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再生不良性貧血

著者: 中尾眞二 金沢大学医薬保健学域医学系血液内科学

監修: 木崎昌弘 埼玉医科大学総合医療センター

著者校正/監修レビュー済:2020/06/05
参考ガイドライン:
再生不良性貧血診療の参照ガイド2019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、多くの例で再燃を招く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アレルが欠失した白血球が検出される場合は、免疫病態の存在が特に濃厚と考えられる。患者のHLA-A抗原がヘテロ接合体である例やHLA-B61(B*40:02)陽性例では、モノクローナル抗体とフローサイトメトリーを用いてHLAクラスI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。
※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、実際の保険適用の査定において保険適用及び保険適用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用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,アレクシオン,協和キリン)[2021年]
監修:木崎昌弘 : 講演料(ブリストル・マイヤーズスクイブ,ヤンセンファーマ,ノバルティスファーマ,セルジーン,MSD,小野薬品,武田薬品,大日本住友製薬),研究費・助成金など(武田薬品),奨学(奨励)寄付など(協和キリン,中外製薬,武田薬品,小野薬品,第一三共)[2021年]

改訂のポイント:
  1. 再生不良性貧血診療の参照ガイド2019年改訂版に基づき、以下の点を改訂した。
  1. シクロスポリンの保険適用が従来の重症再生不良性貧血のみから、非重症再生不良性貧血を含むすべての重症度の再生不良性貧血に拡大された。これを受けて、輸血が不要な軽症・中等症の再生不良性貧血に対する初回治療をシクロスポリン3.5㎎/㎏より開始し、8週間後に効果がなければ、トロンボポエチンレセプター作動薬(thrombopoietin receptor agonist: TPO-RA)の追加を含む治療方針の変更を検討することとした。
  1. ウサギ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療法を受ける患者に対して、TPO-RAのエルトロンボパグ(EPAG)の併用が保険で認められるようになった。このため、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を追加することとした。
  1. ATG・シクロスポリン・EPAG療法後、3カ月経過時点で網赤血球や血小板の増加がまったくみられない場合は、EPAGをロミプロスチム(ROMI)に変更するとともに、蛋白同化ステロイドのプリモボランまたはダナゾール(保険適用外)の追加を検討することとした。

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、申請し認定されると保険料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. 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 

著者: 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
雑誌名: 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  N Engl J Med. 2015 Jul 2;373(1):35-47. doi: 10.1056/NEJ・・・
著者: 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
雑誌名: 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  Haematologica. 2010 Jun;95(6):976-82. doi: 10.3324/haem・・・
著者: 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
雑誌名: 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  Br J Haematol. 2019 Oct;187(2):227-237. doi: 10.1111/bj・・・
著者: 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
雑誌名: 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  Blood. 2011 Sep 1;118(9):2618-21. doi: 10.1182/blood-20・・・
著者: 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
雑誌名: 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  Blood. 2011 Dec 15;118(25):6601-9. doi: 10.1182/blood-2・・・
著者: 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
雑誌名: 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  Exp Hematol. 2016 Oct;44(10):931-939.e3. doi: 10.1016/j・・・
著者: Chizuru Saito, Ken Ishiyama, Hirohito Yamazaki, Yoshitaka Zaimoku, Shinji Nakao
雑誌名: 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  Br J Haematol. 2016 Oct;175(2):246-251. doi: 10.1111/bj・・・
著者: Chiharu Sugimori, Tatsuya Chuhjo, Xingmin Feng, Hirohito Yamazaki, Akiyoshi Takami, Masanao Teramura, Hideaki Mizoguchi, Mitsuhiro Omine, Shinji Nakao
雑誌名: 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  Blood. 2006 Feb 15;107(4):1308-14. doi: 10.1182/blood-2・・・
著者: Chiharu Sugimori, Kanako Mochizuki, Zhirong Qi, Naomi Sugimori, Ken Ishiyama, Yukio Kondo, Hirohito Yamazaki, Akiyoshi Takami, Hirokazu Okumura, Shinji Nakao
雑誌名: 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  Br J Haematol. 2009 Oct;147(1):102-12. doi: 10.1111/j.1・・・
著者: Nobuhiro Nishio, Hiroshi Yagasaki, Yoshiyuki Takahashi, Hideki Muramatsu, Asahito Hama, Nao Yoshida, Kazuko Kudo, Seiji Kojima
雑誌名: 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  Int J Hematol. 2009 May;89(4):409-13. doi: 10.1007/s121・・・
著者: Hirohito Yamazaki, Chiharu Sugimori, Tatsuya Chuhjo, Shinji Nakao
雑誌名: 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  Int J Hematol. 2007 Apr;85(3):186-90. doi: 10.1532/IJH9・・・
著者: 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
雑誌名: 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  Blood. 2011 Apr 28;117(17):4434-41. doi: 10.1182/blood-・・・
著者: Masanao Teramura, Akiro Kimura, Satsuki Iwase, Yuji Yonemura, Shinji Nakao, Akio Urabe, Mitsuhiro Omine, Hideaki Mizoguchi
雑誌名: 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  Blood. 2007 Sep 15;110(6):1756-61. doi: 10.1182/blood-2・・・
著者: Seiji Kojima, Akira Ohara, Masahiro Tsuchida, Toru Kudoh, Ryoji Hanada, Yuri Okimoto, Takashi Kaneko, Toshikuni Takano, Koichiro Ikuta, Ichiro Tsukimoto, Japan Childhood Aplastic Anemia Study Group
雑誌名: Blood. 2002 Aug 1;100(3):786-90.
Abstract/Text Long-term survivors of acquired aplastic anemia (AA) have an increased risk of developing myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) after immunosuppressive therapy (IST). It is uncertain whether the increased survival time simply discloses the natural history of AA as a premalignant disease or whether secondary disease is related to the therapy itself. Between November 1992 and September 1997, 113 AA children with normal cytogenetics at diagnosis were treated with IST using antithymocyte globulin, cyclosporin, and danazol with or without granulocyte colony-stimulating factor (G-CSF). We assessed risk factors for developing MDS/AML by Cox proportional hazards models. Twelve of 113 patients developed MDS between 9 and 81 months following the time of diagnosis, giving a cumulative incidence of 13.7 +/- 3.9%. The following cytogenetic abnormalities were observed at the time of diagnosis of MDS: monosomy 7 (6 patients), monosomy7/trisomy21 (1 patient), trisomy 11 (1 patient), del (11) (9?:14) (1 patient), add (9q) (1 patient), add 7 (q 32) (1 patient), and trisomy 9 (1 patient). The number of days of G-CSF therapy and nonresponse to therapy at 6 months were statistically significant risk factors by multivariate analysis. The present study suggests a close relationship between long-term use of G-CSF and secondary MDS in nonresponders to IST.

PMID 12130487  Blood. 2002 Aug 1;100(3):786-90.
著者: Phillip Scheinberg, Steven H Fischer, Li Li, Olga Nunez, Colin O Wu, Elaine M Sloand, Jeffrey I Cohen, Neal S Young, A John Barrett
雑誌名: 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  Blood. 2007 Apr 15;109(8):3219-24. doi: 10.1182/blood-2・・・
著者: Kinya Ohata, Noriko Iwaki, Takeharu Kotani, Yukio Kondo, Hirohito Yamazaki, Shinji Nakao
雑誌名: 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  Acta Haematol. 2012;127(2):96-9. doi: 10.1159/000333609・・・
著者: Hiroyuki Takamatsu, Raita Araki, Ryosei Nishimura, Akihiro Yachie, J Luis Espinoza, Hirokazu Okumura, Takashi Yoshida, Kiyotaka Kuzushima, Shinji Nakao
雑誌名: 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  J Clin Virol. 2016 Jul;80:82-6. doi: 10.1016/j.jcv.2016・・・
著者: Regis Peffault de Latour, Sylvie Chevret, Charlotte Jubert, Anne Sirvent, Claire Galambrun, Annalisa Ruggeri, Virginie Gandemer, Jérôme Cornillon, Fanny Rialland, Jean-Hugues Dalle, Edouard Forcade, Benedicte Bruno, Catherine Paillard, Pierre S Rorlich, Alexandra Salmon, Sabine Fürst, Flore Sicre de Fontbrune, Marie Therese Rubio, Jacques-Olivier Bay, Mohamad Mohty, Jerome Larghero, Eliane Gluckman, Gerard Socié, Francophone Society of Bone Marrow Transplantation and Cellular Therapy
雑誌名: Blood. 2018 Aug 16;132(7):750-754. doi: 10.1182/blood-2018-01-829630. Epub 2018 May 14.
Abstract/Text Outcomes remain poor for refractory severe aplastic anemia (SAA) patients. Alternative donor transplantation may be considered, but results from previous studies are not encouraging. We conducted a prospective nationwide phase 2 study to assess unrelated cord blood (CB) transplantation (CBT) efficacy and safety in refractory SAA patients (Aplastic Anemia and Cord Blood Transplantation protocol). To demonstrate a significant difference in 1-year survival from 20% (null hypothesis) to 50% (alternative hypothesis), we needed to include 25 transplanted patients and therefore included 26 (median age, 16 years). Eligibility criteria required 1 or 2 unrelated CB units, containing separately or together >4 × 107 frozen nucleated cells (NCs) per kilogram of recipient body weight. Conditioning regimen comprised fludarabine (FLU), cyclophosphamide (CY), antithymocyte globulin (ATG), and 2-Gy total body irradiation (TBI). With a median follow-up of 38.8 months, engraftment occurred in 23 patients (88%); cumulative incidences of grade II-IV acute and chronic graft-versus-host disease were 45.8% and 36%, respectively. Twenty-three patients were alive at 1 year, with an 88.5% overall survival (OS) rate, differing significantly from the expected 20% (P < .0001; 84% OS at 2 years). CBT with units containing ≥4 × 107 frozen NCs per kilogram is therefore a valuable curative option for young adults with refractory SAA and no available matched unrelated donors. This trial was registered at www.clinicaltrials.gov as #NCT01343953.

© 2018 by The American Society of Hematology.
PMID 29760162  Blood. 2018 Aug 16;132(7):750-754. doi: 10.1182/blood-2・・・
著者: 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
雑誌名: 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  Blood. 2019 Jun 13;133(24):2575-2585. doi: 10.1182/bloo・・・
著者: S Nakao, H Takamatsu, T Chuhjo, M Ueda, S Shiobara, T Matsuda, T Kaneshige, H Mizoguchi
雑誌名: 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  Blood. 1994 Dec 15;84(12):4257-61.

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