今日の臨床サポート

発作性夜間血色素尿症(PNH)

著者: 西村純一1) 大阪大学大学院医学系研究科 血液・腫瘍内科

著者: 金倉 譲2) 一般財団法人 住友病院

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:2020/07/09
参考ガイドライン:
厚生労働科学研究費補助金 難治性疾患克服研究事業 特発性造血障害に関する調査研究班:発作性夜間ヘモグロビン尿症診療の参照ガイド 令和1年改訂版
患者向け説明資料

概要・推奨   

  1. PNHの診断には抗CD55および抗CD59モノクローナル抗体またはFLAERを用いたフローサイトメトリー法が有用である(推奨度1)。
  1. PNH溶血に対するプレドニゾロンの副作用は、隔日投与とすることで軽減できる(推奨度2)。
  1. PNHの輸血には、必ずしも洗浄赤血球は必要なく、通常の赤血球濃厚液で十分である(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:
西村純一 : 報酬額(アレクシオン,中外)[2021年]
金倉 譲 : 特に申告事項無し[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. 上記ガイドラインに基づき、主に診断、重症度、治療などについて改訂を行った。新規治療薬としてラブリズマブが追加された。

病態・疫学・診察

疾患情報  
  1. 発作性夜間血色素尿症(paroxysmal nocturnal hemoglobinuria、 PNH)は、PIGAを含むGPIアンカー合成に関わる遺伝子に変異を持った造血幹細胞がクローン性に拡大した結果、補体介在性の血管内溶血を主徴とする造血幹細胞疾患である。(定義)
  1. 補体介在性の血管内溶血とそれに伴うヘモグロビン尿、 血栓症 、 骨髄不全 を3大症状とするが、それぞれの症状の程度と全体のバランスは症例ごとにさまざまで1例として同じ症例はない。特徴的な早朝ヘモグロビン尿を呈する症例は、全体の1/4から1/3にすぎない。 血栓症 はわが国ではまれであるが、PNHに特徴的な合併症である。 再生不良性貧血 (aplastic anemia、 AA)を代表とする後天性骨髄不全疾患としばしば合併・相互移行する。<図表>(病態)
 
典型的なPNH症例のヘモグロビン尿

このような特徴的な早朝ヘモグロビン尿を呈する症例は、全体の1/4から1/3にすぎない。

 
  1. 確定診断のための溶血所見としては、血清LDH値上昇、網赤血球増加、間接ビリルビン値上昇、血清ハプトグロビン値低下が参考になる。PNHタイプ赤血球(III型)が1%以上で、血清LDH値が正常上限の1.5倍以上であれば、臨床的PNHと診断してよい。<図表>(診断基準)
  1. 発作性夜間血色素尿症は、指定難病であり、「溶血所見に基づいた重症度分類」で中等症以上または軽症でも特段の理由がある場合などでは申請し、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。([https://www.nanbyou.or.jp/entry/3784])
  1.  難病法に基づく医療費助成制度 
問診・診察のポイント  
  1. 骨髄不全の既往を確認する。(例:AA 再生不良性貧血 、 骨髄異形成症候群 (myelodysplastic syndromes、MDS)、 貧血 などの既往と輸血歴)

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

著者: Charles Parker, Mitsuhiro Omine, Stephen Richards, Jun-Ichi Nishimura, Monica Bessler, Russell Ware, Peter Hillmen, Lucio Luzzatto, Neal Young, Taroh Kinoshita, Wendell Rosse, Gerard Socié, International PNH Interest Group
雑誌名: Blood. 2005 Dec 1;106(12):3699-709. doi: 10.1182/blood-2005-04-1717. Epub 2005 Jul 28.
Abstract/Text
PMID 16051736  Blood. 2005 Dec 1;106(12):3699-709. doi: 10.1182/blood-・・・
著者: Robert A Brodsky
雑誌名: Blood. 2009 Jun 25;113(26):6522-7. doi: 10.1182/blood-2009-03-195966. Epub 2009 Apr 16.
Abstract/Text Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal blood disorder that manifests with hemolytic anemia, bone marrow failure, and thrombosis. Many of the clinical manifestations of the disease result from complement-mediated intravascular hemolysis. Allogeneic bone marrow transplantation is the only curative therapy for PNH. Eculizumab, a monoclonal antibody that blocks terminal complement activation, is highly effective in reducing hemolysis, improving quality of life, and reducing the risk for thrombosis in PNH patients. Insights into the relevance of detecting PNH cells in PNH and other bone marrow failure disorders are highlighted, and indications for treating PNH patients with bone marrow transplantation and eculizumab are explored.

PMID 19372253  Blood. 2009 Jun 25;113(26):6522-7. doi: 10.1182/blood-2・・・
著者: Michael J Borowitz, Fiona E Craig, Joseph A Digiuseppe, Andrea J Illingworth, Wendell Rosse, D Robert Sutherland, Carl T Wittwer, Stephen J Richards, Clinical Cytometry Society
雑誌名: Cytometry B Clin Cytom. 2010 Jul;78(4):211-30. doi: 10.1002/cyto.b.20525.
Abstract/Text BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematopoietic stem cell disorder characterized by a somatic mutation in the PIGA gene, leading to a deficiency of proteins linked to the cell membrane via glycophosphatidylinositol (GPI) anchors. While flow cytometry is the method of choice for identifying cells deficient in GPI-linked proteins and is, therefore, necessary for the diagnosis of PNH, to date there has not been an attempt to standardize the methodology used to identify these cells.
METHODS: In this document, we present a consensus effort that describes flow cytometric procedures for detecting PNH cells.
RESULTS: We discuss clinical indications and offer recommendations on data interpretation and reporting but mostly focus on analytical procedures important for analysis. We distinguish between routine analysis (defined as identifying an abnormal population of 1% or more) and high-sensitivity analysis (in which as few as 0.01% PNH cells are detected). Antibody panels and gating strategies necessary for both procedures are presented in detail. We discuss methods for assessing PNH populations in both white blood cells and red blood cells and the relative advantages of measuring each. We present steps needed to validate the more elaborate high-sensitivity techniques, including the need for careful titration of reagents and determination of background rates in normal populations, and discuss technical pitfalls that might affect interpretation.
CONCLUSIONS: This document should both enable laboratories interested in beginning PNH testing to establish a valid procedure and allow experienced laboratories to improve their techniques.

(c) 2010 Clinical Cytometry Society.
PMID 20533382  Cytometry B Clin Cytom. 2010 Jul;78(4):211-30. doi: 10.・・・
著者: Hongbo Wang, Tatsuya Chuhjo, Shizuka Yasue, Mitsuhiro Omine, Shinji Nakao
雑誌名: Blood. 2002 Dec 1;100(12):3897-902. doi: 10.1182/blood-2002-03-0799. Epub 2002 Aug 8.
Abstract/Text A minor population of blood cells deficient of glycosylphosphatidylinositol (GPI)-anchored membrane proteins is often detected in patients with aplastic anemia (AA), though the clinical significance of such paroxysmal nocturnal hemoglobinuria (PNH)-type cells remains unclear. To clarify this issue, we studied 164 patients with myelodysplastic syndrome (MDS) for the presence of CD55(-)CD59(-) granulocytes and red blood cells using sensitive flow cytometry. Among the different subgroups of MDS, a significant increase (ie, at least 0.003%) of PNH-type cells was detected in 21 of 119 patients with refractory anemia (RA); this frequency (17.6%) of RA patients with increased PNH-type cells (PNH(+) patients) was much lower than what we previously reported (52.0%) for AA patients. PNH(+) RA patients had distinct clinical features compared with RA patients without increased PNH-type cells (PNH(-) patients), such as less pronounced morphologic abnormality of blood cells, more severe thrombocytopenia, lower rates of karyotypic abnormality (4.8% vs 32.8%) and of progression to acute leukemia (0% vs 6.2%), higher probability of response to cyclosporine therapy (77.8% vs 0%), and higher incidence of HLA-DR15 (90.5% vs 18.5%). These data indicate that the presence of a minor population of PNH-type cells suggests a benign type of bone marrow failure, probably caused by an immunologic mechanism. To choose an appropriate therapy, peripheral blood should be tested using sensitive flow cytometry for the presence of PNH-type cells in all patients with bone marrow failure before treatment.

PMID 12393738  Blood. 2002 Dec 1;100(12):3897-902. doi: 10.1182/blood-・・・
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: Peter Hillmen, Claire Hall, Judith C W Marsh, Modupe Elebute, Michael P Bombara, Beth E Petro, Matthew J Cullen, Stephen J Richards, Scott A Rollins, Christopher F Mojcik, Russell P Rother
雑誌名: N Engl J Med. 2004 Feb 5;350(6):552-9. doi: 10.1056/NEJMoa031688.
Abstract/Text BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) arises from a somatic mutation of the PIG-A gene in a hematopoietic stem cell and the subsequent production of blood cells with a deficiency of surface proteins that protect the cells against attack by the complement system. We tested the clinical efficacy of eculizumab, a humanized antibody that inhibits the activation of terminal complement components, in patients with PNH.
METHODS: Eleven transfusion-dependent patients with PNH received infusions of eculizumab (600 mg) every week for four weeks, followed one week later by a 900-mg dose and then by 900 mg every other week through week 12. Clinical and biochemical indicators of hemolysis were measured throughout the trial.
RESULTS: Mean lactate dehydrogenase levels decreased from 3111 IU per liter before treatment to 594 IU per liter during treatment (P=0.002). The mean percentage of PNH type III erythrocytes increased from 36.7 percent of the total erythrocyte population to 59.2 percent (P=0.005). The mean and median transfusion rates decreased from 2.1 and 1.8 units per patient per month to 0.6 and 0.0 units per patient per month, respectively (P=0.003 for the comparison of the median rates). Episodes of hemoglobinuria were reduced by 96 percent (P<0.001), and measurements of the quality of life improved significantly.
CONCLUSIONS: Eculizumab is safe and well tolerated in patients with PNH. This antibody against terminal complement protein C5 reduces intravascular hemolysis, hemoglobinuria, and the need for transfusion, with an associated improvement in the quality of life in patients with PNH.

Copyright 2004 Massachusetts Medical Society
PMID 14762182  N Engl J Med. 2004 Feb 5;350(6):552-9. doi: 10.1056/NEJ・・・
著者: Anita Hill, Peter Hillmen, Stephen J Richards, Dupe Elebute, Judith C Marsh, Jason Chan, Christopher F Mojcik, Russell P Rother
雑誌名: Blood. 2005 Oct 1;106(7):2559-65. doi: 10.1182/blood-2005-02-0564. Epub 2005 Jun 28.
Abstract/Text Paroxysmal nocturnal hemoglobinuria (PNH) is a hematologic disorder characterized by clonal expansion of red blood cells (RBCs) lacking the ability to inhibit complement-mediated hemolysis. Eculizumab, a humanized monoclonal antibody that binds the C5 complement protein, blocks serum hemolytic activity. This study evaluated the long-term safety and efficacy of eculizumab in 11 patients with PNH during an open-label extension trial. After completion of an initial 12-week study, all patients chose to participate in the 52-week extension study. Eculizumab, administered at 900 mg every 12 to 14 days, was sufficient to completely and consistently block complement activity in all patients. A dramatic reduction in hemolysis was maintained throughout the study, with a decrease in lactate dehydrogenase (LDH) levels from 3110.7 IU/L before treatment to 622.4 IU/L (P = .002). The proportion of PNH type III RBCs increased from 36.7% at baseline to 58.4% (P = .005). The paroxysm rate of days with gross evidence of hemoglobinuria per patient each month decreased from 3.0 during screening to 0.2 (P < .001) during treatment. The median transfusion rate decreased from 1.8 U per patient each month before eculizumab treatment to 0.3 U per patient each month (P = .001) during treatment. Statistically significant improvements in quality-of-life measures were also maintained during the extension study. Eculizumab continued to be safe and well tolerated, and all patients completed the study. The close relationship between sustained terminal complement inhibition, hemolysis, and symptoms was demonstrated.

PMID 15985537  Blood. 2005 Oct 1;106(7):2559-65. doi: 10.1182/blood-20・・・
著者: Peter Hillmen, Neal S Young, Jörg Schubert, Robert A Brodsky, Gerard Socié, Petra Muus, Alexander Röth, Jeffrey Szer, Modupe O Elebute, Ryotaro Nakamura, Paul Browne, Antonio M Risitano, Anita Hill, Hubert Schrezenmeier, Chieh-Lin Fu, Jaroslaw Maciejewski, Scott A Rollins, Christopher F Mojcik, Russell P Rother, Lucio Luzzatto
雑誌名: N Engl J Med. 2006 Sep 21;355(12):1233-43. doi: 10.1056/NEJMoa061648.
Abstract/Text BACKGROUND: We tested the safety and efficacy of eculizumab, a humanized monoclonal antibody against terminal complement protein C5 that inhibits terminal complement activation, in patients with paroxysmal nocturnal hemoglobinuria (PNH).
METHODS: We conducted a double-blind, randomized, placebo-controlled, multicenter, phase 3 trial. Patients received either placebo or eculizumab intravenously; eculizumab was given at a dose of 600 mg weekly for 4 weeks, followed 1 week later by a 900-mg dose and then 900 mg every other week through week 26. The two primary end points were the stabilization of hemoglobin levels and the number of units of packed red cells transfused. Biochemical indicators of intravascular hemolysis and the patients' quality of life were also assessed.
RESULTS: Eighty-seven patients underwent randomization. Stabilization of hemoglobin levels in the absence of transfusions was achieved in 49% (21 of 43) of the patients assigned to eculizumab and none (0 of 44) of those assigned to placebo (P<0.001). During the study, a median of 0 units of packed red cells was administered in the eculizumab group, as compared with 10 units in the placebo group (P<0.001). Eculizumab reduced intravascular hemolysis, as shown by the 85.8% lower median area under the curve for lactate dehydrogenase plotted against time (in days) in the eculizumab group, as compared with the placebo group (58,587 vs. 411,822 U per liter; P<0.001). Clinically significant improvements were also found in the quality of life, as measured by scores on the Functional Assessment of Chronic Illness Therapy-Fatigue instrument (P<0.001) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Of the 87 patients, 4 in the eculizumab group and 9 in the placebo group had serious adverse events, none of which were considered to be treatment-related; all these patients recovered without sequelae.
CONCLUSIONS: Eculizumab is an effective therapy for PNH.

2006 Massachusetts Medical Society
PMID 16990386  N Engl J Med. 2006 Sep 21;355(12):1233-43. doi: 10.1056・・・
著者: Robert A Brodsky, Neal S Young, Elisabetta Antonioli, Antonio M Risitano, Hubert Schrezenmeier, Jörg Schubert, Anna Gaya, Luke Coyle, Carlos de Castro, Chieh-Lin Fu, Jaroslaw P Maciejewski, Monica Bessler, Henk-André Kroon, Russell P Rother, Peter Hillmen
雑誌名: Blood. 2008 Feb 15;111(4):1840-7. doi: 10.1182/blood-2007-06-094136. Epub 2007 Nov 30.
Abstract/Text The terminal complement inhibitor eculizumab was recently shown to be effective and well tolerated in patients with paroxysmal nocturnal hemoglobinuria (PNH). Here, we extended these observations with results from an open-label, non-placebo-controlled, 52-week, phase 3 clinical safety and efficacy study evaluating eculizumab in a broader PNH patient population. Eculizumab was administered by intravenous infusion at 600 mg every 7 +/- 2 days for 4 weeks; 900 mg 7 +/- 2 days later; followed by 900 mg every 14 +/- 2 days for a total treatment period of 52 weeks. Ninety-seven patients at 33 international sites were enrolled. Patients treated with eculizumab responded with an 87% reduction in hemolysis, as measured by lactate dehydrogenase levels (P < .001). Baseline fatigue scores in the FACIT-Fatigue instrument improved by 12.2 +/- 1.1 points (P < .001). Eculizumab treatment led to an improvement in anemia. The increase in hemoglobin level occurred despite a reduction in transfusion requirements from a median of 8.0 units of packed red cells per patient before treatment to 0.0 units per patient during the study (P < .001). Overall, transfusions were reduced 52% from a mean of 12.3 to 5.9 units of packed red cells per patient. Forty-nine patients (51%) achieved transfusion independence for the entire 52-week period. Improvements in hemolysis, fatigue, and transfusion requirements with eculizumab were independent of baseline levels of hemolysis and degree of thrombocytopenia. Quality of life measures were also broadly improved with eculizumab treatment. This study demonstrates that the beneficial effects of eculizumab treatment in patients with PNH are applicable to a broader population of PNH patients than previously studied. This trial is registered at http://clinicaltrials.gov as NCT00130000.

PMID 18055865  Blood. 2008 Feb 15;111(4):1840-7. doi: 10.1182/blood-20・・・
著者: Yuzuru Kanakura, Kazuma Ohyashiki, Tsutomu Shichishima, Shinichiro Okamoto, Kiyoshi Ando, Haruhiko Ninomiya, Tatsuya Kawaguchi, Shinji Nakao, Hideki Nakakuma, Jun-ichi Nishimura, Taroh Kinoshita, Camille L Bedrosian, Marye Ellen Valentine, Gus Khursigara, Keiya Ozawa, Mitsuhiro Omine
雑誌名: Int J Hematol. 2011 Jan;93(1):36-46. doi: 10.1007/s12185-010-0748-9. Epub 2011 Jan 12.
Abstract/Text Paroxysmal nocturnal hemoglobinuria (PNH) is a progressive and life-threatening disease characterized by complement-mediated chronic hemolysis, resulting in serious life-threatening complications and early mortality. Eculizumab, a humanized anti-C5 monoclonal antibody that inhibits terminal complement activation, has been shown to reduce hemolysis in PNH patients. The pivotal open-label, 12-week phase II registration study (AEGIS) was designed to evaluate the efficacy and safety of eculizumab in Japanese patients with PNH. This trial achieved its primary endpoint of reducing intravascular hemolysis with high statistical significance. Twenty-seven of the 29 patients responded to eculizumab treatment, resulting in an 87% reduction in hemolysis (P < 0.0001) and subsequent improvement in anemia (P = 0.0003) despite reduction in transfusion requirements (P = 0.006). Fatigue and dyspnea significantly improved within 1-2 weeks of eculizumab treatment and the improvement was independent of changes in hemoglobin. Chronic kidney disease (CKD) was common (66%) and eculizumab treatment improved CKD in 41% of patients at 12 weeks (P < 0.001). Elevated thrombotic risk was evident in Japanese PNH patients and eculizumab treatment normalized D: -dimer levels in 45% of patients with elevated D: -dimers at baseline (P < 0.001). The AEGIS results demonstrate that eculizumab is effective, safe and well tolerated in Japanese patients with PNH.

PMID 21222185  Int J Hematol. 2011 Jan;93(1):36-46. doi: 10.1007/s1218・・・
著者: Antonio M Risitano, Rosario Notaro, Ludovica Marando, Bianca Serio, Danilo Ranaldi, Elisa Seneca, Patrizia Ricci, Fiorella Alfinito, Andrea Camera, Giacomo Gianfaldoni, Angela Amendola, Carla Boschetti, Eros Di Bona, Giorgio Fratellanza, Filippo Barbano, Francesco Rodeghiero, Alberto Zanella, Anna Paola Iori, Carmine Selleri, Lucio Luzzatto, Bruno Rotoli
雑誌名: Blood. 2009 Apr 23;113(17):4094-100. doi: 10.1182/blood-2008-11-189944. Epub 2009 Jan 29.
Abstract/Text In paroxysmal nocturnal hemoglobinuria (PNH) hemolytic anemia is due mainly to deficiency of the complement regulator CD59 on the surface of red blood cells (RBCs). Eculizumab, an antibody that targets complement fraction 5 (C5), has proven highly effective in abolishing complement-mediated intravascular hemolysis in PNH; however, the hematologic benefit varies considerably among patients. In the aim to understand the basis for this variable response, we have investigated by flow cytometry the binding of complement fraction 3 (C3) on RBCs from PNH patients before and during eculizumab treatment. There was no evidence of C3 on RBCs of untreated PNH patients; by contrast, in all patients on eculizumab (n = 41) a substantial fraction of RBCs had C3 bound on their surface, and this was entirely restricted to RBCs with the PNH phenotype (CD59(-)). The proportion of C3(+) RBCs correlated significantly with the reticulocyte count and with the hematologic response to eculizumab. In 3 patients in whom (51)Cr labeling of RBCs was carried out while on eculizumab, we have demonstrated reduced RBC half-life in vivo, with excess (51)Cr uptake in spleen and in liver. Binding of C3 by PNH RBCs may constitute an additional disease mechanism in PNH, strongly enhanced by eculizumab treatment and producing a variable degree of extravascular hemolysis.

PMID 19179465  Blood. 2009 Apr 23;113(17):4094-100. doi: 10.1182/blood・・・
著者: Richard J Kelly, Anita Hill, Louise M Arnold, Gemma L Brooksbank, Stephen J Richards, Matthew Cullen, Lindsay D Mitchell, Dena R Cohen, Walter M Gregory, Peter Hillmen
雑誌名: Blood. 2011 Jun 23;117(25):6786-92. doi: 10.1182/blood-2011-02-333997. Epub 2011 Apr 1.
Abstract/Text Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder with increased mortality and morbidity resulting from intravascular hemolysis. Eculizumab, a monoclonal antibody against the complement protein 5, stops the intravascular hemolysis in PNH. We evaluated 79 consecutive patients treated with eculizumab in Leeds between May 2002 and July 2010. The survival of patients treated with eculizumab was not different from age- and sex-matched normal controls (P = .46) but was significantly better than 30 similar patients managed before eculizumab (P = .030). Three patients on eculizumab, all over 50 years old, died of causes unrelated to PNH. Twenty-one patients (27%) had a thrombosis before starting eculizumab (5.6 events per 100 patient-years) compared with 2 thromboses on eculizumab (0.8 events per 100 patient-years; P < .001). Twenty-one patients with no previous thrombosis discontinued warfarin on eculizumab with no thrombotic sequelae. Forty of 61 (66%) patients on eculizumab for more than 12 months achieved transfusion independence. The 12-month mean transfusion requirement reduced from 19.3 units before eculizumab to 5.0 units in the most recent 12 months on eculizumab (P < .001). Eculizumab dramatically alters the natural course of PNH, reducing symptoms and disease complications as well as improving survival to a similar level to that of the general population.

PMID 21460245  Blood. 2011 Jun 23;117(25):6786-92. doi: 10.1182/blood-・・・
著者: Jun-ichi Nishimura, Masaki Yamamoto, Shin Hayashi, Kazuma Ohyashiki, Kiyoshi Ando, Andres L Brodsky, Hideyoshi Noji, Kunio Kitamura, Tetsuya Eto, Toru Takahashi, Masayoshi Masuko, Takuro Matsumoto, Yuji Wano, Tsutomu Shichishima, Hirohiko Shibayama, Masakazu Hase, Lan Li, Krista Johnson, Alberto Lazarowski, Paul Tamburini, Johji Inazawa, Taroh Kinoshita, Yuzuru Kanakura
雑誌名: N Engl J Med. 2014 Feb 13;370(7):632-9. doi: 10.1056/NEJMoa1311084.
Abstract/Text BACKGROUND: Eculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement-mediated hemolysis associated with paroxysmal nocturnal hemoglobinuria (PNH). The molecular basis for the poor response to eculizumab in a small population of Japanese patients is unclear.
METHODS: We assessed the sequences of the gene encoding C5 in patients with PNH who had either a good or poor response to eculizumab. We also evaluated the functional properties of C5 as it was encoded in these patients.
RESULTS: Of 345 Japanese patients with PNH who received eculizumab, 11 patients had a poor response. All 11 had a single missense C5 heterozygous mutation, c.2654G → A, which predicts the polymorphism p.Arg885His. The prevalence of this mutation among the patients with PNH (3.2%) was similar to that among healthy Japanese persons (3.5%). This polymorphism was also identified in a Han Chinese population. A patient in Argentina of Asian ancestry who had a poor response had a very similar mutation, c.2653C → T, which predicts p.Arg885Cys. Nonmutant and mutant C5 both caused hemolysis in vitro, but only nonmutant C5 bound to and was blocked by eculizumab. In vitro hemolysis due to nonmutant and mutant C5 was completely blocked with the use of N19-8, a monoclonal antibody that binds to a different site on C5 than does eculizumab.
CONCLUSIONS: The functional capacity of C5 variants with mutations at Arg885, together with their failure to undergo blockade by eculizumab, account for the poor response to this agent in patients who carry these mutations. (Funded by Alexion Pharmaceuticals and the Ministry of Health, Labor, and Welfare of Japan.).

PMID 24521109  N Engl J Med. 2014 Feb 13;370(7):632-9. doi: 10.1056/NE・・・
著者: Jong Wook Lee, Flore Sicre de Fontbrune, Lily Wong Lee Lee, Viviani Pessoa, Sandra Gualandro, Wolfgang Füreder, Vadim Ptushkin, Scott T Rottinghaus, Lori Volles, Lori Shafner, Rasha Aguzzi, Rajendra Pradhan, Hubert Schrezenmeier, Anita Hill
雑誌名: Blood. 2019 Feb 7;133(6):530-539. doi: 10.1182/blood-2018-09-876136. Epub 2018 Dec 3.
Abstract/Text Ravulizumab (ALXN1210), a new complement C5 inhibitor, provides immediate, complete, and sustained C5 inhibition. This phase 3, open-label study assessed the noninferiority of ravulizumab to eculizumab in complement inhibitor-naive adults with paroxysmal nocturnal hemoglobinuria (PNH). Patients with lactate dehydrogenase (LDH) ≥1.5 times the upper limit of normal and at least 1 PNH symptom were randomized 1:1 to receive ravulizumab or eculizumab for 183 days (N = 246). Coprimary efficacy end points were proportion of patients remaining transfusion-free and LDH normalization. Secondary end points were percent change from baseline in LDH, change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, proportion of patients with breakthrough hemolysis, stabilized hemoglobin, and change in serum free C5. Ravulizumab was noninferior to eculizumab for both coprimary and all key secondary end points (Pinf < .0001): transfusion avoidance (73.6% vs 66.1%; difference of 6.8% [95% confidence interval (CI), -4.66, 18.14]), LDH normalization (53.6% vs 49.4%; odds ratio, 1.19 [0.80, 1.77]), percent reduction in LDH (-76.8% vs -76.0%; difference [95% CI], -0.83% [-5.21, 3.56]), change in FACIT-Fatigue score (7.07 vs 6.40; difference [95% CI], 0.67 [-1.21, 2.55]), breakthrough hemolysis (4.0% vs 10.7%; difference [95% CI], -6.7% [-14.21, 0.18]), and stabilized hemoglobin (68.0% vs 64.5%; difference [95% CI], 2.9 [-8.80, 14.64]). The safety and tolerability of ravulizumab and eculizumab were similar; no meningococcal infections occurred. In conclusion, ravulizumab given every 8 weeks achieved noninferiority compared with eculizumab given every 2 weeks for all efficacy end points, with a similar safety profile. This trial was registered at www.clinicaltrials.gov as #NCT02946463.

© 2019 by The American Society of Hematology.
PMID 30510080  Blood. 2019 Feb 7;133(6):530-539. doi: 10.1182/blood-20・・・
著者: Austin G Kulasekararaj, Anita Hill, Scott T Rottinghaus, Saskia Langemeijer, Richard Wells, F Ataulfo Gonzalez-Fernandez, Anna Gaya, Jong Wook Lee, Emilio Ojeda Gutierrez, Caroline I Piatek, Jeff Szer, Antonio Risitano, Shinji Nakao, Eric Bachman, Lori Shafner, Andrew I Damokosh, Stephan Ortiz, Alexander Röth, Regis Peffault de Latour
雑誌名: Blood. 2019 Feb 7;133(6):540-549. doi: 10.1182/blood-2018-09-876805. Epub 2018 Dec 3.
Abstract/Text Ravulizumab, a new complement component C5 inhibitor administered every 8 weeks, was noninferior to eculizumab administered every 2 weeks in complement-inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH). This study assessed noninferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy. In this phase 3, open-label, multicenter study, 195 PNH patients on labeled-dose (900 mg every 2 weeks) eculizumab for >6 months were randomly assigned 1:1 to switch to ravulizumab (n = 97) or continue eculizumab (n = 98). Primary efficacy end point was percentage change in lactate dehydrogenase (LDH) from baseline to day 183. Key secondary end points included proportion of patients with breakthrough hemolysis, change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, transfusion avoidance, and stabilized hemoglobin. In 191 patients completing 183 days of treatment, ravulizumab was noninferior to eculizumab (Pinf < .0006 for all end points), including percentage change in LDH (difference, 9.21% [95% confidence interval (CI), -0.42 to 18.84], P = .058 for superiority), breakthrough hemolysis (difference, 5.1 [95% CI, -8.89 to 18.99]), change in FACIT-Fatigue score (difference, 1.47 [95% CI, -0.21 to 3.15]), transfusion avoidance (difference, 5.5 [95% CI, -4.27 to 15.68]), and stabilized hemoglobin (difference, 1.4 [95% CI, -10.41 to 13.31]). The most frequently reported adverse event was headache (26.8%, ravulizumab; 17.3%, eculizumab). No meningococcal infections or discontinuations due to adverse events occurred. Patients with PNH may be safely and effectively switched from labeled-dose eculizumab administered every 2 weeks to ravulizumab administered every 8 weeks. This trial was funded by Alexion Pharmaceuticals, Inc., and is registered at www.clinicaltrials.gov as #NCT03056040.

© 2019 by The American Society of Hematology.
PMID 30510079  Blood. 2019 Feb 7;133(6):540-549. doi: 10.1182/blood-20・・・
著者: W F Rosse
雑誌名: Blood. 1982 Jul;60(1):20-3.
Abstract/Text Patients with PNH may be treated with a number of known agents. As in all patients with a chronic disease, a regimen tolerable over a long period of time must be selected. Knowledge and anticipation of complications and their proper treatment are essential parts in the treatment. When these principals are used, many patients may live reasonable lives for very long periods of time.

PMID 7044450  Blood. 1982 Jul;60(1):20-3.
著者: M E Brecher, H F Taswell
雑誌名: Transfusion. 1989 Oct;29(8):681-5.
Abstract/Text Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon, acquired clonal stem cell disorder primarily affecting red cells that have an abnormal sensitivity to complement lysis. Since 1948, the use of saline-washed red cells (WRBCs) has been advocated to minimize hemolysis after transfusion to patients with PNH. Thirty-eight years of experience (1950 through 1987) with patients who had PNH were reviewed. Twenty-three patients with a positive Ham's test had been transfused with 556 blood components, including 431 RBC products: 94 units of whole blood, 208 units of packed RBCs, 80 units of white cell-poor RBCs, 38 units of WRBCs, 5 units of frozen RBCs, and 6 units of intraoperatively salvaged RBCs. Only one documented episode of posttransfusion hemolysis related to the underlying diagnosis of PNH was found, and it was associated with the transfusion of a unit of type O whole blood to an AB-positive individual. This unit contained ABO-incompatible plasma; this case was similar to one in an earlier report from which originated the recommendation for using WRBCs. The posttransfusion increment in hemoglobin concentration in patients receiving ABO-identical packed RBCs was comparable to that in patients receiving frozen or washed RBCs. These findings indicate that the use of WRBCs is unnecessary and that patients with PNH should be transfused with group-specific blood and blood products.

PMID 2799892  Transfusion. 1989 Oct;29(8):681-5.
著者: Peter Hillmen, Petra Muus, Ulrich Dührsen, Antonio M Risitano, Jörg Schubert, Lucio Luzzatto, Hubert Schrezenmeier, Jeffrey Szer, Robert A Brodsky, Anita Hill, Gerard Socié, Monica Bessler, Scott A Rollins, Leonard Bell, Russell P Rother, Neal S Young
雑誌名: Blood. 2007 Dec 1;110(12):4123-8. doi: 10.1182/blood-2007-06-095646. Epub 2007 Aug 16.
Abstract/Text Hemolysis and hemoglobinemia contribute to serious clinical sequelae in hemolytic disorders. In paroxysmal nocturnal hemoglobinuria (PNH) patients, hemolysis can contribute to thromboembolism (TE), the most feared complication in PNH, and the leading cause of disease-related deaths. We evaluated whether long-term treatment with the complement inhibitor eculizumab reduces the rate of TE in patients with PNH. Clinical trial participants included all patients in the 3 eculizumab PNH clinical studies, which recruited patients between 2002 and 2005 (n = 195); patients from these studies continued treatment in the current multinational open-label extension study. Thromboembolism rate with eculizumab treatment was compared with the pretreatment rate in the same patients. The TE event rate with eculizumab treatment was 1.07 events/100 patient-years compared with 7.37 events/100 patient-years (P < .001) prior to eculizumab treatment (relative reduction, 85%; absolute reduction, 6.3 TE events/100 patient-years). With equalization of the duration of exposure before and during treatment for each patient, TE events were reduced from 39 events before eculizumab to 3 events during eculizumab (P < .001). The TE event rate in antithrombotic-treated patients (n = 103) was reduced from 10.61 to 0.62 events/100 patient-years with eculizumab treatment (P < .001). These results show that eculizumab treatment reduces the risk of clinical thromboembolism in patients with PNH. This study is registered at http://clinicaltrials.gov (study ID no. NCT00122317).

PMID 17702897  Blood. 2007 Dec 1;110(12):4123-8. doi: 10.1182/blood-20・・・
著者: R L Paquette, R Yoshimura, C Veiseh, L Kunkel, J Gajewski, P J Rosen
雑誌名: Br J Haematol. 1997 Jan;96(1):92-7.
Abstract/Text Seven patients with paroxysmal nocturnal haemoglobinuria (PNH) were treated with antithymocyte globulin (ATG). Each patient received ATG (20 mg/kg/d) for 8 d and prednisone to prevent or control serum sickness. Three patients experienced a sustained improvement in at least one peripheral blood cytopenia, including one patient who had a complete trilineage response. Several pretreatment clinical features appeared to be associated with response to ATG. All responding patients had hypoproliferative features including depressed platelet counts (< 30 x 10(9)/l), and a minor degree of chronic haemolysis as indicated by relatively low reticulocyte counts (< 100 x 10(9)/l), lactate dehydrogenase (< 1000 U/l) and total bilirubin (< 17 mumol/l) levels. Responding patients continued to have chronic low-grade haemolysis after their response to immunosuppression that was similar to that observed prior to treatment. The non-responding patients had a classic haemolytic form of PNH characterized by elevated reticulocyte counts (> 100 x 10(9)/l), lactate dehydrogenase (> 2000 U/l) and total bilirubin (> 17 mumol/l) levels. The impaired haemopoiesis that occurs in hypoproliferative PNH may respond to ATG treatment, but the haemolytic component of the disease, and hence the PNH clone, is not altered by immunosuppressive therapy.

PMID 9012693  Br J Haematol. 1997 Jan;96(1):92-7.
著者: Peter Hillmen, Modupe Elebute, Richard Kelly, Alvaro Urbano-Ispizua, Anita Hill, Russell P Rother, Gus Khursigara, Chieh-Lin Fu, Mitsuhiro Omine, Paul Browne, Wendell Rosse
雑誌名: Am J Hematol. 2010 Aug;85(8):553-9. doi: 10.1002/ajh.21757.
Abstract/Text Paroxysmal nocturnal hemoglobinuria (PNH) is a debilitating and life-threatening disease in which lysis of PNH red blood cells frequently manifests with chronic hemolysis, anemia, and thrombosis. Renal damage in PNH is associated with chronic hemosiderosis and/or microvascular thrombosis. We determined the incidence of renal dysfunction or damage, defined by stages of chronic kidney disease (CKD), in a large cohort of PNH patients and evaluated the safety and efficacy of the complement inhibitor eculizumab in altering its progression. Renal dysfunction or damage was observed in 65% of the study population at baseline with 21% of patients with later stage CKD or kidney failure (glomerular filtration rate [GFR]
(c) 2010 Wiley-Liss, Inc.
PMID 20658586  Am J Hematol. 2010 Aug;85(8):553-9. doi: 10.1002/ajh.21・・・
著者: Anita Hill, Russell P Rother, Peter Hillmen
雑誌名: Haematologica. 2005 Dec;90(12 Suppl):ECR40.
Abstract/Text Aberrant smooth muscle dystonia during hemolytic episodes in paroxysmal nocturnal hemoglobinuria (PNH) is implicated in the symptoms of abdominal pain, dysphagia and erectile dysfunction. Here we report two PNH patients treated with the complement inhibitor, eculizumab. Complement inhibition has been sustained for over 2 years and results in resolution of intravascular hemolysis and amelioration of symptoms associated with smooth muscle contractions.

PMID 16464755  Haematologica. 2005 Dec;90(12 Suppl):ECR40.
著者: Anita Hill, Russell P Rother, Xunde Wang, Sidney M Morris, Kerry Quinn-Senger, Richard Kelly, Stephen J Richards, Monica Bessler, Leonard Bell, Peter Hillmen, Mark T Gladwin
雑誌名: Br J Haematol. 2010 May;149(3):414-25. doi: 10.1111/j.1365-2141.2010.08096.x. Epub 2010 Mar 8.
Abstract/Text Pulmonary hypertension (PH) is a common complication of haemolytic anaemia. Intravascular haemolysis leads to nitric oxide (NO) depletion, endothelial and smooth muscle dysregulation, and vasculopathy, characterized by progressive hypertension. PH has been reported in patients with paroxysmal nocturnal haemoglobinuria (PNH), a life-threatening haemolytic disease. We explored the relationship between haemolysis, systemic NO, arginine catabolism and measures of PH in 73 PNH patients enrolled in the placebo-controlled TRIUMPH (Transfusion Reduction Efficacy and Safety Clinical Investigation Using Eculizumab in Paroxysmal Nocturnal Haemoglobinuria) study. At baseline, intravascular haemolysis was associated with elevated NO consumption (P < 0.0001) and arginase-1 release (P < 0.0001). Almost half of the patients in the trial had elevated levels (> or =160 pg/ml) of N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of pulmonary vascular resistance and right ventricular dysfunction previously shown to indicate PH. Eculizumab treatment significantly reduced haemolysis (P < 0.001), NO depletion (P < 0.001), vasomotor tone (P < 0.05), dyspnoea (P = 0.006) and resulted in a 50% reduction in the proportion of patients with elevated NT-proBNP (P < 0.001) within 2 weeks of treatment. Importantly, the significant improvements in dyspnoea and NT-proBNP levels occurred without significant changes in anaemia. These data demonstrated that intravascular haemolysis in PNH produces a state of NO catabolism leading to signs of PH, including elevated NT pro-BNP and dyspnoea that are significantly improved by treatment with eculizumab.

PMID 20230403  Br J Haematol. 2010 May;149(3):414-25. doi: 10.1111/j.1・・・
著者: Alexey V Danilov, Hedy Smith, Sabrina Craigo, Dianne M Feeney, Valerie Relias, Kenneth B Miller
雑誌名: Leuk Res. 2009 Jun;33(6):e4-5. doi: 10.1016/j.leukres.2008.09.008. Epub 2008 Oct 25.
Abstract/Text
PMID 18952283  Leuk Res. 2009 Jun;33(6):e4-5. doi: 10.1016/j.leukres.2・・・
著者: Alexey V Danilov, Robert A Brodsky, Sabrina Craigo, Hedy Smith, Kenneth B Miller
雑誌名: Leuk Res. 2010 May;34(5):566-71. doi: 10.1016/j.leukres.2009.10.025. Epub 2009 Dec 1.
Abstract/Text Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal stem cell disorder, which affects women of child-bearing age. PNH is associated with thrombotic complications, which are the main causes of morbidity and mortality. Management of a pregnant woman with PNH remains a challenge due to high incidence of thrombotic complications and the difficulty of differentiating a PNH crisis from the complications of pregnancy. PNH is associated with an increased rate of premature labor and fetal loss. Eculizumab, a humanized monoclonal antibody directed against the terminal complement protein C5, has revolutionized treatment of PNH. However, the role of eculizumab in pregnancy is unclear. We review the current strategies for the management of pregnant women with PNH, underline the controversies and present our recommendations.

Copyright (c) 2009 Elsevier Ltd. All rights reserved.
PMID 19954846  Leuk Res. 2010 May;34(5):566-71. doi: 10.1016/j.leukres・・・
著者: Richard Kelly, Louise Arnold, Stephen Richards, Anita Hill, Charlotte Bomken, John Hanley, Andrew Loughney, Jon Beauchamp, Gus Khursigara, Russell P Rother, Elizabeth Chalmers, Andrew Fyfe, Edward Fitzsimons, Ryotaro Nakamura, Anna Gaya, Antonio M Risitano, Jörg Schubert, Derek Norfolk, Nigel Simpson, Peter Hillmen
雑誌名: Br J Haematol. 2010 May;149(3):446-50. doi: 10.1111/j.1365-2141.2010.08099.x. Epub 2010 Feb 11.
Abstract/Text In Paroxysmal nocturnal haemoglobinuria (PNH), pregnancy is associated with increased maternal and foetal complications to such an extent that the condition has been considered relatively contra-indicated in PNH. Eculizumab has revolutionized the treatment of PNH. We evaluate its use in pregnancy to date. We report on seven patients exposed to eculizumab at different stages of pregnancy including the first two patients to receive the drug from conception to delivery. There was no evidence of complement blockade from cord blood samples taken at delivery. Eculizumab appears safe to use in this setting and is likely to prevent many of the complications usually observed.

PMID 20151973  Br J Haematol. 2010 May;149(3):446-50. doi: 10.1111/j.1・・・
著者: Roberto Marasca, Valeria Coluccio, Rita Santachiara, Giovanna Leonardi, Giuseppe Torelli, Rosario Notaro, Lucio Luzzatto
雑誌名: Br J Haematol. 2010 Sep;150(6):707-8. doi: 10.1111/j.1365-2141.2010.08258.x.
Abstract/Text
PMID 20553271  Br J Haematol. 2010 Sep;150(6):707-8. doi: 10.1111/j.13・・・
著者: Richard J Kelly, Britta Höchsmann, Jeff Szer, Austin Kulasekararaj, Sophie de Guibert, Alexander Röth, Ilene C Weitz, Elina Armstrong, Antonio M Risitano, Christopher J Patriquin, Louis Terriou, Petra Muus, Anita Hill, Michelle P Turner, Hubert Schrezenmeier, Regis Peffault de Latour
雑誌名: N Engl J Med. 2015 Sep 10;373(11):1032-9. doi: 10.1056/NEJMoa1502950.
Abstract/Text BACKGROUND: Eculizumab, a humanized monoclonal antibody against complement protein C5 that inhibits terminal complement activation, has been shown to prevent complications of paroxysmal nocturnal hemoglobinuria (PNH) and improve quality of life and overall survival, but data on the use of eculizumab in women during pregnancy are scarce.
METHODS: We designed a questionnaire to solicit data on pregnancies in women with PNH and sent it to the members of the International PNH Interest Group and to the physicians participating in the International PNH Registry. We assessed the safety and efficacy of eculizumab in pregnant patients with PNH by examining the birth and developmental records of the children born and adverse events in the mothers.
RESULTS: Of the 94 questionnaires that were sent out, 75 were returned, representing a response rate of 80%. Data on 75 pregnancies in 61 women with PNH were evaluated. There were no maternal deaths and three fetal deaths (4%). Six miscarriages (8%) occurred during the first trimester. Requirements for transfusion of red cells increased during pregnancy, from a mean of 0.14 units per month in the 6 months before pregnancy to 0.92 units per month during pregnancy. Platelet transfusions were given in 16 pregnancies. In 54% of pregnancies that progressed past the first trimester, the dose or the frequency of use of eculizumab had to be increased. Low-molecular-weight heparin was used in 88% of the pregnancies. Ten hemorrhagic events and 2 thrombotic events were documented; both thrombotic events occurred during the postpartum period. A total of 22 births (29%) were premature. Twenty cord-blood samples were examined for the presence of eculizumab; the drug was detected in 7 of the samples. A total of 25 babies were breast-fed, and in 10 of these cases, breast milk was examined for the presence of eculizumab; the drug was not detected in any of the 10 breast-milk samples.
CONCLUSIONS: Eculizumab provided benefit for women with PNH during pregnancy, as evidenced by a high rate of fetal survival and a low rate of maternal complications. (ClinicalTrials.gov number, NCT01374360.).

PMID 26352814  N Engl J Med. 2015 Sep 10;373(11):1032-9. doi: 10.1056/・・・

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