今日の臨床サポート

成人T細胞白血病・リンパ腫

著者: 塚崎邦弘 埼玉医科大学国際医療センター  造血器腫瘍科

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:2021/09/15
現在監修レビュー中
患者向け説明資料

概要・推奨   

  1. 初発高悪性度ATLに対し最も推奨される治療法はVCAP-AMP-VECP療法である(推奨度1
  1. くすぶり型、予後不良因子を持たない慢性型に対する化学療法は生存期間の延長にはつながるというデータはなく、無治療経過観察が推奨される(推奨度2)
  1. ATLに対する初回化学療法後一定の治療反応性が見られた症例に対しては、HLA一致血縁、非血縁ドナーが得られた場合、upfrontでのallo-HSCTは長期生存が期待できる治療法として推奨される(推奨度2)
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:
塚崎邦弘 : 研究費・助成金など(HUYABIO,Celgene,Bayer,第一三共,協和キリン),奨学(奨励)寄付など(中外製薬)[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. 造血器腫瘍診療ガイドライン 2018年版補訂版と2019年のATL国際的コンセンサス改訂版によって、抗体医薬併用化学療法、同種造血幹細胞移植療法(allo-HSCT)、皮膚病変を有するATLなどについて改訂した。

病態・疫学・診察

疾患情報  
  1. 成人T細胞白血病・リンパ腫(ATL)は、ヒトT細胞白血病ウイルス-I(HTLV-1)が病因の末梢性T細胞腫瘍である。
  1. 感染者が多数いる西南九州、中南米、アフリカとそこからの移民に多発する。
  1. 日本に約100万人いるキャリアのうち、毎年約1000人がATLを発症する。
  1. 母児感染によるキャリアの数%が、平均年齢約70歳でATLを発症する。患者の急速な高齢化が進んでいる。
  1. HTLV-1感染経路としては、母乳による母子感染、輸血などの血液による感染、性交渉が重要である。日本では、HTLV-1キャリア妊婦への人工栄養の推奨、HTLV-1感染血の輸血不使用により感染予防策が講じられている。
  1. 臨床病態は無治療でも長期生存する場合から、化学療法でも数週間で死亡する場合まで幅広い。
  1. 難治性であり、予後因子解析と臨床病態による病型分類が治療方針の決定には有用である。
問診・診察のポイント  
  1. ATLは白血化リンパ腫であり、リンパ節腫大、肝脾腫のほか皮膚その他の全身臓器に浸潤することがあるので、必ず全身の診察を行う。

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文献 

著者: Yumi Takasaki, Masako Iwanaga, Yoshitaka Imaizumi, Masayuki Tawara, Tatsuro Joh, Tomoko Kohno, Yasuaki Yamada, Shimeru Kamihira, Schuichi Ikeda, Yasushi Miyazaki, Masao Tomonaga, Kunihiro Tsukasaki
雑誌名: Blood. 2010 Jun 3;115(22):4337-43. doi: 10.1182/blood-2009-09-242347. Epub 2010 Mar 26.
Abstract/Text The long-term prognosis of indolent adult T-cell leukemia-lymphoma (ATL) is not clearly elucidated. From 1974 to 2003, newly diagnosed indolent ATL in 90 patients (65 chronic type and 25 smoldering type) was analyzed. The median survival time was 4.1 years; 12 patients remained alive for more than 10 years, 44 progressed to acute ATL, and 63 patients died. The estimated 5-, 10-, and 15-year survival rates were 47.2%, 25.4%, and 14.1%, respectively, with no plateau in the survival curve. Although most patients were treated with watchful waiting, 12 patients were treated with chemotherapy. Kaplan-Meier analyses showed that advanced performance status (PS), neutrophilia, high concentration of lactate dehydrogenase, more than 3 extranodal lesions, more than 4 total involved lesions, and receiving chemotherapy were unfavorable prognostic factors for survival. Multivariate Cox analysis showed that advanced PS was a borderline significant independent factor in poor survival (hazard ratio, 2.1, 95% confidence interval, 1.0-4.6; P = .06), but it was not a factor when analysis was limited to patients who had not received chemotherapy. The prognosis of indolent ATL in this study was poorer than expected. These findings suggest that even patients with indolent ATL should be carefully observed in clinical practice. Further studies are required to develop treatments for indolent ATL.

PMID 20348391  Blood. 2010 Jun 3;115(22):4337-43. doi: 10.1182/blood-2・・・
著者: Y Yamada, M Tomonaga, H Fukuda, S Hanada, A Utsunomiya, M Tara, M Sano, S Ikeda, K Takatsuki, M Kozuru, K Araki, F Kawano, M Niimi, K Tobinai, T Hotta, M Shimoyama
雑誌名: Br J Haematol. 2001 May;113(2):375-82.
Abstract/Text This phase II trial was performed to evaluate the efficacy of a new granulocyte colony-stimulating factor (G-CSF)-supported multi-agent chemotherapy protocol, LSG15, for aggressive adult T-cell leukaemia-lymphoma (ATL). Ninety-six previously untreated patients with aggressive ATL were enrolled and grouped as: acute type (58), lymphoma type (28) and unfavourable chronic type (10). Therapy consisted of seven cycles of VCAP (vincristine, cyclophosphamide, doxorubicin and prednisone), AMP (doxorubicin, ranimustine and prednisone) and VECP (vindesine, etoposide, carboplatin and prednisone). G-CSF was administered during the intervals between chemotherapy until neutrophil reconstitution was achieved. Eighty-one per cent of the 93 eligible patients responded [95% confidence interval (CI), 71.1-88.1%], with 33 patients obtaining complete response (35.5%) and 42 obtaining partial response (45.2%). The median survival time (MST) after registration was 13 months and the median follow-up duration of the 20 surviving patients was 4.2 years (range 2.8-5.6). Overall survival at 2 years was estimated to be 31.3% (95% CI, 22.0-40.5%). Grade 4 haematological toxicity of neutropenia and thrombocytopenia were observed in 65.3% and 52.6% of the patients respectively, but grade 4 non-haematological toxicity was observed in only one patient. LSG15 is feasible with mild non-haematological toxicity and improved the clinical outcome of ATL patients. MST and overall survival at 2 years were superior to those obtained by our previous trials.

PMID 11380402  Br J Haematol. 2001 May;113(2):375-82.
著者: Kunihiro Tsukasaki, Atae Utsunomiya, Haruhiko Fukuda, Taro Shibata, Takuya Fukushima, Yoshifusa Takatsuka, Shuichi Ikeda, Masato Masuda, Haruhisa Nagoshi, Ryuzo Ueda, Kazuo Tamura, Masayuki Sano, Saburo Momita, Kazunari Yamaguchi, Fumio Kawano, Shuichi Hanada, Kensei Tobinai, Masanori Shimoyama, Tomomitsu Hotta, Masao Tomonaga, Japan Clinical Oncology Group Study JCOG9801
雑誌名: J Clin Oncol. 2007 Dec 1;25(34):5458-64. doi: 10.1200/JCO.2007.11.9958. Epub 2007 Oct 29.
Abstract/Text PURPOSE: Our previous phase II trial for treating human T-lymphotropic virus type I-associated adult T-cell leukemia-lymphoma (ATLL) with vincristine, cyclophosphamide, doxorubicin, and prednisone (VCAP), doxorubicin, ranimustine, and prednisone (AMP), and vindesine, etoposide, carboplatin, and prednisone (VECP) showed promising results. To test the superiority of VCAP-AMP-VECP over biweekly cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), we conducted a randomized controlled trial exclusively for ATLL.
PATIENTS AND METHODS: Previously untreated patients with aggressive ATLL were assigned to receive either six courses of VCAP-AMP-VECP every 4 weeks or eight courses of biweekly CHOP. Both treatments were supported with granulocyte colony-stimulating factor and intrathecal prophylaxis.
RESULTS: A total of 118 patients were enrolled. The complete response (CR) rate was higher in the VCAP-AMP-VECP arm than in biweekly CHOP arm (40% v 25%, respectively; P = .020). Progression-free survival rate at 1 year was 28% in the VCAP-AMP-VECP arm compared with 16% in the CHOP arm (P = .100, two-sided P = .200). Overall survival (OS) at 3 years was 24% in the VCAP-AMP-VECP arm and 13% in the CHOP arm (P = .085, two-sided P = .169). For VCAP-AMP-VECP versus biweekly CHOP, grade 4 neutropenia, grade 4 thrombocytopenia, and grade 3 or 4 infection rates were 98% v 83%, 74% v 17%, and 32% v 15%, respectively. There were three toxic deaths in the VCAP-AMP-VECP arm.
CONCLUSION: The longer OS at 3 years and higher CR rate with VCAP-AMP-VECP compared with biweekly CHOP suggest that VCAP-AMP-VECP might be a more effective regimen at the expense of higher toxicities, providing the basis for future investigations in the treatment of ATLL.

PMID 17968021  J Clin Oncol. 2007 Dec 1;25(34):5458-64. doi: 10.1200/J・・・
著者: T Fukushima, Y Miyazaki, S Honda, F Kawano, Y Moriuchi, M Masuda, R Tanosaki, A Utsunomiya, N Uike, S Yoshida, J Okamura, M Tomonaga
雑誌名: Leukemia. 2005 May;19(5):829-34. doi: 10.1038/sj.leu.2403682.
Abstract/Text Adult T-cell leukemia/lymphoma (ATLL) is a distinct peripheral T-cell neoplasm that is highly resistant to chemotherapy. Several groups, including ours, have reported encouraging results of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with ATLL. To confirm our previous report and to establish the basis for a phase II clinical study, we analyzed 40 allo-HSCT for acute and lymphoma types of ATLL in seven institutions in Japan between 1997 and 2002. All evaluable cases entered complete remission (CR) after allo-HSCT and the median survival time was 9.6 months for all patients. The estimated 3-year overall and relapse-free survival, and disease relapse were 45.3, 33.8 and 39.3%, respectively. Among 10 cases with ATLL relapse, five cases achieved CR again: three by the reduction or cessation of immunosuppressive agents, which suggested a graft-versus-ATLL (GvATLL) effect. However, univariate or multivariate analysis did not show any benefit of graft-versus-host disease (GVHD) on the prevention of relapse. These results suggested that allo-HSCT was effective for some patients with aggressive ATLL, and that the GvATLL effect could be achieved even without GVHD. A new phase II trial to test the efficacy of allo-HSCT for ATLL is warranted.

PMID 15744352  Leukemia. 2005 May;19(5):829-34. doi: 10.1038/sj.leu.24・・・
著者: Masakatsu Hishizawa, Junya Kanda, Atae Utsunomiya, Shuichi Taniguchi, Tetsuya Eto, Yukiyoshi Moriuchi, Ryuji Tanosaki, Fumio Kawano, Yasushi Miyazaki, Masato Masuda, Koji Nagafuji, Masamichi Hara, Minoko Takanashi, Shunro Kai, Yoshiko Atsuta, Ritsuro Suzuki, Takakazu Kawase, Keitaro Matsuo, Tokiko Nagamura-Inoue, Shunichi Kato, Hisashi Sakamaki, Yasuo Morishima, Jun Okamura, Tatsuo Ichinohe, Takashi Uchiyama
雑誌名: Blood. 2010 Aug 26;116(8):1369-76. doi: 10.1182/blood-2009-10-247510. Epub 2010 May 17.
Abstract/Text Allogeneic hematopoietic stem cell transplantation (HSCT) is increasingly used as a curative option for adult T-cell leukemia (ATL), an intractable mature T-cell neoplasm causally linked with human T-cell leukemia virus type I (HTLV-I). We compared outcomes of 386 patients with ATL who underwent allogeneic HSCT using different graft sources: 154 received human leukocyte antigen (HLA)-matched related marrow or peripheral blood; 43 received HLA-mismatched related marrow or peripheral blood; 99 received unrelated marrow; 90 received single unit unrelated cord blood. After a median follow-up of 41 months (range, 1.5-102), 3-year overall survival for entire cohort was 33% (95% confidence interval, 28%-38%). Multivariable analysis revealed 4 recipient factors significantly associated with lower survival rates: older age (> 50 years), male sex, status other than complete remission, and use of unrelated cord blood compared with use of HLA-matched related grafts. Treatment-related mortality rate was higher among patients given cord blood transplants; disease-associated mortality was higher among male recipients or those given transplants not in remission. Among patients who received related transplants, donor HTLV-I seropositivity adversely affected disease-associated mortality. In conclusion, allogeneic HSCT using currently available graft source is an effective treatment in selected patients with ATL, although greater effort is warranted to reduce treatment-related mortality.

PMID 20479287  Blood. 2010 Aug 26;116(8):1369-76. doi: 10.1182/blood-2・・・
著者: Jun Okamura, Atae Utsunomiya, Ryuji Tanosaki, Naokuni Uike, Shunro Sonoda, Mari Kannagi, Masao Tomonaga, Mine Harada, Nobuhiro Kimura, Masato Masuda, Fumio Kawano, Yuji Yufu, Hiroyoshi Hattori, Hiroshi Kikuchi, Yoshio Saburi
雑誌名: Blood. 2005 May 15;105(10):4143-5. doi: 10.1182/blood-2004-11-4193. Epub 2005 Jan 21.
Abstract/Text Sixteen patients with adult T-cell leukemia/lymphoma (ATL) who were all over 50 years of age underwent allogeneic stem cell transplantation with reduced-conditioning intensity (RIST) from HLA-matched sibling donors after a conditioning regimen consisting of fludarabine (180 mg/m2), busulfan (8 mg/kg), and rabbit antithymocyte globulin (5 mg/kg). The observed regimen-related toxicities and nonhematologic toxicities were all found to be acceptable. Disease relapse was the main cause of treatment failure. Three patients who had a relapse subsequently responded to a rapid discontinuation of the immunosuppressive agent and thereafter achieved another remission. After RIST, the human T-cell leukemia virus type 1 (HTLV-1) proviral load became undetectable in 8 patients. RIST is thus considered to be a feasible treatment for ATL. Our data also suggest the presence of a possible graft-versus-ATL effect; an anti-HTLV-1 activity was also found to be associated with this procedure.

PMID 15665110  Blood. 2005 May 15;105(10):4143-5. doi: 10.1182/blood-2・・・
著者: Ryuji Tanosaki, Naokuni Uike, Atae Utsunomiya, Yoshio Saburi, Masato Masuda, Masao Tomonaga, Tetsuya Eto, Michihiro Hidaka, Mine Harada, Ilseung Choi, Takeharu Yamanaka, Mari Kannagi, Masao Matsuoka, Jun Okamura
雑誌名: Biol Blood Marrow Transplant. 2008 Jun;14(6):702-8. doi: 10.1016/j.bbmt.2008.03.010.
Abstract/Text Allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for adult T cell leukemia/lymphoma (ATLL), but shows high mortality. We evaluated the feasibility of reduced-intensity transplantation using fludarabine and busulfan, with particular focus on the clinical impact of antithymocyte globulin (ATG) in the conditioning regimen. Fourteen elderly patients with aggressive ATLL were enrolled in the current study without ATG, and were compared to those in 15 patients who were treated similarly, but with ATG, in our previous study. Engraftment was prompt, and treatment was tolerable. Overall (OS) and progression-free survival (PFS) at 3 years were 36% and 31%, respectively. HTVL-1 proviral load became undetectable by the polymerase chain reaction in 62% of patients. Compared to the previous study with ATG, complete donor chimera was significantly delayed. Although early relapse tended to be decreased, OS or PFS was not improved significantly. Analysis of combined data from both our current and previous studies disclosed that grade I-II acute GVHD was the only factor that favorably affected OS and PFS. These data suggested the presence of a graft-versus-ATLL effect and the feasibility of a transplant procedure without ATG in elderly ATLL patients, but could not demonstrate the clinical benefit of incorporating ATG.

PMID 18489996  Biol Blood Marrow Transplant. 2008 Jun;14(6):702-8. doi・・・
著者: I Choi, R Tanosaki, N Uike, A Utsunomiya, M Tomonaga, M Harada, T Yamanaka, M Kannagi, J Okamura, ATLL allo-HSCT Study Group
雑誌名: Bone Marrow Transplant. 2011 Jan;46(1):116-8. doi: 10.1038/bmt.2010.92. Epub 2010 Apr 19.
Abstract/Text We have previously conducted clinical trials of allogeneic hematopoietic SCT with reduced-intensity conditioning regimen (RIC) for adult T-cell leukemia/lymphoma (ATLL)-a disease caused by human T-lymphotropic virus type 1 (HTLV-1) infection and having a dismal prognosis. Long-term follow-up studies of these trials revealed that 10 of the 29 patients have survived for a median of 82 months (range, 54-100 months) after RIC, indicating a possible curability of the disease by RIC. However, we have also observed that the patterns of post-RIC changes in HTLV-1 proviral load over time among the 10 survivors were classified into three patterns. This is the first report to clarify the long-term outcomes after RIC for ATLL patients.

PMID 20400987  Bone Marrow Transplant. 2011 Jan;46(1):116-8. doi: 10.1・・・

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