今日の臨床サポート

血球貪食症候群

著者: 新井文子 聖マリアンナ医科大学 血液・腫瘍内科

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:2021/10/06
現在監修レビュー中
患者向け説明資料

概要・推奨   

  1. HLHの初期治療として推奨されるのは94およびHLH-2004である(推奨度1)
  1. 家族性HLHの場合はHLH-94による初期治療に引き続き早期に造血幹細胞移植を行う。移植前処置としてはRICが推奨される。幹細胞ソースは骨髄が推奨されるが、供給不可能であれば臍帯血移植を選択する(推奨度2)
  1. 二次性HLHの場合、リンパ腫など悪性腫瘍は原疾患の治療方針に従う。リンパ腫以外の場合、慢性活動性EBウイルス感染症では同種造血幹細胞移植の適応となるため、除外する必要がある(推奨度2)
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧には
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が
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:
新井文子 : 未申告[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. 日本小児血液・がん学会 組織球症委員会監修:小児HLH診療ガイドライン2020を参考に、家族性HLHの第一選択はHLH-94であること、予後因子についての記載を修正した。

病態・疫学・診察

疾患情報  
  1. 血球貪食症候群(hemophagocytic lymphohistiocytosis、HLHもしくはhemophagocytic syndrome、HPS)は、骨髄、リンパ節、肝臓、脾臓などの網内系組織において、活性化したマクロファージなどの組織球が血液細胞を貪食し、発熱、肝障害などとともに著明な血球減少が生じる重篤な疾患である。病態:何らかの原因で活性化したリンパ球が過剰なサイトカインを分泌した結果生じる。PRF 、SAP、XIAPなどの遺伝子異常を背景に生じる家族性HLHと、悪性腫瘍(リンパ腫など)、感染症(ウイルス感染など)、自己免疫性疾患などに伴う二次性HLH(続発性)がある。
  1. スウェーデンでは常染色体劣性の家族性HLHは、新生児5万人に1人というデータがある[1][2]。わが国では2001年から2005年までの5年間で799例が報告されているが、家族性はそのうち4.1%で、二次性が95%以上であったと報告されている[1]。その結果から類推される本邦の発症数は年間約150例とされる。
問診・診察のポイント  
  1. 持続性の発熱に加え、肝脾腫大による腹部症状の急速な進行、さらに紫斑、点状出血などの皮下出血や、鼻粘膜、口腔粘膜、肛門などからの粘膜出血などをみた場合、本症候群を疑う。思春期までの若年者ではEBウイルスなど感染症や遺伝子異常に基づく家族性が、成人ではリンパ腫、ウイルス感染症、自己免疫性疾患などの基礎疾患を合併する二次性が多いため、これらを疑わせる病歴や臨床症状の有無について問診で確認する。特に成人例の基礎疾患ではリンパ腫が最も多いため、リンパ節腫脹に加え、先行する体重減少、発熱の経緯などに注意する。意識障害、神経症状、髄膜刺激症状は重要な確認事項である。

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。

最新のエビデンスに基づいた二次文献データベース「今日の臨床サポート」。
常時アップデートされており、最新のエビデンスを各分野のエキスパートが豊富な図表や処方・検査例を交えて分かりやすく解説。日常臨床で遭遇するほぼ全ての症状・疾患から薬剤・検査情報まで瞬時に検索可能です。

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文献 

著者: Eiichi Ishii, Shouichi Ohga, Shinsaku Imashuku, Masaki Yasukawa, Hiroyuki Tsuda, Ikuo Miura, Ken Yamamoto, Hisanori Horiuchi, Kenzo Takada, Koichi Ohshima, Shigeo Nakamura, Naoko Kinukawa, Kazuo Oshimi, Keisei Kawa
雑誌名: Int J Hematol. 2007 Jul;86(1):58-65. doi: 10.1532/IJH97.07012.
Abstract/Text Hemophagocytic lymphohistiocytosis (HLH), a disorder of the mononuclear phagocyte system, can be classified into two distinct forms: primary HLH (FHL) and secondary HLH. To clarify the epidemiology and clinical outcome for each HLH subtype, we conducted a nationwide survey of HLH in Japan. Since 799 patients were diagnosed in 292 institutions of Japan between 2001 and 2005, the annual incidence of HLH was estimated as 1 in 800,000 per year. Among them, 567 cases were actually analyzed in this study. The most frequent subtype was Epstein-Barr virus (EBV)-associated HLH, followed by other infection- or lymphoma-associated HLH. Age distribution showed a peak of autoimmune disease- and infection-associated HLH in children, while FHL and lymphoma-associated HLH occurred almost exclusively in infants and the elderly, respectively. The 5-year overall survival rate exceeded 80% for patients with EBV- or other infection-associated HLH, was intermediate for those with FHL or B-cell lymphoma-associated HLH, and poor for those with T/NK cell lymphoma-associated HLH (<15%). Although this nationwide survey establishes the heterogeneous characteristics of HLH, the results should be useful in planning prospective studies to identify the most effective therapy for each HLH subtype.

PMID 17675268  Int J Hematol. 2007 Jul;86(1):58-65. doi: 10.1532/IJH97・・・
著者: J I Henter, G Elinder, O Söder, A Ost
雑誌名: Acta Paediatr Scand. 1991 Apr;80(4):428-35.
Abstract/Text We retrospectively studied the incidence of familial hemophagocytic lymphohistiocytosis (FHL) in children during the 16-year period 1971-86. First, all departments of pediatrics, pathology, and infectious diseases were enquired for children with FHL or disorders resembling FHL. Secondly, the causes of death of all children who died during the study period in Sweden (n = 19,542) were also investigated. Files and histological specimens were further studied in selected children. By using a set of inclusion/exclusion criteria, we found 32 children with FHL. The incidence was 1.2/1,000,000 children per year. One child per 50,000 live borns developed FHL during this period. The sex ratio was close to 1:1. Prominent early clinical signs were fever (91%), splenomegaly (84%), hepatomegaly (90%), rash (43%), and lymph node enlargement (42%). Neurological symptoms, which developed in 47%, could totally dominate the clinical picture and develop prior to other symptoms and signs. Common laboratory findings were pancytopenia, hypertriglyceridemia, hypofibrinogenemia, elevated serum transaminases, hyperbilirubinemia, hyponatremia, hypoalbuminemia, and a moderate spinal fluid pleocytosis. Chest X-ray often revealed mostly discrete pulmonary infiltrates. FHL is an underdiagnosed disease and in only 11/32 children was diagnosis made during their lifetime. It is important to be aware of the disorder as potential therapy now exists.

PMID 2058392  Acta Paediatr Scand. 1991 Apr;80(4):428-35.
著者: Jan-Inge Henter, Annacarin Horne, Maurizio Aricó, R Maarten Egeler, Alexandra H Filipovich, Shinsaku Imashuku, Stephan Ladisch, Ken McClain, David Webb, Jacek Winiarski, Gritta Janka
雑誌名: Pediatr Blood Cancer. 2007 Feb;48(2):124-31. doi: 10.1002/pbc.21039.
Abstract/Text In HLH-94, the first prospective international treatment study for hemophagocytic lymphohistiocytosis (HLH), diagnosis was based on five criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). In HLH-2004 three additional criteria are introduced; low/absent NK-cell-activity, hyperferritinemia, and high-soluble interleukin-2-receptor levels. Altogether five of these eight criteria must be fulfilled, unless family history or molecular diagnosis is consistent with HLH. HLH-2004 chemo-immunotherapy includes etoposide, dexamethasone, cyclosporine A upfront and, in selected patients, intrathecal therapy with methotrexate and corticosteroids. Subsequent hematopoietic stem cell transplantation (HSCT) is recommended for patients with familial disease or molecular diagnosis, and patients with severe and persistent, or reactivated, disease. In order to hopefully further improve diagnosis, therapy and biological understanding, participation in HLH studies is encouraged.

PMID 16937360  Pediatr Blood Cancer. 2007 Feb;48(2):124-31. doi: 10.10・・・
著者: Kazuyuki Shimada, Kosei Matsue, Kazuhito Yamamoto, Takuhei Murase, Naoaki Ichikawa, Masataka Okamoto, Nozomi Niitsu, Hiroshi Kosugi, Norifumi Tsukamoto, Hiroshi Miwa, Hideki Asaoku, Ako Kikuchi, Morio Matsumoto, Yoshio Saburi, Yasufumi Masaki, Motoko Yamaguchi, Shigeo Nakamura, Tomoki Naoe, Tomohiro Kinoshita
雑誌名: J Clin Oncol. 2008 Jul 1;26(19):3189-95. doi: 10.1200/JCO.2007.15.4278. Epub 2008 May 27.
Abstract/Text PURPOSE: To evaluate the safety and efficacy of rituximab-containing chemotherapies for intravascular large B-cell lymphoma (IVLBCL).
PATIENTS AND METHODS: We retrospectively analyzed 106 patients (59 men, 47 women) with IVLBCL who received chemotherapy either with rituximab (R-chemotherapy, n = 49) or without rituximab (chemotherapy, n = 57) between 1994 and 2007 in Japan. The median patient age was 67 years (range, 34 to 84 years). The International Prognostic Index was high-intermediate/high in 97% of patients.
RESULTS: The complete response rate was higher for patients in the R-chemotherapy group (82%) than for those in the chemotherapy group (51%; P = .001). The median duration of follow-up for surviving patients was 18 months (range, 1 to 95 months). Progression-free survival (PFS) and overall survival (OS) rates at 2 years after diagnosis were significantly higher for patients in the R-chemotherapy group (PFS, 56%; OS, 66%) than for patients in the chemotherapy group (PFS, 27% with P = .001; OS, 46% with P = 0.01). Multivariate analysis revealed that the use of rituximab was favorably associated with PFS (hazard ratio [HR], 0.45; 95% CI, 0.25 to 0.80; P = .006) and OS (HR, 0.42; 95% CI, 0.21 to 0.85; P = .016). Treatment-related death was observed in three patients (6%) who received R-chemotherapy and in five patients (9%) who received chemotherapy.
CONCLUSION: Our data suggest improved clinical outcomes for patients with IVLBCL in the rituximab era. Future prospective studies of rituximab-containing chemotherapies are warranted.

PMID 18506023  J Clin Oncol. 2008 Jul 1;26(19):3189-95. doi: 10.1200/J・・・
著者: Ritsuro Suzuki, Motoko Yamaguchi, Koji Izutsu, Go Yamamoto, Kenzo Takada, Yasuaki Harabuchi, Yasushi Isobe, Hiroshi Gomyo, Tadashi Koike, Masataka Okamoto, Rie Hyo, Junji Suzumiya, Shigeo Nakamura, Keisei Kawa, Kazuo Oshimi, NK-cell Tumor Study Group
雑誌名: Blood. 2011 Dec 1;118(23):6018-22. doi: 10.1182/blood-2011-05-354142. Epub 2011 Oct 7.
Abstract/Text Epstein-Barr virus (EBV)-DNA was prospectively analyzed in plasma and mononuclear cells (MNCs) from peripheral blood in patients with extranodal natural killer (NK)/T-cell lymphoma, nasal type, to evaluate the clinical significance for diagnosis, monitoring the tumor burden, and prognostication. Thirty-three patients were enrolled, and 32 were evaluable. Pretreatment plasma and MNC EBV-DNA was detectable in 14 (range, 50-71 000 copies/mL) and 6 patients (range, 20-780 copies/μg DNA), respectively, and both were well correlated (r = 0.8741, P < .0001). Detectable plasma EBV-DNA was associated with higher clinical stage (P = .02), presence of B symptoms (P = .02), worse performance status (P = .02), and higher serum soluble IL-2 receptor level (P < .0001). Twenty-two patients attained complete response. Plasma EBV-DNA level was significantly higher in nonresponders than in responders (mean, 16,472 vs 2,645 copies/mL; P = .02). Multivariate analysis showed clinical stage (hazard ratio, 9.0; 95% confidence interval, 1.8%-45.0%) and pretreatment plasma EBV-DNA (hazard ratio, 10.6; 95% confidence interval, 1.3%-87.0%) were significant prognostic factors. Three-year overall survival of plasma EBV-DNA positive and negative patients was 42.9% and 94.4%, respectively (P = .0009). Plasma was a preferable sample for this purpose in NK/T-cell lymphoma, nasal type, and EBV-DNA level was a good indicator for response and overall survival.

PMID 21984805  Blood. 2011 Dec 1;118(23):6018-22. doi: 10.1182/blood-2・・・
著者: Motoko Yamaguchi, Kensei Tobinai, Masahiko Oguchi, Naoki Ishizuka, Yukio Kobayashi, Yasushi Isobe, Kenichi Ishizawa, Nobuo Maseki, Kuniaki Itoh, Noriko Usui, Izumi Wasada, Tomohiro Kinoshita, Tomomitsu Hotta, Kunihiro Tsukasaki, Kazuo Oshimi
雑誌名: J Clin Oncol. 2012 Nov 10;30(32):4044-6. doi: 10.1200/JCO.2012.45.6541. Epub 2012 Oct 8.
Abstract/Text
PMID 23045573  J Clin Oncol. 2012 Nov 10;30(32):4044-6. doi: 10.1200/J・・・
著者: Motoko Yamaguchi, Yok-Lam Kwong, Won Seog Kim, Yoshinobu Maeda, Chizuko Hashimoto, Cheolwon Suh, Koji Izutsu, Fumihiro Ishida, Yasushi Isobe, Eisaburo Sueoka, Junji Suzumiya, Takao Kodama, Hiroshi Kimura, Rie Hyo, Shigeo Nakamura, Kazuo Oshimi, Ritsuro Suzuki
雑誌名: J Clin Oncol. 2011 Nov 20;29(33):4410-6. doi: 10.1200/JCO.2011.35.6287. Epub 2011 Oct 11.
Abstract/Text PURPOSE: To explore a more effective treatment for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer/T-cell lymphoma, nasal type (ENKL), we conducted a phase II study of the steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) regimen.
PATIENTS AND METHODS: Patients with newly diagnosed stage IV, relapsed, or refractory disease and a performance status of 0 to 2 were eligible. Two cycles of SMILE chemotherapy were administered as the protocol treatment. The primary end point was the overall response rate (ORR) after the protocol treatment.
RESULTS: A total of 38 eligible patients were enrolled. The median age was 47 years (range, 16 to 67 years), and the male:female ratio was 21:17. The disease status was newly diagnosed stage IV in 20 patients, first relapse in 14 patients, and primary refractory in four patients. The eligibility was revised to include lymphocyte counts of 500/μL or more because the first two patients died from infections. No treatment-related deaths were observed after the revision. The ORR and complete response rate after two cycles of SMILE chemotherapy were 79% (90% CI, 65% to 89%) and 45%, respectively. In the 28 patients who completed the protocol treatment, 19 underwent hematopoietic stem-cell transplantation. The 1-year overall survival rate was 55% (95% CI, 38% to 69%). Grade 4 neutropenia was observed in 92% of the patients. The most common grade 3 or 4 nonhematologic complication was infection (61%).
CONCLUSION: SMILE chemotherapy is an effective treatment for newly diagnosed stage IV, relapsed or refractory ENKL. Myelosuppression and infection during the treatment should be carefully managed.

PMID 21990393  J Clin Oncol. 2011 Nov 20;29(33):4410-6. doi: 10.1200/J・・・
著者: Ichiro Yonese, Chizuko Sakashita, Ken-Ichi Imadome, Tohru Kobayashi, Masahide Yamamoto, Akihisa Sawada, Yoshinori Ito, Noriko Fukuhara, Asao Hirose, Yusuke Takeda, Masanori Makita, Tomoyuki Endo, Shun-Ichi Kimura, Masataka Ishimura, Osamu Miura, Shouichi Ohga, Hiroshi Kimura, Shigeyoshi Fujiwara, Ayako Arai
雑誌名: Blood Adv. 2020 Jul 14;4(13):2918-2926. doi: 10.1182/bloodadvances.2020001451.
Abstract/Text Systemic chronic active Epstein-Barr virus infection (sCAEBV) was defined as a T- or NK-cell neoplasm in the 2017 World Health Organization (WHO) classification. To clarify the clinical features of sCAEBV under this classification and review the effects of chemotherapy, we performed a nationwide survey in Japan from 2016 through 2018 of patients with sCAEBV newly diagnosed from January 2003 through March 2016. One hundred cases were evaluated. The patients were aged 1 to 78 years (median, 21) and included 53 males and 47 females. Spontaneous regression was not observed in patients with active disease. In the childhood-onset group (age, <9 years), 78% of the patients were male. In contrast, 85% of the patients in the elderly-onset group (age, >45 years) were female. The prognosis of the childhood-onset group was better than those of the adolescent/adult- and elderly-onset groups. The main chemotherapies used were a combination of cyclosporine A, steroids, and etoposide (cooling therapy) in 52 cases and cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) in 45 cases. The rate of complete response (CR), defined as complete resolution of disease activity, was 17% for cooling therapy and 13% for CHOP. Virological CR was not observed. The 3-year overall survival rates in patients treated with chemotherapy only (n = 20), chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT; n = 47), and allo-HSCT only (n = 12) were 0%, 65%, and 82%, respectively. Distinct characteristics were observed between childhood- and elderly-onset sCAEBV, and they appeared to be different disorders. Chemotherapy is currently insufficient to resolve disease activity and eradicate infected cells. The development of an effective treatment is urgently needed.

© 2020 by The American Society of Hematology.
PMID 32598475  Blood Adv. 2020 Jul 14;4(13):2918-2926. doi: 10.1182/bl・・・
著者: Helena Trottestam, Annacarin Horne, Maurizio Aricò, R Maarten Egeler, Alexandra H Filipovich, Helmut Gadner, Shinsaku Imashuku, Stephan Ladisch, David Webb, Gritta Janka, Jan-Inge Henter, Histiocyte Society
雑誌名: Blood. 2011 Oct 27;118(17):4577-84. doi: 10.1182/blood-2011-06-356261. Epub 2011 Sep 6.
Abstract/Text Hemophagocytic lymphohistiocytosis (HLH) used to have a dismal prognosis. We report the final results of HLH-94, the largest prospective diagnostic/therapeutic HLH study so far. The treatment includes immunosuppressive and cytotoxic therapy aiming at clinical remission, followed by HSCT in patients with familial, persistent, or recurrent disease. Altogether, 249 patients fulfilled inclusion criteria and started HLH-94 therapy (July 1994-December 2003); 227 (91%) were followed-up for ≥ 5 years. At 6.2 years median follow-up, estimated 5-year probability of survival was 54% ± 6%. Seventy-two patients (29%) died before HSCT, 64 within 1 year, 97% of whom had active disease. In 124 patients who underwent HSCT, 5-year survival was 66 ± 8%; tendency to increased survival (P = .064) in patients with nonactive disease at HSCT. Patients with familial disease had a 5-year survival of 50% ± 13%; none survived without HSCT. Patients deceased during the first 2 months more often had jaundice, edema, and elevated creatinine. Forty-nine patients (20%) were alive without signs of HLH activity and off-therapy > 1-year without HSCT; they presented at older age (P < .001), were more often female (P = .011), and less often had CNS disease (P < .001) or hepatomegaly (P = .007). To conclude, HLH-94 chemoimmunotherapy has considerably improved outcome in HLH. Collaborative efforts are needed to further reduce early mortality, HSCT-related mortality, and neurologic late effects.

PMID 21900192  Blood. 2011 Oct 27;118(17):4577-84. doi: 10.1182/blood-・・・
著者: Jan-Inge Henter, AnnaCarin Samuelsson-Horne, Maurizio Aricò, R Maarten Egeler, Göran Elinder, Alexandra H Filipovich, Helmut Gadner, Shinsaku Imashuku, Diane Komp, Stephan Ladisch, David Webb, Gritta Janka, Histocyte Society
雑誌名: Blood. 2002 Oct 1;100(7):2367-73. doi: 10.1182/blood-2002-01-0172.
Abstract/Text Hemophagocytic lymphohistiocytosis (HLH) comprises familial (primary) hemophagocytic lymphohistiocytosis (FHL) and secondary HLH (SHLH), both clinically characterized by fever, hepatosplenomegaly, and cytopenia. FHL, an autosomal recessive disease invariably fatal when untreated, is associated with defective triggering of apoptosis and reduced cytotoxic activity, resulting in a widespread accumulation of T lymphocytes and activated macrophages. In 1994 the Histiocyte Society initiated a prospective international collaborative therapeutic study (HLH-94), aiming at improved survival. It combined chemotherapy and immunotherapy (etoposide, corticosteroids, cyclosporin A, and, in selected patients, intrathecal methotrexate), followed by bone marrow transplantation (BMT) in persistent, recurring, and/or familial disease. Between July 1, 1994, and June 30, 1998, 113 eligible patients aged no more than 15 years from 21 countries started HLH-94. All had either an affected sibling (n = 25) and/or fulfilled the Histiocyte Society diagnostic criteria. At a median follow-up of 3.1 years, the estimated 3-year probability of survival overall was 55% (95% confidence interval +/- 9%), and in the familial cases, 51% (+/- 20%). Twenty enrolled children were alive and off therapy for more than 12 months without BMT. For patients who received transplants (n = 65), died prior to BMT (n = 25), or were still on therapy (n = 3), the 3-year survival was 45% (+/- 10%). The 3-year probability of survival after BMT was 62% (+/- 12%). HLH-94 is very effective, allowing BMT in most patients. Survival of children with HLH has been greatly improved.

PMID 12239144  Blood. 2002 Oct 1;100(7):2367-73. doi: 10.1182/blood-20・・・
著者: Ryu Yanagisawa, Yozo Nakazawa, Kazuyuki Matsuda, Takahiro Yasumi, Hirokazu Kanegane, Shouichi Ohga, Akira Morimoto, Yoshiko Hashii, Masue Imaizumi, Yasuhiro Okamoto, Akiko M Saito, Keizo Horibe, Eiichi Ishii, HLH/LCH committee members of the Japan Children’s Cancer Group
雑誌名: Int J Hematol. 2019 Feb;109(2):206-213. doi: 10.1007/s12185-018-02572-z. Epub 2018 Dec 7.
Abstract/Text Recent advances in intensive chemo- and immunotherapy have contributed to the outcome of hemophagocytic lymphohistiocytosis (HLH); however, the prognosis of HLH in children differs by HLH subtype. In Japan, secondary HLH, particularly Epstein-Barr virus-associated HLH (EBV-HLH), is the most common HLH subtype. The prognosis of HLH has improved in recent years. We here conducted a prospective study of 73 patients who were treated with HLH-2004 protocol in Japan. EBV-HLH, familial HLH (FHL), and HLH of unknown etiology were seen in 41, 9, and 23 patients, respectively. Patients with resistant or relapsed disease after HLH-2004 treatment and those with FHL received hematopoietic stem cell transplantation (HSCT). The induction rate after initial therapy was 58.9%, and the 3-year overall survival (OS) rate of all patients was 73.9% and differed significantly among those with EBV-HLH, FHL, and HLH of unknown etiology. Of the 17 patients who received HSCT, the 3-year OS rates of those with and without complete resolution before HSCT were 83.3% and 54.5%, respectively. Outcomes in children with HLH who were treated with the same protocol differed among HLH subtypes. Appropriate strategy for each subtype should be established in future studies.

PMID 30535855  Int J Hematol. 2019 Feb;109(2):206-213. doi: 10.1007/s1・・・
著者: Elisabet Bergsten, AnnaCarin Horne, Maurizio Aricó, Itziar Astigarraga, R Maarten Egeler, Alexandra H Filipovich, Eiichi Ishii, Gritta Janka, Stephan Ladisch, Kai Lehmberg, Kenneth L McClain, Milen Minkov, Scott Montgomery, Vasanta Nanduri, Diego Rosso, Jan-Inge Henter
雑誌名: Blood. 2017 Dec 21;130(25):2728-2738. doi: 10.1182/blood-2017-06-788349. Epub 2017 Sep 21.
Abstract/Text Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. In the HLH-94 study, with an estimated 5-year probability of survival (pSu) of 54% (95% confidence interval, 48%-60%), systemic therapy included etoposide, dexamethasone, and, from week 9, cyclosporine A (CSA). Hematopoietic stem cell transplantation (HSCT) was indicated in patients with familial/genetic, relapsing, or severe/persistent disease. In HLH-2004, CSA was instead administered upfront, aiming to reduce pre-HSCT mortality and morbidity. From 2004 to 2011, 369 children aged <18 years fulfilled HLH-2004 inclusion criteria (5 of 8 diagnostic criteria, affected siblings, and/or molecular diagnosis in FHL-causative genes). At median follow-up of 5.2 years, 230 of 369 patients (62%) were alive (5-year pSu, 61%; 56%-67%). Five-year pSu in children with (n = 168) and without (n = 201) family history/genetically verified FHL was 59% (52%-67%) and 64% (57%-71%), respectively (familial occurrence [n = 47], 58% [45%-75%]). Comparing with historical data (HLH-94), using HLH-94 inclusion criteria, pre-HSCT mortality was nonsignificantly reduced from 27% to 19% (P = .064 adjusted for age and sex). Time from start of therapy to HSCT was shorter compared with HLH-94 (P =020 adjusted for age and sex) and reported neurological alterations at HSCT were 22% in HLH-94 and 17% in HLH-2004 (using HLH-94 inclusion criteria). Five-year pSu post-HSCT overall was 66% (verified FHL, 70% [63%-78%]). Additional analyses provided specific suggestions on potential pre-HSCT treatment improvements. HLH-2004 confirms that a majority of patients may be rescued by the etoposide/dexamethasone combination but intensification with CSA upfront, adding corticosteroids to intrathecal therapy, and reduced time to HSCT did not improve outcome significantly.

© 2017 by The American Society of Hematology.
PMID 28935695  Blood. 2017 Dec 21;130(25):2728-2738. doi: 10.1182/bloo・・・
著者: Rebecca A Marsh, Gretchen Vaughn, Mi-Ok Kim, Dandan Li, Sonata Jodele, Sarita Joshi, Parinda A Mehta, Stella M Davies, Michael B Jordan, Jack J Bleesing, Alexandra H Filipovich
雑誌名: Blood. 2010 Dec 23;116(26):5824-31. doi: 10.1182/blood-2010-04-282392. Epub 2010 Sep 20.
Abstract/Text Recent experience suggests that reduced-intensity conditioning (RIC) regimens can improve the outcomes of patients with hemophagocytic lymphohistiocytosis (HLH) undergoing allogeneic hematopoietic cell transplantation (HCT). However, studies directly comparing RIC to myeloablative conditioning (MAC) regimens are lacking. Forty patients with HLH underwent allogeneic HCT between 2003-2009 at Cincinnati Children's Hospital. Fourteen patients received MAC consisting of busulfan, cyclophosphamide, and antithymocyte globulin plus or minus etoposide. Twenty-six patients received RIC consisting of fludarabine, melphalan, and alemtuzumab. All patients engrafted. Acute graft-versus-host disease grades II to III occurred in 14% of MAC patients and 8% of RIC patients (P = .3171). Posttransplantation mixed donor/recipient chimerism developed in 18% of MAC patients and 65% of RIC patients (P = .0110). The majority of patients with mixed chimerism received intervention with reduction of immune suppression plus or minus donor lymphocyte infusion or stem cell boost, which stabilized or increased donor contribution to hematopoiesis and prevented relapse of HLH in all but 1 patient. Grade II to III graft-versus-host disease occurred in 5 of 14 RIC patients after donor lymphocyte infusion. The overall estimated 3-year survival after HCT was 43% (confidence interval = ± 26%) for MAC patients and 92% (confidence interval = ± 11%) for RIC patients (P = .0001). We conclude that RIC significantly improves the outcome of patients with HLH undergoing allogeneic HCT.

PMID 20855862  Blood. 2010 Dec 23;116(26):5824-31. doi: 10.1182/blood-・・・
著者: F Schuster, D K Stachel, I Schmid, F A Baumeister, U B Graubner, M Weiss, R J Haas, B H Belohradsky
雑誌名: Bone Marrow Transplant. 2001 Aug;28(4):409-12. doi: 10.1038/sj.bmt.1703114.
Abstract/Text Griscelli syndrome is characterized by partial albinism with variable immunodeficiency. Two different gene loci are responsible for this rare, autosomal recessive disease: the myosin Va gene and the RAB27A gene. As recently reported, only patients with mutations of the RAB27A gene suffer from immunodeficiency and hemophagocytic lymphohistiocytosis. Thus, only patients who suffer from the Griscelli syndrome with mutations of the RAB27A gene should receive BMT/PBSCT, which is the only curative therapy. Due to the risk of early relapse or severe infections, BMT/PBSCT should be carried out as soon as possible; if patients do not have HLA-identical family members, valuable time may be lost by searching for an HLA-identical unrelated donor. We report the first peripheral blood stem cell transplant (PBSCT) with T cell depletion in a 6-month-old girl with Griscelli syndrome, and a deletion of the RAB27A gene. The donor was her phenotypically HLA-identical mother. Conditioning included busulfan, VP16 and cyclophosphamide. The patient was transfused with 15.4 x 10(6)CD34-positive cells/kg and 17.6 x 10(3) CD3-positive cells/kg recipient weight. Three months after the transplant, a curable lymphoproliferative syndrome occurred. 26 months after the transplant, the patient is doing well with stable mixed chimerism (52% donor cells).

PMID 11571516  Bone Marrow Transplant. 2001 Aug;28(4):409-12. doi: 10.・・・
著者: Akihisa Sawada, Shouichi Ohga, Eiichi Ishii, Masami Inoue, Keiko Okada, Jiro Inagaki, Hiroaki Goto, Nobuhiro Suzuki, Kazutoshi Koike, Yoshiko Atsuta, Ritsuro Suzuki, Hiromasa Yabe, Keisei Kawa, Koji Kato, Koji Yasutomo
雑誌名: Int J Hematol. 2013 Aug;98(2):223-30. doi: 10.1007/s12185-013-1391-z. Epub 2013 Jul 11.
Abstract/Text A nationwide retrospective analysis was performed on patients who received allogeneic hematopoietic stem cell transplantation for primary or familial hemophagocytic lymphohistiocytosis (HLH) in Japan. The present analysis investigated whether reduced-intensity conditioning (RIC) followed by cord blood transplantation (CBT) (RIC-CBT) is feasible, compared to the outcomes of myeloablative conditioning and bone marrow transplantation. Based on the JSHCT data, 53 patients were analyzed. The overall survival rate (OS) was 65.4 ± 6.6 %. RIC-CBT (n = 13) was not inferior to other methods. Patients with a performance status of PS 4 (ECOG scale) with HLH-associated severe organ dysfunction during the initiation of conditioning had extremely poor outcomes. The OS rate in the RIC-CBT patients, excluding those with a performance status 4, was 80.0 ± 12.6 %. RIC may reduce treatment-related mortality; in addition, patients with engraftment failure, which is the main adverse event following RIC-CBT, were successfully rescued with secondary CBT. Unrelated cord blood may represent an alternative source if a patient has no related donor. As a RIC regimen for CBT, 140 mg/m(2) melphalan with fludarabine and anti-lymphocyte globulin or anti-thymocyte globulin may be feasible, but further dosage optimization should be performed in controlled clinical trials.

PMID 23843148  Int J Hematol. 2013 Aug;98(2):223-30. doi: 10.1007/s121・・・
著者: Munira Shabbir, John Lucas, John Lazarchick, Keisuke Shirai
雑誌名: Hematol Oncol. 2011 Jun;29(2):100-6. doi: 10.1002/hon.960. Epub 2010 Aug 30.
Abstract/Text Hemophagocytic lymphohistiocytosis (HLH) is rare in adults and is usually fatal without treatment. We present a consecutive series of 18 adults with HLH diagnosed at our institution between 2004 and 2009. All diagnoses were confirmed by pathology. The median age at diagnosis was 56 years (range: 18-73 years), with a male: female ratio of 2:1. Patients uniformly presented with fever. Fifty-five per cent of the patients presented with evidence of hepatomegaly or splenomegaly. All of the patients had at least a bi- or trilineage cytopenia. Elevated liver enzymes, hyperferritinemia, hypertriglyceridemia and hyperfibrinogenemia were seen in 50, 100, 40 and 50% of patients, respectively. The presumed causes were as follows; haematological malignancies (n = 4), post-autologous stem cell transplant (n = 2), infection (n = 2), rheumatologic illness (n = 2), sickle cell disease (n = 1), post-orthotopic liver transplant (n = 1) and idiopathic (n = 3). The median time from suspicion to diagnosis was 5 days (1-27 days). Corticosteroids and/or cyclosporine were the most frequently used treatment regimen. Other agents used were etoposide, IVIG, cyclophosphamide and chemotherapy. The mortality rate was 72%, with multi-system organ failure being the most common cause of death. Median survival time from diagnosis was 35 days. Six patients are alive to date. In a univariate analysis, the presence of fever was the only factor that was statistically significant for predicting a poor prognosis (early mortality) (p = 0.05). In conclusion, a high index of suspicion is the critical factor for early diagnosis. Early treatment with immunosuppressant is warranted, and a thorough diagnostic evaluation to identify the underlying cause should be undertaken.

Copyright © 2010 John Wiley & Sons, Ltd.
PMID 20809477  Hematol Oncol. 2011 Jun;29(2):100-6. doi: 10.1002/hon.9・・・
著者: Han-Seung Park, Dae-Young Kim, Je-Hwan Lee, Jung-Hee Lee, Sung-Doo Kim, Young-Hun Park, Jae Seok Lee, Bo Youn Kim, Mijin Jeon, Young-Ah Kang, Young-Shin Lee, Miee Seol, Yeon-Joo Lee, Young-Suk Lim, Seongsoo Jang, Chan-Jeoung Park, Hyun-Sook Chi, Kyoo-Hyung Lee
雑誌名: Ann Hematol. 2012 Jun;91(6):897-904. doi: 10.1007/s00277-011-1380-3. Epub 2011 Dec 8.
Abstract/Text Although hemophagocytic syndrome (HS) featuring secondary hemophagocytic lymphohistiocytosis (HLH) has a grave prognosis, little is known about the natural course of the disease. Patients who showed the clinical features of HLH as well as tissue-proven hemophagocytosis when seen at Asan Medical Center between 1999 and 2010 were included in this analysis. Patients with proven lymphoma were excluded. The median age of our 23 study patients was 49 years. Epstein-Barr virus was suspected to have caused HS in 16 (70%) patients and hepatitis A virus in one patient. Twenty-two patients were treated, 13 according to the HLH protocol and nine using immunosuppressive agents such as corticosteroid and/or cyclosporine. Five patients undertook allogeneic hematopoietic cell transplantation (HCT) during their treatment-dependent relapse (n = 4) or responsive status (n = 1). After the median follow-up of 180 days, 17 (74%) died and six (26%) were alive. The median time from initial presentation until death was 41 days among those patients who died. The serum fibrinogen level ≥166 mg/dL determined at the initial visit was significantly associated with the survival time according to univariate analysis. The low histiocyte proportion in bone marrow and early initiation of treatment tended to correlate with a favorable outcome. On multivariate analysis, serum fibrinogen ≥166 mg/dL (hazard ratio, 0.175, P = 0.018) was an independent clinical factor for determining the patient survival time. Despite appropriate patient management, the outcome of HS featuring HLH was grave. The serum fibrinogen level at the initial presentation was significant, and selected patients obtained some benefit from allogeneic HCT.

PMID 22147006  Ann Hematol. 2012 Jun;91(6):897-904. doi: 10.1007/s0027・・・
著者: Hyogo Nakakura, Akira Ashida, Hideki Matsumura, Takuji Murata, Katsuyuki Nagatoya, Nobuhisa Shibahara, Toru Inoue, Hiroshi Tamai
雑誌名: Ther Apher Dial. 2009 Feb;13(1):71-6. doi: 10.1111/j.1744-9987.2009.00607.x.
Abstract/Text An infantile case of hemophagocytic syndrome (HPS) with systemic juvenile idiopathic arthritis (s-JIA), refractory to methylprednisolone pulse therapy and cyclosporine A administration, was successfully treated by plasma exchange. The patient was a one-year-old Japanese girl who had developed recurrent steroid-dependent signs, including fever, skin eruption, and hepatopathy, while in France, where she had been diagnosed as having s-JIA at eight months of age. As a high fever and rheumatoid rash were evident on arrival at our hospital, she was admitted and given intravenous methylprednisolone pulse therapy and cyclosporine A. She developed pancytopenia with a generalized clonic seizure, high fever, and liver dysfunction after her cytomegalovirus (CMV) titer became positive during the course of treatment; therefore, she was treated with ganciclovir. She was subsequently diagnosed as having HPS complicating s-JIA from the findings of a bone marrow aspirate. At this time, her blood examination data including a high level of C-reactive protein and hyperferritinemia, suggested that her s-JIA was very active, and the pancytopenia continued after her CMV titer became negative. Therefore, CMV infection against a background of active s-JIA could have triggered the HPS in this case. Because the HPS was resistant to an immunosuppressive regime of methylprednisolone pulse therapy and cyclosporine A, plasma exchange therapy was started. After three sessions of this therapy, the patient's symptoms and laboratory data were markedly improved. Our experience suggests that plasma exchange should be considered as a therapeutic tool for HPS refractory to conventional therapy.

PMID 19379173  Ther Apher Dial. 2009 Feb;13(1):71-6. doi: 10.1111/j.17・・・
著者: Yoshihisa Tateishi, Shigeto Oda, Tomohito Sadahiro, Masataka Nakamura, You Hirayama, Ryuzo Abe, Hiroyuki Hirasawa
雑誌名: Transfus Apher Sci. 2009 Feb;40(1):33-40. doi: 10.1016/j.transci.2008.11.001. Epub 2008 Dec 20.
Abstract/Text Reactive (or secondary) hemophagocytic syndrome (RHS) is a potentially lethal condition and characterized by hypercytokinemia. Immune modulating drugs sometimes fail to achieve satisfactory control. Therefore we investigate the efficacy of continuous hemodiafiltration using a polymethyl methacrylate membrane hemofilter (PMMA-CHDF) for cytokine removal in patients with RHS. Eight consecutive patients who admitted to our ICU with RHS complicating organ failures and refractory to medical therapy were initiated intensive care including PMMA-CHDF. Although remission was achieved in six patients, remaining two patients died of exacerbation of underlying diseases. Changes in blood levels of tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) as indices of cytokine network activation, and serum ferritin level as an index of severity of RHS were investigated during PMMA-CHDF. PMMA-CHDF performed for 3 days significantly reduced blood TNF-alpha level (183+/-159 pg/ml to 84+/-98 pg/ml, p<0.05) and also blood IL-6 level (1113+/-903 pg/ml to 402+/-411 pg/ml, p<0.01). Furthermore, serum ferritin level was significantly decreased 3 days after initiation of PMMA-CHDF (52390+/-65168 ng/ml to 4136+/-2932 ng/ml, p<0.05) although it tended to increase before initiation of PMMA-CHDF. No PMMA-CHDF-related adverse events were observed in any of the patients. PMMA-CHDF was effective to remove cytokine and improved disease severity. Thus, PMMA-CHDF may be an adjunctive treatment in RHS refractory to medical therapy.

PMID 19097821  Transfus Apher Sci. 2009 Feb;40(1):33-40. doi: 10.1016/・・・
著者: Larisa Broglie, Lauren Pommert, Sridhar Rao, Monica Thakar, Rachel Phelan, David Margolis, Julie Talano
雑誌名: Blood Adv. 2017 Aug 22;1(19):1533-1536. doi: 10.1182/bloodadvances.2017007526. Epub 2017 Aug 17.
Abstract/Text Optimal salvage therapy for refractory HLH is unknown.In our patient, ruxolitinib treatment led to clinical remission of refractory HLH.

PMID 29296794  Blood Adv. 2017 Aug 22;1(19):1533-1536. doi: 10.1182/bl・・・
著者: Camille Keenan, Kim E Nichols, Sabrin Albeituni
雑誌名: Front Immunol. 2021;12:614704. doi: 10.3389/fimmu.2021.614704. Epub 2021 Feb 16.
Abstract/Text Hemophagocytic lymphohistiocytosis (HLH) is a rare hyperinflammatory syndrome driven by overactive T cells and macrophages that abundantly secrete numerous pro-inflammatory cytokines, including interferon (IFN)-gamma, interleukin (IL)-1-beta, IL-2, IL-6, IL-10, IL-18, and tumor necrosis factor (TNF). The release of these and other cytokines underlies many of the clinical and pathologic manifestations of HLH, which if left untreated, can lead to multi-organ failure and death. The advent of etoposide-based regimens, such as the Histiocyte Society HLH-94 and HLH-2004 protocols, has substantially decreased the mortality associated with HLH. Nevertheless, the 5-year survival remains low at ~60%. To improve upon these results, studies have focused on the use of novel cytokine-directed therapies to dampen inflammation in HLH. Among the agents being tested is ruxolitinib, a potent inhibitor of the Janus Kinase (JAK) and Signal Transducer and Activation of Transcription (STAT) pathway, which functions downstream of many HLH-associated cytokines. Here, we review the basic biology of HLH, including the role of cytokines in disease pathogenesis, and discuss the use of ruxolitinib in the treatment of HLH.

Copyright © 2021 Keenan, Nichols and Albeituni.
PMID 33664745  Front Immunol. 2021;12:614704. doi: 10.3389/fimmu.2021.・・・
著者: Franco Locatelli, Michael B Jordan, Carl Allen, Simone Cesaro, Carmelo Rizzari, Anupama Rao, Barbara Degar, Timothy P Garrington, Julian Sevilla, Maria-Caterina Putti, Franca Fagioli, Martina Ahlmann, Jose-Luis Dapena Diaz, Michael Henry, Fabrizio De Benedetti, Alexei Grom, Genevieve Lapeyre, Philippe Jacqmin, Maria Ballabio, Cristina de Min
雑誌名: N Engl J Med. 2020 May 7;382(19):1811-1822. doi: 10.1056/NEJMoa1911326.
Abstract/Text BACKGROUND: Primary hemophagocytic lymphohistiocytosis is a rare syndrome characterized by immune dysregulation and hyperinflammation. It typically manifests in infancy and is associated with high mortality.
METHODS: We investigated the efficacy and safety of emapalumab (a human anti-interferon-γ antibody), administered with dexamethasone, in an open-label, single-group, phase 2-3 study involving patients who had received conventional therapy before enrollment (previously treated patients) and previously untreated patients who were 18 years of age or younger and had primary hemophagocytic lymphohistiocytosis. The patients could enter a long-term follow-up study until 1 year after allogeneic hematopoietic stem-cell transplantation or until 1 year after the last dose of emapalumab, if transplantation was not performed. The planned 8-week treatment period could be shortened or extended if needed according to the timing of transplantation. The primary efficacy end point was the overall response, which was assessed in the previously treated patients according to objective clinical and laboratory criteria.
RESULTS: At the cutoff date of July 20, 2017, a total of 34 patients (27 previously treated patients and 7 previously untreated patients) had received emapalumab; 26 patients completed the study. A total of 63% of the previously treated patients and 65% of the patients who received an emapalumab infusion had a response; these percentages were significantly higher than the prespecified null hypothesis of 40% (P = 0.02 and P = 0.005, respectively). In the previously treated group, 70% of the patients were able to proceed to transplantation, as were 65% of the patients who received emapalumab. At the last observation, 74% of the previously treated patients and 71% of the patients who received emapalumab were alive. Emapalumab was not associated with any organ toxicity. Severe infections developed in 10 patients during emapalumab treatment. Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis.
CONCLUSIONS: Emapalumab was an efficacious targeted therapy for patients with primary hemophagocytic lymphohistiocytosis. (Funded by NovImmune and the European Commission; NI-0501-04 and NI-0501-05 ClinicalTrials.gov numbers, NCT01818492 and NCT02069899.).

Copyright © 2020 Massachusetts Medical Society.
PMID 32374962  N Engl J Med. 2020 May 7;382(19):1811-1822. doi: 10.105・・・

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