survival and failure-free survival rates at 5 years were 91% and 37%, respectively. These data indicate that CsA alone can achieve a sustained remission in approximately 40% of AA patients, with a low probability of inducing secondary clonal diseases. Given its low toxicity and because the effectiveness of CsA can be judged within 2 months of therapy, CsA may be the first drug of choice at outpatient clinics for AA patients not requiring transfusions.

PMID 17483052
Régis Peffault de Latour, Austin Kulasekararaj, Simona Iacobelli, Sofie R Terwel, Riley Cook, Morag Griffin, Constantijn J M Halkes, Christian Recher, Fiorenza Barraco, Edouard Forcade, Juan-Carlos Vallejo, Beatrice Drexler, Jean-Baptiste Mear, Alexander E Smith, Emanuele Angelucci, Reinier A P Raymakers, Marco R de Groot, Etienne Daguindau, Erfan Nur, Wilma Barcellini, Nigel H Russell, Louis Terriou, Anna-Paola Iori, Ursula La Rocca, Anna Sureda, Isabel Sánchez-Ortega, Blanca Xicoy, Isidro Jarque, James Cavenagh, Flore Sicre de Fontbrune, Serena Marotta, Talha Munir, Jennifer M L Tjon, Suzanne Tavitian, Aline Praire, Laurence Clement, Florence Rabian, Luana Marano, Anita Hill, Elena Palmisani, Petra Muus, Fabiana Cacace, Camilla Frieri, Maria-Teresa van Lint, Jakob R Passweg, Judith C W Marsh, Gérard Socié, Ghulam J Mufti, Carlo Dufour, Antonio M Risitano, Severe Aplastic Anemia Working Party of the European Society for Blood and Marrow Transplantation
Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia.
N Engl J Med. 2022 Jan 6;386(1):11-23. doi: 10.1056/NEJMoa2109965.
Abstract/Text BACKGROUND: A single-group, phase 1-2 study indicated that eltrombopag improved the efficacy of standard immunosuppressive therapy that entailed horse antithymocyte globulin (ATG) plus cyclosporine in patients with severe aplastic anemia.
METHODS: In this prospective, investigator-led, open-label, multicenter, randomized, phase 3 trial, we compared the efficacy and safety of horse ATG plus cyclosporine with or without eltrombopag as front-line therapy in previously untreated patients with severe aplastic anemia. The primary end point was a hematologic complete response at 3 months.
RESULTS: Patients were assigned to receive immunosuppressive therapy (Group A, 101 patients) or immunosuppressive therapy plus eltrombopag (Group B, 96 patients). The percentage of patients who had a complete response at 3 months was 10% in Group A and 22% in Group B (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P = 0.01). At 6 months, the overall response rate (the percentage of patients who had a complete or partial response) was 41% in Group A and 68% in Group B. The median times to the first response were 8.8 months (Group A) and 3.0 months (Group B). The incidence of severe adverse events was similar in the two groups. With a median follow-up of 24 months, a karyotypic abnormality that was classified as myelodysplastic syndrome developed in 1 patient (Group A) and 2 patients (Group B); event-free survival was 34% and 46%, respectively. Somatic mutations were detected in 29% (Group A) and 31% (Group Β) of the patients at baseline; these percentages increased to 66% and 55%, respectively, at 6 months, without affecting the hematologic response and 2-year outcome.
CONCLUSIONS: The addition of eltrombopag to standard immunosuppressive therapy improved the rate, rapidity, and strength of hematologic response among previously untreated patients with severe aplastic anemia, without additional toxic effects. (Funded by Novartis and others; RACE ClinicalTrials.gov number, NCT02099747; EudraCT number, 2014-000363-40.).

Copyright © 2022 Massachusetts Medical Society.
PMID 34986284
André Tichelli, Hubert Schrezenmeier, Gérard Socié, Judith Marsh, Andrea Bacigalupo, Ulrich Dührsen, Anke Franzke, Michael Hallek, Eckhard Thiel, Martin Wilhelm, Britta Höchsmann, Alain Barrois, Kim Champion, Jakob R Passweg
A randomized controlled study in patients with newly diagnosed severe aplastic anemia receiving antithymocyte globulin (ATG), cyclosporine, with or without G-CSF: a study of the SAA Working Party of the European Group for Blood and Marrow Transplantation.
Blood. 2011 Apr 28;117(17):4434-41. doi: 10.1182/blood-2010-08-304071. Epub 2011 Jan 13.
Abstract/Text We evaluated the role of granulocyte colony-stimulating factor (G-CSF) in patients with severe aplastic anemia (SAA) treated with antithymocyte globulin (ATG) and cyclosporine (CSA). Between January 2002 and July 2008, 192 patients with newly diagnosed SAA not eligible for transplantation were entered into this multicenter, randomized study to receive ATG/CSA with or without G-CSF. Overall survival (OS) at 6 years was 76% ± 4%, and event-free survival (EFS) was 42% ± 4%. No difference in OS/EFS was seen between patients randomly assigned to receive or not to receive G-CSF, neither for the entire cohort nor in subgroups stratified by age and disease severity. Patients treated with G-CSF had fewer infectious episodes (24%) and hospitalization days (82%) compared with patients without G-CSF (36%; P = .006; 87%; P = .0003). In a post hoc analysis of patients receiving G-CSF, the lack of a neutrophil response by day 30 was associated with significantly lower response rate (56% vs 81%; P = .048) and survival (65% vs 87%; P = .031). G-CSF added to standard ATG and CSA reduces the rate of early infectious episodes and days of hospitalization in very SAA patients and might allow early identification of nonresponders but has no effect on OS, EFS, remission, relapse rates, and mortality. This study was registered at www.clinicaltrials.gov as NCT01163942.

PMID 21233311
Masanao Teramura, Akiro Kimura, Satsuki Iwase, Yuji Yonemura, Shinji Nakao, Akio Urabe, Mitsuhiro Omine, Hideaki Mizoguchi
Treatment of severe aplastic anemia with antithymocyte globulin and cyclosporin A with or without G-CSF in adults: a multicenter randomized study in Japan.
Blood. 2007 Sep 15;110(6):1756-61. doi: 10.1182/blood-2006-11-050526. Epub 2007 May 25.
Abstract/Text We report the results of a randomized study to elucidate whether addition of granulocyte colony-stimulating factor (G-CSF) to immunosuppressive therapy is valuable for the treatment of severe aplastic anemia (SAA) in adults. A total of 101 previously untreated patients (median age, 54 years; range, 19 to 75 years) were randomized to receive antithymocyte globulin (ATG) and cyclosporin A (CyA) (G-CSF- group) or ATG, CyA, and G-CSF (G-CSF+ group). In the G-CSF+ group, the hematologic response rate at 6 months was higher (77% vs 57%; P = .03) than in the G-CSF- group. No differences were observed between the groups in terms of the incidence of infections and febrile episodes. There were no differences between the G-CSF- group and the G-CSF+ group in terms of survival (88% vs 94% at 4 years), and the development of myelodysplastic syndrome (MDS)/acute leukemia (AL) (1 patient vs 2 patients). However, the relapse rate was lower in the G-CSF+ group compared with the G-CSF- group (42% vs 15% at 4 years; P = .01). Further follow-up is required to elucidate the role of G-CSF in immunosuppressive therapy for adult SAA.

PMID 17526862
Phillip Scheinberg, Steven H Fischer, Li Li, Olga Nunez, Colin O Wu, Elaine M Sloand, Jeffrey I Cohen, Neal S Young, A John Barrett
Distinct EBV and CMV reactivation patterns following antibody-based immunosuppressive regimens in patients with severe aplastic anemia.
Blood. 2007 Apr 15;109(8):3219-24. doi: 10.1182/blood-2006-09-045625. Epub 2006 Dec 5.
Abstract/Text The natural history of EBV and CMV reactivation and the potential for serious complications following antibody-based immunosuppressive treatment for bone marrow failure syndromes in the absence of transplantation is not known. We monitored blood for EBV and CMV reactivation by polymerase chain reaction (PCR) weekly in 78 consecutive patients (total of 99 immunosuppressive courses) with aplastic anemia. Four regimens were studied: (1) HC, horse ATG/cyclosporine; (2) HCS, horse ATG/CsA/sirolimus; (3) RC, rabbit ATG/CsA; and (4) CP, alemtuzumab. There were no cases of EBV or CMV disease, but EBV reactivation occurred in 82 (87%) of 94 and CMV reactivation in 19 (33%) of 57 seropositive patients after starting immunosuppression. The median peak EBV copies were higher in the RC group when compared with HC, HCS, and alemtuzumab (P < .001). The median duration of PCR positivity for EBV was higher in the RC group compared with HC, HCS, and alemtuzumab (P = .001). Subclinical reactivation of both EBV and CMV is common and nearly always self-limited in patients with bone marrow failure receiving immunosuppression; different regimens are associated with different intensity of immunosuppression as measured by viral load and lymphocyte count; and viral reactivation patterns differ according to immunosuppressive regimens.

PMID 17148582
Kinya Ohata, Noriko Iwaki, Takeharu Kotani, Yukio Kondo, Hirohito Yamazaki, Shinji Nakao
An Epstein-Barr virus-associated leukemic lymphoma in a patient treated with rabbit antithymocyte globulin and cyclosporine for hepatitis-associated aplastic anemia.
Acta Haematol. 2012;127(2):96-9. doi: 10.1159/000333609. Epub 2011 Dec 15.
Abstract/Text Lymphoproliferative disorders (LPDs) are generally caused by uncontrolled B-cell proliferation induced by the Epstein-Barr virus (EBV) in the setting of impaired EBV-specific T-cell immunity, particularly when there is pharmacological immunosuppression including antithymocyte globulin. We herein present an unusual case of EBV associated with LPD (EBV-LPD) in which LPD occurred 3 weeks after the use of rabbit antithymocyte globulin administered for severe hepatitis-associated aplastic anemia; the patient died of fulminant leukemic lymphoma 5 days after the onset. We also review the pertinent literature on EBV-LPD after immunosuppressive therapy and document the efficacy of EBV viral load monitoring and the need for preemptive therapy.

Copyright © 2011 S. Karger AG, Basel.
PMID 22178718
Hiroyuki Takamatsu, Raita Araki, Ryosei Nishimura, Akihiro Yachie, J Luis Espinoza, Hirokazu Okumura, Takashi Yoshida, Kiyotaka Kuzushima, Shinji Nakao
Epstein-Barr virus-associated leukemic lymphoma after allogeneic stem cell transplantation.
J Clin Virol. 2016 Jul;80:82-6. doi: 10.1016/j.jcv.2016.04.020. Epub 2016 May 6.
Abstract/Text Leukemic Epstein-Barr virus (EBV)-associated post-transplant lymphoproliferative diseases (PTLD) following allogeneic hematopoietic stem cell transplantation are extremely rare. We can successfully treat an EBV-associated leukemic lymphoma patient with rituximab, cidofovir, and donor lymphocyte infusion (DLI). In the present case, EBV-specific T cells that were present in the peripheral blood before rituximab administration treatment rapidly increased after DLI in association with a decrease in the EBV-DNA load.

Copyright © 2016 Elsevier B.V. All rights reserved.
PMID 27218416
Amy E DeZern, Marianna L Zahurak, Heather J Symons, Kenneth R Cooke, Gary L Rosner, Douglas E Gladstone, Carol Ann Huff, Lode J Swinnen, Philip Imus, Ivan Borrello, Nina Wagner-Johnston, Richard F Ambinder, Leo Luznik, Javier Bolaños-Meade, Ephraim J Fuchs, Richard J Jones, Robert A Brodsky
Haploidentical BMT for severe aplastic anemia with intensive GVHD prophylaxis including posttransplant cyclophosphamide.
Blood Adv. 2020 Apr 28;4(8):1770-1779. doi: 10.1182/bloodadvances.2020001729.
Abstract/Text Severe aplastic anemia (SAA) is a stem cell disorder often treated with bone marrow transplantation (BMT) to reconstitute hematopoiesis. Outcomes of related HLA-haploidentical (haplo) donors after reduced-intensity conditioning with intensive graft-versus-host disease (GVHD) prophylaxis including posttransplantation cyclophosphamide are presented here from 37 SAA, 20 relapsed/refractory (R/R), and 17 treatment-naïve (TN) SAA patients. Median follow-up is 32 months (90% confidence interval [CI], 29-44). The median age was 25 (range, 4-69) years. The median time to neutrophil recovery was 17 days (range, 15-88). Four of 37 patients (11%) experienced graft failure (GF). There was 1 primary GF of 20 patients in the R/R group and 3 of 17 in the TN group at 200 cGy (1 primary, 2 secondary), but none in the 10 patients who received 400 cGy total body irradiation. Two patients with GF succumbed to infection and 2 were rescued with second haplo BMT. The overall survival for all patients is 94% (90% CI, 88-100) at 1 and 2 years. The cumulative incidence of grade II-IV acute GVHD at day 100 is 11%. The cumulative index of chronic GVHD at 2 years is 8%. Similar results were seen in 10 SAA patients who received the identical nonmyeloablative regimen with posttransplant cyclophosphamide but matched donor transplants. Haplo BMT with posttransplant cyclophosphamide represents a potential cure in SAA, with all 20 R/R currently alive, disease-free, and with no evidence of active GVHD. Extending this approach to TN patients was associated with higher GF rates, but an increase in total body irradiation dose to 400 cGy was associated with durable engraftment without greater early toxicity. Nonmyeloablative haplo BMT in TN SAA could lead to a paradigm shift, such that essentially all patients can proceed quickly to safe, curative BMT. These trials were registered at www.cincialtrials.gov as #NCT02224872) and #NCT02833805.

© 2020 by The American Society of Hematology.
PMID 32343796
Thomas Winkler, Xing Fan, James Cooper, Ronan Desmond, David J Young, Danielle M Townsley, Phillip Scheinberg, Sophia Grasmeder, Andre Larochelle, Marie Desierto, Janet Valdez, Jennifer Lotter, Colin Wu, Ruba N Shalhoub, Katherine R Calvo, Neal S Young, Cynthia E Dunbar
Treatment optimization and genomic outcomes in refractory severe aplastic anemia treated with eltrombopag.
Blood. 2019 Jun 13;133(24):2575-2585. doi: 10.1182/blood.2019000478. Epub 2019 Apr 16.
Abstract/Text Eltrombopag (EPAG) received approval from the US Food and Drug Administration for the treatment of refractory severe aplastic anemia (rSAA) based on treatment of 43 patients with doses escalating from 50 to 150 mg daily for 12 weeks. Response kinetics suggested that more prolonged administration of EPAG at a dose of 150 mg could speed and improve response rates. We enrolled 40 patients with rSAA in a study of EPAG 150 mg daily, with a primary end point of response at 24 weeks. Twenty (50%) of 40 patients responded at 24 weeks; 5 (25%) of 20 would have been deemed nonresponders at 12 weeks, the end point of the previous study. Fifteen of the 19 responding patients continuing on EPAG had drug discontinued for robust response; 5 of the 15 required EPAG re-initiation for relapse, with all recovering response. To analyze risk of clonal progression, we combined long-term data from the 83 patients with rSAA enrolled in both studies. Evolution to an abnormal karyotype occurred in 16 (19%), most within 6 months of EPAG initiation. Targeted deep sequencing/whole-exome sequencing was performed pre-EPAG and at primary response end point and/or time of clonal evolution or longest follow-up. Cytogenetic evolution did not correlate with mutational status, and overall mutated allele fractions of myeloid cancer genes did not increase on EPAG. In summary, extended administration of EPAG at a dose of 150 mg for 24 weeks rescued responses in some patients with rSAA not responding at 12 weeks. The temporal relationship between clonal evolution and drug exposure suggests that EPAG may promote expansion of dormant preexisting clones with an aberrant karyotype. The studies were registered at www.clinicaltrials.gov as #NCT00922883 and #NCT01891994.

PMID 30992268
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
Efficacy and safety of romiplostim in refractory aplastic anaemia: a Phase II/III, multicentre, open-label study.
Br J Haematol. 2021 Jan;192(1):190-199. doi: 10.1111/bjh.17190. Epub 2020 Nov 5.
Abstract/Text 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.

© 2020 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.
PMID 33152120
Kohei Hosokawa, Hirohito Yamazaki, Mikoto Tanabe, Tatsuya Imi, Naomi Sugimori, Shinji Nakao
High-dose romiplostim accelerates hematologic recovery in patients with aplastic anemia refractory to eltrombopag.
Leukemia. 2021 Mar;35(3):906-909. doi: 10.1038/s41375-020-0950-6. Epub 2020 Jul 3.
Abstract/Text
PMID 32616921
Masataka Ise, Hiromitsu Iizuka, Yoshimasa Kamoda, Masako Hirao, Michiko Kida, Kensuke Usuki
Romiplostim is effective for eltrombopag-refractory aplastic anemia: results of a retrospective study.
Int J Hematol. 2020 Dec;112(6):787-794. doi: 10.1007/s12185-020-02971-1. Epub 2020 Sep 2.
Abstract/Text Eltrombopag (EPAG) and romiplostim (ROM), thrombopoietin receptor-agonists with demonstrated efficacy against aplastic anemia (AA) in prospective controlled studies, were authorized in Japan for use in adults with aplastic anemia in 2017 and 2019, respectively. So far, no data are available on the potential contribution of switching from ROM to EPAG or vice versa in terms of efficacy or tolerance. Efficacies and tolerance profiles of ten patients, who failed to respond to the maximum dose of EPAG and then switched to ROM, were evaluated. All ten patients received a maximum dose of ROM (20 μg/kg/week). At a median follow-up of twelve months, seven of ten patients (70%) had achieved either neutrophil, erythroid, or platelet response, including one complete response. No patients showed platelet count fluctuations that were reported during ROM treatment for immune thrombocytopenia. In univariate analysis of the relationship between efficacy and demographics, the response had a correlation with neither factors. None of the patients stopped the ROM treatment because of adverse events. Although a larger number of patients and a longer follow-up period are needed to confirm our findings, our results show the efficacy of ROM in patients with EPAG-refractory AA.

PMID 32876852
S Nakao, H Takamatsu, T Chuhjo, M Ueda, S Shiobara, T Matsuda, T Kaneshige, H Mizoguchi
Identification of a specific HLA class II haplotype strongly associated with susceptibility to cyclosporine-dependent aplastic anemia.
Blood. 1994 Dec 15;84(12):4257-61.
Abstract/Text Hematopoietic function of some aplastic anemia (AA) patients is dependent on the administration of cyclosporine (CyA). To investigate whether certain HLA class II genes are associated with susceptibility to such CyA-dependent AA, we determined the HLA class II alleles of 59 AA patients treated with CyA. Among 26 patients successfully treated with CyA, 13 required a small dose of CyA to maintain stable hematopoiesis. Of these 13 AA patients, 10 shared an HLA class II haplotype of DRB1*1501-DQA1*0102-DQB1*0602. None of the 13 responders who obtained a sustained remission off CyA therapy possessed this haplotype. In the 10 patients who shared the HLA class II haplotype, single-strand conformation polymorphism analysis of each gene fragment of this haplotype failed to detect a polymorphism in the nucleotide sequence. When the AA patients were assessed for their likelihood to respond to CyA therapy, the response rate in patients with this haplotype (71%) was significantly higher than that of patients with another haplotype associated with HLA-DR2, DRB1*1502-DQA1*0103-DQB1*0601 (36%) and that of patients without HLA-DR2 (35%). These findings indicate that the CyA-dependent response of AA is closely related to an HLA class II haplotype of DRB1*1501-DQA1*0102-DQB1*0602 and suggest that, in AA patients with this haplotype, immune mechanisms play an important role in the pathogenesis of bone marrow failure.

PMID 7994040
Abstract/Text
PMID 27585953

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