今日の臨床サポート

非ホジキンリンパ腫

著者: 渡辺隆 三重大学大学院医学系研究科 個別化がん免疫治療学

監修: 木崎昌弘 埼玉医科大学総合医療センター

著者校正/監修レビュー済:2021/03/24
患者向け説明資料

概要・推奨   

  1. びまん性大細胞型B細胞リンパ腫において予後不良とされる60歳以上の高齢者に対して、CHOP療法にリツキシマブを上乗せすることによって生命予後が改善される(推奨度1)
  1. 予後不良因子をもたない60歳以下の若年者びまん性大細胞型B細胞リンパ腫においてもCHOP療法にリツキシマブを併用したほうが生命予後の改善が得られる(推奨度1)
  1. リツキシマブ登場以前には、びまん性大細胞型B細胞リンパ腫の限局期患者においてはCHOP療法のサイクル数を減らして追加放射線治療が推奨された(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:
渡辺隆 : 企業などが提供する寄付講座(ユナイテッド・イミュニティ株式会社,ブライトパス・バイオ株式会社)[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. 定期レビューを行い、濾胞性リンパ腫の初発時での治療選択肢、マントル細胞リンパ腫・小リンパ球性リンパ腫・末梢性T細胞リンパ腫の再発時の治療についてエビデンスを追記した。
  1. マントル細胞リンパ腫では、その後の長期観察結果により全生存での優位性を示すエビデンスを追加した。
  1. 治療抵抗性のびまん性大細胞型B細胞リンパ腫の再発時の治療オプションとしてCAR-T細胞療法のエビデンスも追記した。
  1. WHO分類の改訂版(42017年)により病名の追加・修正を行った。

病態・疫学・診察

疾患情報  
  1. 非ホジキンリンパ腫はWHO分類にみられるように多くの病型が存在する。そのため、適切な検体を用いて病理診断を確定することが重要である。同時に全身検索により病期を決定し、適切な治療方針を立てる必要がある。
  1. 悪性リンパ腫の全悪性腫瘍死亡に占める割合は3.3%であるが増加傾向にある。
  1. 2016年わが国における悪性リンパ腫の粗罹患率は人口10万当たり男11.4、女8.5であり、日本全国での年間患者発生数は約2万9,700人と推定される。わが国では全悪性リンパ腫の約94%を非ホジキンリンパ腫(NHL)が占める。
  1. 非ホジキンリンパ腫は「B細胞腫瘍」と「T/NK細胞腫瘍」に大別され、B細胞リンパ腫が悪性リンパ腫の7割(後者はNHLの25%)を占める。びまん性大細胞型B細胞リンパ腫(DLBCL)は、NHLの約45%を占め、日本全体で年間13,000人程度発生すると予測される。濾胞性リンパ腫はNHL全体の13.5%を、節外性MALTリンパ腫は9%を占める。
  1. リスクファクターとしては、ウイルス(Epstein-Barr virus[EBV]、C型肝炎、human T-cell leukemia virus type 1[HTLV-1])、農薬曝露、慢性炎症、免疫抑制などがある。MALTリンパ腫・濾胞辺縁帯リンパ腫の病因の一部には、感染症・炎症が関係している。胃MALTリンパ腫でピロリ菌の感染頻度は92~98%。唾液腺、甲状腺のMALTリンパ腫では自己免疫疾患に関係しており、それぞれSjögren症候群、橋本病などの自己免疫疾患に合併することがある。
問診・診察のポイント  
問診:
  1. リンパ節腫脹を来した患者が来院した際には、必ずその前後に発熱や、リンパ節の腫脹速度や自発痛・圧痛の有無を聴取する。

今なら12か月分の料金で14ヶ月利用できます(個人契約、期間限定キャンペーン)

11月30日(火)までにお申込みいただくと、
通常12ヵ月の使用期間が2ヶ月延長となり、14ヵ月ご利用いただけるようになります。

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文献 

著者:
雑誌名: N Engl J Med. 1993 Sep 30;329(14):987-94. doi: 10.1056/NEJM199309303291402.
Abstract/Text BACKGROUND: Although many patients with intermediate-grade or high-grade (aggressive) non-Hodgkin's lymphoma are cured by combination chemotherapy, the remainder are not cured and ultimately die of their disease. The Ann Arbor classification, used to determine the stage of this disease, does not consistently distinguish between patients with different long-term prognoses. This project was undertaken to develop a model for predicting outcome in patients with aggressive non-Hodgkin's lymphoma on the basis of the patients' clinical characteristics before treatment.
METHODS: Adults with aggressive non-Hodgkin's lymphoma from 16 institutions and cooperative groups in the United States, Europe, and Canada who were treated between 1982 and 1987 with combination-chemotherapy regimens containing doxorubicin were evaluated for clinical features predictive of overall survival and relapse-free survival. Features that remained independently significant in step-down regression analyses of survival were incorporated into models that identified groups of patients of all ages and groups of patients no more than 60 years old with different risks of death.
RESULTS: In 2031 patients of all ages, our model, based on age, tumor stage, serum lactate dehydrogenase concentration, performance status, and number of extranodal disease sites, identified four risk groups with predicted five-year survival rates of 73 percent, 51 percent, 43 percent, and 26 percent. In 1274 patients 60 or younger, an age-adjusted model based on tumor stage, lactate dehydrogenase level, and performance status identified four risk groups with predicted five-year survival rates of 83 percent, 69 percent, 46 percent, and 32 percent. In both models, the increased risk of death was due to both a lower rate of complete responses and a higher rate of relapse from complete response. These two indexes, called the international index and the age-adjusted international index, were significantly more accurate than the Ann Arbor classification in predicting long-term survival.
CONCLUSIONS: The international index and the age-adjusted international index should be used in the design of future therapeutic trials in patients with aggressive non-Hodgkin's lymphoma and in the selection of appropriate therapeutic approaches for individual patients.

PMID 8141877  N Engl J Med. 1993 Sep 30;329(14):987-94. doi: 10.1056/・・・
著者: Philippe Solal-Céligny, Pascal Roy, Philippe Colombat, Josephine White, Jim O Armitage, Reyes Arranz-Saez, Wing Y Au, Monica Bellei, Pauline Brice, Dolores Caballero, Bertrand Coiffier, Eulogio Conde-Garcia, Chantal Doyen, Massimo Federico, Richard I Fisher, Javier F Garcia-Conde, Cesare Guglielmi, Anton Hagenbeek, Corinne Haïoun, Michael LeBlanc, Andrew T Lister, Armando Lopez-Guillermo, Peter McLaughlin, Noël Milpied, Pierre Morel, Nicolas Mounier, Stephen J Proctor, Ama Rohatiner, Paul Smith, Pierre Soubeyran, Hervé Tilly, Umberto Vitolo, Pier-Luigi Zinzani, Emanuele Zucca, Emili Montserrat
雑誌名: Blood. 2004 Sep 1;104(5):1258-65. doi: 10.1182/blood-2003-12-4434. Epub 2004 May 4.
Abstract/Text The prognosis of follicular lymphomas (FL) is heterogeneous and numerous treatments may be proposed. A validated prognostic index (PI) would help in evaluating and choosing these treatments. Characteristics at diagnosis were collected from 4167 patients with FL diagnosed between 1985 and 1992. Univariate and multivariate analyses were used to propose a PI. This index was then tested on 919 patients. Five adverse prognostic factors were selected: age (> 60 years vs < or = 60 years), Ann Arbor stage (III-IV vs I-II), hemoglobin level (< 120 g/L vs > or = 120 g/L), number of nodal areas (> 4 vs < or = 4), and serum LDH level (above normal vs normal or below). Three risk groups were defined: low risk (0-1 adverse factor, 36% of patients), intermediate risk (2 factors, 37% of patients, hazard ratio [HR] of 2.3), and poor risk (> or = 3 adverse factors, 27% of patients, HR = 4.3). This Follicular Lymphoma International Prognostic Index (FLIPI) appeared more discriminant than the International Prognostic Index proposed for aggressive non-Hodgkin lymphomas. Results were very similar in the confirmation group. The FLIPI may be used for improving treatment choices, comparing clinical trials, and designing studies to evaluate new treatments.

PMID 15126323  Blood. 2004 Sep 1;104(5):1258-65. doi: 10.1182/blood-20・・・
著者: Massimo Federico, Monica Bellei, Luigi Marcheselli, Stefano Luminari, Armando Lopez-Guillermo, Umberto Vitolo, Barbara Pro, Stefano Pileri, Alessandro Pulsoni, Pierre Soubeyran, Sergio Cortelazzo, Giovanni Martinelli, Maurizio Martelli, Luigi Rigacci, Luca Arcaini, Francesco Di Raimondo, Francesco Merli, Elena Sabattini, Peter McLaughlin, Philippe Solal-Céligny
雑誌名: J Clin Oncol. 2009 Sep 20;27(27):4555-62. doi: 10.1200/JCO.2008.21.3991. Epub 2009 Aug 3.
Abstract/Text PURPOSE: The aim of the F2 study was to verify whether a prospective collection of data would enable the development of a more accurate prognostic index for follicular lymphoma (FL) by using parameters which could not be retrospectively studied before, and by choosing progression-free survival (PFS) as principal end point.
PATIENTS AND METHODS: Between January 2003 and May 2005, 1,093 patients with a newly diagnosed FL were registered and 942 individuals receiving antilymphoma therapy were selected as the study population. The variables we used for score definition were selected by means of bootstrap resampling procedures on 832 patients with complete data. Procedures to select the model that would minimize errors were also performed.
RESULTS: After a median follow-up of 38 months, 261 events for PFS evaluation were recorded. beta2-microglobulin higher than the upper limit of normal, longest diameter of the largest involved node longer than 6 cm, bone marrow involvement, hemoglobin level lower than 12 g/dL, and age older than 60 years were factors independently predictive for PFS. Using these variables, a prognostic model was devised to identify three groups at different levels of risk. The 3-year PFS rate was 91%, 69%, and 51% for patients at low, intermediate, and high risk, respectively (log-rank = 64.6; P < .00001). The 3-year survival rate was 99%, 96%, and 84% for patients at low, intermediate, and high risk, respectively (P < .0001).
CONCLUSION: Follicular Lymphoma International Prognostic Index 2 is a simple prognostic index based on easily available clinical data and may represent a promising new tool for the identification of patients with FL at different risk in the era of immunochemotherapy.

PMID 19652063  J Clin Oncol. 2009 Sep 20;27(27):4555-62. doi: 10.1200/・・・
著者: Andrea Gallamini, Caterina Stelitano, Roberta Calvi, Monica Bellei, Daniele Mattei, Umberto Vitolo, Fortunato Morabito, Maurizio Martelli, Ercole Brusamolino, Emilio Iannitto, Francesco Zaja, Sergio Cortelazzo, Luigi Rigacci, Liliana Devizzi, Giuseppe Todeschini, Gino Santini, Maura Brugiatelli, Massimo Federico, Intergruppo Italiano Linfomi
雑誌名: Blood. 2004 Apr 1;103(7):2474-9. doi: 10.1182/blood-2003-09-3080. Epub 2003 Nov 26.
Abstract/Text To assess the prognosis of peripheral T-cell lymphoma unspecified, we retrospectively analyzed 385 cases fulfilling the criteria defined by the World Health Organization classification. Factors associated with a worse overall survival (OS) in a univariate analysis were age older than 60 years (P=.0002), equal to or more than 2 extranodal sites (P=.0002), lactic dehydrogenase (LDH) value at normal levels or above (P<.0001), performance status (PS) equal to or more than 2 (P< or =.0001), stage III or higher (P=.0001), and bone marrow involvement (P=.0001). Multivariate analysis showed that age (relative risk, 1.732; 95% CI, 1.300-2.309; P<.0001), PS (relative risk, 1.719; 95% CI, 1.269-2.327, P<.0001), LDH level (relative risk, 1.905; 95% CI, 1.415-2.564; P<.0001), and bone marrow involvement (relative risk, 1.454; 95% CI, 1.045-2.023; P=.026) were factors independently predictive for survival. Using these 4 variables we constructed a new prognostic model that singled out 4 groups at different risk: group 1, no adverse factors, with 5-year and 10-year OS of 62.3% and 54.9%, respectively; group 2, one factor, with a 5-year and 10-year OS of 52.9% and 38.8%, respectively; group 3, 2 factors, with 5-year and 10-year OS of 32.9% and 18.0%, respectively; group 4, 3 or 4 factors, with a 5-year and 10-year OS of 18.3 and 12.6%, respectively (P< or =.0001; log-rank, 66.79).

PMID 14645001  Blood. 2004 Apr 1;103(7):2474-9. doi: 10.1182/blood-200・・・
著者: P Feugier, A Van Hoof, C Sebban, P Solal-Celigny, R Bouabdallah, C Fermé, B Christian, E Lepage, H Tilly, F Morschhauser, P Gaulard, G Salles, A Bosly, C Gisselbrecht, F Reyes, B Coiffier
雑誌名: J Clin Oncol. 2005 Jun 20;23(18):4117-26. doi: 10.1200/JCO.2005.09.131. Epub 2005 May 2.
Abstract/Text PURPOSE: To analyze the long-term outcome of patients included in the Lymphome Non Hodgkinien study 98-5 (LNH98-5) comparing cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) to rituximab plus CHOP (R-CHOP) in elderly patients with diffuse large B-cell lymphoma.
PATIENTS AND METHODS: LNH98-5 was a randomized study that included 399 previously untreated patients, age 60 to 80 years, with diffuse large B-cell lymphoma. Patients received eight cycles of classical CHOP (cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), vincristine 1.4 mg/m(2), and prednisone 40 mg/m(2) for 5 days) every 3 weeks. In R-CHOP, rituximab 375 mg/m(2) was administered the same day as CHOP. Survivals were analyzed using the intent-to-treat principle.
RESULTS: Median follow-up is 5 years at present. Event-free survival, progression-free survival, disease-free survival, and overall survival remain statistically significant in favor of the combination of R-CHOP (P = .00002, P < .00001, P < .00031, and P < .0073, respectively, in the log-rank test). Patients with low-risk or high-risk lymphoma according to the age-adjusted International Prognostic Index have longer survivals if treated with the combination. No long-term toxicity appeared to be associated with the R-CHOP combination.
CONCLUSION: Using the combination of R-CHOP leads to significant improvement of the outcome of elderly patients with diffuse large B-cell lymphoma, with significant survival benefit maintained during a 5-year follow-up. This combination should become the standard for treating these patients.

PMID 15867204  J Clin Oncol. 2005 Jun 20;23(18):4117-26. doi: 10.1200/・・・
著者: Takashi Watanabe, Kensei Tobinai, Taro Shibata, Kunihiro Tsukasaki, Yasuo Morishima, Nobuo Maseki, Tomohiro Kinoshita, Takayo Suzuki, Motoko Yamaguchi, Kiyoshi Ando, Michinori Ogura, Masafumi Taniwaki, Naokuni Uike, Kengo Takeuchi, Shigeru Nawano, Takashi Terauchi, Tomomitsu Hotta
雑誌名: J Clin Oncol. 2011 Oct 20;29(30):3990-8. doi: 10.1200/JCO.2011.34.8508. Epub 2011 Sep 19.
Abstract/Text PURPOSE: Rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is one of the most effective front-line therapies to treat indolent B-cell lymphoma. Granulocyte colony-stimulating factor (G-CSF), which potentiates antibody-dependent rituximab cytotoxicity, is used to shorten CHOP intervals. To improve progression-free survival (PFS) in patients treated with R-CHOP as the primary end point, we conducted a phase III study.
PATIENTS AND METHODS: Patients with untreated stages III to IV indolent B-cell lymphoma were randomly assigned to six cycles of R-CHOP every 3 weeks (R-CHOP-21) or every 2 weeks (R-CHOP-14) with G-CSF. Maintenance rituximab was not allowed.
RESULTS: Three hundred patients were enrolled. At the median follow-up time of 5.2 years, there was no significant difference in PFS between arms for the 299 eligible patients; the median was 3.7 (R-CHOP-21) v 4.7 (R-CHOP-14) years, 57% v 58% at 3 years, and 41% v 43% at 6 years, respectively (hazard ratio [HR], 0.92; 95% CI, 0.68 to 1.25; one-sided P = .30). The median overall survival (OS) time was not reached in either arm, and there was no significant difference (6-year OS: 87% [R-CHOP-21] v 88% [R-CHOP-14]; HR, 1.15; 95% CI, 0.57 to 2.30; one-sided P = .65). Although grade 4 neutropenia and grade 3 infections were more frequent in the R-CHOP-21 group, R-CHOP was feasible in both arms.
CONCLUSION: The R-CHOP dose-dense strategy failed to improve PFS of patients with untreated indolent B-cell lymphoma. Further improvement of first-line treatment or investigations on postremission therapy following R-CHOP should be explored.

PMID 21931035  J Clin Oncol. 2011 Oct 20;29(30):3990-8. doi: 10.1200/J・・・
著者: Bertrand Coiffier, Eric Lepage, Josette Briere, Raoul Herbrecht, Hervé Tilly, Reda Bouabdallah, Pierre Morel, Eric Van Den Neste, Gilles Salles, Philippe Gaulard, Felix Reyes, Pierre Lederlin, Christian Gisselbrecht
雑誌名: N Engl J Med. 2002 Jan 24;346(4):235-42. doi: 10.1056/NEJMoa011795.
Abstract/Text BACKGROUND: The standard treatment for patients with diffuse large-B-cell lymphoma is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Rituximab, a chimeric monoclonal antibody against the CD20 B-cell antigen, has therapeutic activity in diffuse large-B-cell lymphoma. We conducted a randomized trial to compare CHOP chemotherapy plus rituximab with CHOP alone in elderly patients with diffuse large-B-cell lymphoma.
METHODS: Previously untreated patients with diffuse large-B-cell lymphoma, 60 to 80 years old, were randomly assigned to receive either eight cycles of CHOP every three weeks (197 patients) or eight cycles of CHOP plus rituximab given on day 1 of each cycle (202 patients).
RESULTS: The rate of complete response was significantly higher in the group that received CHOP plus rituximab than in the group that received CHOP alone (76 percent vs. 63 percent, P=0.005). With a median follow-up of two years, event-free and overall survival times were significantly higher in the CHOP-plus-rituximab group (P<0.001 and P=0.007, respectively). The addition of rituximab to standard CHOP chemotherapy significantly reduced the risk of treatment failure and death (risk ratios, 0.58 [95 percent confidence interval, 0.44 to 0.77] and 0.64 [0.45 to 0.89], respectively). Clinically relevant toxicity was not significantly greater with CHOP plus rituximab.
CONCLUSIONS: The addition of rituximab to the CHOP regimen increases the complete-response rate and prolongs event-free and overall survival in elderly patients with diffuse large-B-cell lymphoma, without a clinically significant increase in toxicity.

PMID 11807147  N Engl J Med. 2002 Jan 24;346(4):235-42. doi: 10.1056/N・・・
著者: Bertrand Coiffier, Catherine Thieblemont, Eric Van Den Neste, Gérard Lepeu, Isabelle Plantier, Sylvie Castaigne, Sophie Lefort, Gérald Marit, Margaret Macro, Catherine Sebban, Karim Belhadj, Dominique Bordessoule, Christophe Fermé, Hervé Tilly
雑誌名: Blood. 2010 Sep 23;116(12):2040-5. doi: 10.1182/blood-2010-03-276246. Epub 2010 Jun 14.
Abstract/Text We report the outcome of patients included in the LNH-98.5 study, which compared cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) to rituximab plus CHOP (R-CHOP) therapy in 399 patients with diffuse large B-cell lymphoma (DLBCL) aged 60 to 80 years, with a median follow-up time of 10 years. Clinical event information was updated in all living patients (with the exception of 3 patients) in 2009. Survival end points were improved in patients treated with R-CHOP: the 10-year progression-free survival was 36.5%, compared with 20% with CHOP alone, and the 10-year overall survival was 43.5% compared with 27.6%. The same risk of death due to other diseases, secondary cancers, and late relapses was observed in both study arms. Relapses occurring after 5 years represented 7% of all disease progressions. The results from the 10-year analysis confirm the benefits and tolerability of the addition of rituximab to CHOP. Our findings underscore the need to treat elderly patients as young patients, with the use of curative chemotherapy.

PMID 20548096  Blood. 2010 Sep 23;116(12):2040-5. doi: 10.1182/blood-2・・・
著者: Michael Pfreundschuh, Joerg Schubert, Marita Ziepert, Rudolf Schmits, Martin Mohren, Eva Lengfelder, Marcel Reiser, Christina Nickenig, Michael Clemens, Norma Peter, Carsten Bokemeyer, Hartmut Eimermacher, Anthony Ho, Martin Hoffmann, Roland Mertelsmann, Lorenz Trümper, Leopold Balleisen, Ruediger Liersch, Bernd Metzner, Frank Hartmann, Bertram Glass, Viola Poeschel, Norbert Schmitz, Christian Ruebe, Alfred C Feller, Markus Loeffler, German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)
雑誌名: Lancet Oncol. 2008 Feb;9(2):105-16. doi: 10.1016/S1470-2045(08)70002-0. Epub 2008 Jan 15.
Abstract/Text BACKGROUND: Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) is used to treat patients with non-Hodgkin lymphoma. Interval decrease from 3 weeks of treatment (CHOP-21) to 2 weeks (CHOP-14), and addition of rituximab to CHOP-21 (R-CHOP-21) has been shown to improve outcome in elderly patients with diffuse large B-cell lymphoma (DLBCL). This randomised trial assessed whether six or eight cycles of R-CHOP-14 can improve outcome of these patients compared with six or eight cycles of CHOP-14.
METHODS: 1222 elderly patients (aged 61-80 years) were randomly assigned to six or eight cycles of CHOP-14 with or without rituximab. Radiotherapy was planned to sites of initial bulky disease with or without extranodal involvement. The primary endpoint was event-free survival; secondary endpoints were response, progression during treatment, progression-free survival, overall survival, and frequency of toxic effects. Analyses were done by intention to treat. The trial is registered on National Cancer Institute website, number NCT00052936 and as EU-20243.
FINDINGS: 3-year event-free survival was 47.2% after six cycles of CHOP-14 (95% CI 41.2-53.3), 53.0% (47.0-59.1) after eight cycles of CHOP-14, 66.5% (60.9-72.0) after six cycles of R-CHOP-14, and 63.1% (57.4-68.8) after eight cycles of R-CHOP-14. Compared with six cycles of CHOP-14, the improvement in 3-year event-free survival was 5.8% (-2.8-14.4) for eight cycles of CHOP-14, 19.3% (11.1-27.5) for six cycles of R-CHOP-14, and 15.9% (7.6-24.2) for eight cycles of R-CHOP-14. 3-year overall survival was 67.7% (62.0-73.5) for six cycles of CHOP-14, 66.0% (60.1-71.9) for eight cycles of CHOP-14, 78.1% (73.2-83.0) for six cycles of R-CHOP-14, and 72.5% (67.1-77.9) for eight cycles of R-CHOP-14. Compared with treatment with six cycles of CHOP-14, overall survival improved by -1.7% (-10.0-6.6) after eight cycles of CHOP-14, 10.4% (2.8-18.0) after six cycles of R-CHOP-14, and 4.8% (-3.1-12.7) after eight cycles of R-CHOP-14. In a multivariate analysis that used six cycles of CHOP-14 without rituximab as the reference, and adjusting for known prognostic factors, all three intensified regimens improved 3-year event-free survival (eight cycles of CHOP-14: RR [relative risk] 0.76 [0.60-0.95], p=0.0172; six cycles of R-CHOP-14: RR 0.51 [0.40-0.65], p<0.0001; eight cycles of R-CHOP-14: RR 0.54 [0.43-0.69], p<0.0001). Progression-free survival improved after six cycles of R-CHOP-14 (RR 0.50 [0.38-0.67], p<0.0001), and eight cycles of R-CHOP-14 (RR 0.59 [0.45-0.77], p=0.0001). Overall survival improved only after six cycles of R-CHOP-14 (RR 0.63 [0.46-0.85], p=0.0031). In patients with a partial response after four cycles of chemotherapy, eight cycles were not better than six cycles.
INTERPRETATION: Six cycles of R-CHOP-14 significantly improved event-free, progression-free, and overall survival over six cycles of CHOP-14 treatment. Response-adapted addition of chemotherapy beyond six cycles, though widely practiced, is not justified. Of the four regimens assessed in this study, six cycles of R-CHOP-14 is the preferred treatment for elderly patients, with which other approaches should be compared.

PMID 18226581  Lancet Oncol. 2008 Feb;9(2):105-16. doi: 10.1016/S1470-・・・
著者: Michael Pfreundschuh, Lorenz Trümper, Anders Osterborg, Ruth Pettengell, Marek Trneny, Kevin Imrie, David Ma, Devinder Gill, Jan Walewski, Pier-Luigi Zinzani, Rolf Stahel, Stein Kvaloy, Ofer Shpilberg, Ulrich Jaeger, Mads Hansen, Tuula Lehtinen, Armando López-Guillermo, Claudia Corrado, Adriana Scheliga, Noel Milpied, Myriam Mendila, Michelle Rashford, Evelyn Kuhnt, Markus Loeffler, MabThera International Trial Group
雑誌名: Lancet Oncol. 2006 May;7(5):379-91. doi: 10.1016/S1470-2045(06)70664-7.
Abstract/Text BACKGROUND: The role of rituximab in combination with different CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-like chemotherapy regimens in young patients with good-prognosis diffuse large-B-cell lymphoma remains to be defined. We aimed to compare CHOP-like chemotherapy and rituximab with CHOP-like chemotherapy alone in these patients.
METHODS: 824 patients who were from 18 countries; aged 18-60 years; and who had no risk factors or one risk factor according to age-adjusted International Prognostic Index (IPI), stage II-IV disease, or stage I disease with bulk were enrolled. These patients were randomly assigned to six cycles of CHOP-like chemotherapy and rituximab (n=413) or to six cycles of CHOP-like chemotherapy alone (n=411). Bulky and extranodal sites received additional radiotherapy. The primary endpoint was event-free survival; secondary endpoints were response, progression under therapy, progression-free survival, overall survival, and frequency of toxic effects. Analyses were done by intention to treat and per protocol. This trial is registered at http://www.clinicaltrials.gov, NCT 00064116.
FINDINGS: After a median follow-up of 34 months (range 0.03-61), patients assigned chemotherapy and rituximab had increased 3-year event-free survival compared with those assigned chemotherapy alone (79% [95% CI 75-83] vs 59% [54-64]; difference between groups 20% [13-27], log-rank p<0.0001), and had increased 3-year overall survival (93% [90-95] vs 84% [80-88]; difference between groups 9% [3-13], log-rank p=0.0001). Event-free survival was affected by treatment group, presence of bulky disease, and age-adjusted IPI: after chemotherapy and rituximab, a favourable subgroup (ie, IPI=0, no bulk) could be defined from a less-favourable subgroup (ie, IPI=1 or bulk, or both). Groups did not differ in the frequency of adverse events.
INTERPRETATION: Rituximab added to six cycles of CHOP is an effective treatment for young patients with good-prognosis diffuse large-B-cell lymphoma. The definition of two prognostic subgroups allows for a more refined therapeutic approach for these patients.

PMID 16648042  Lancet Oncol. 2006 May;7(5):379-91. doi: 10.1016/S1470-・・・
著者: Frédéric Peyrade, Fabrice Jardin, Catherine Thieblemont, Antoine Thyss, Jean-François Emile, Sylvie Castaigne, Bertrand Coiffier, Corinne Haioun, Serge Bologna, Olivier Fitoussi, Gérard Lepeu, Christophe Fruchart, Dominique Bordessoule, Michel Blanc, Richard Delarue, Maud Janvier, Bruno Salles, Marc André, Marion Fournier, Philippe Gaulard, Hervé Tilly, Groupe d'Etude des Lymphomes de l'Adulte (GELA) investigators
雑誌名: Lancet Oncol. 2011 May;12(5):460-8. doi: 10.1016/S1470-2045(11)70069-9. Epub 2011 Apr 7.
Abstract/Text BACKGROUND: Diffuse large B-cell lymphoma is a common cancer in elderly patients. Although treatment has been standardised in younger patients, no prospective study has been done in patients over 80 years old. We aimed to investigate the efficacy and safety of a decreased dose of CHOP (doxorubicin, cyclophosphamide, vincristine, and prednisone) chemotherapy with a conventional dose of rituximab in elderly patients with diffuse large B-cell lymphoma.
METHODS: We did a prospective, multicentre, single-arm, phase 2 study of patients aged over 80 years who had diffuse large B-cell lymphoma. Patients were included from 38 centres in France and Belgium. All patients received six cycles of rituximab combined with low-dose CHOP (R-miniCHOP) at 3-week intervals. Patients received 375 mg/m(2) rituximab, 400 mg/m(2) cyclophosphamide, 25 mg/m(2) doxorubicin, and 1 mg vincristine on day 1 of each cycle, and 40 mg/m(2) prednisone on days 1-5. The primary endpoint was overall survival, both unadjusted and adjusted for treatment and baseline prognostic factors. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT01087424.
FINDINGS: 150 patients were enrolled between Jan 9, 2006, and Jan 23, 2009 and 149 were included in the intention-to-treat analyses. Median age was 83 years (range 80-95). After a median follow-up of 20 months (range 0-45), the median overall survival was 29 months (95% CI 21 to upper limit not reached); 2-year overall survival was 59% (49-67%). In multivariate analyses, overall survival was only affected by a serum albumin concentration of 35 g/L or less (hazard ratio 3·2, 95% CI 1·4-7·1; p=0·0053). Median progression-free survival was 21 months (95% CI 13 to upper limit not reached), with a 2-year progression free survival of 47% (38-56). 58 deaths were reported, 33 of which were secondary to lymphoma progression. 12 deaths were attributed to toxicity of the treatment. The most frequent side-effect was haematological toxicity (grade ≥3 neutropenia in 59 patients; febrile neutropenia in 11 patients).
INTERPRETATION: R-miniCHOP offers a good compromise between efficacy and safety in patients aged over 80 years old. R-miniCHOP should be considered as the new standard treatment in this subgroup of patients.
FUNDING: Groupe d'Etude des Lymphomes de l'Adulte (GELA).

Copyright © 2011 Elsevier Ltd. All rights reserved.
PMID 21482186  Lancet Oncol. 2011 May;12(5):460-8. doi: 10.1016/S1470-・・・
著者: T P Miller, S Dahlberg, J R Cassady, D J Adelstein, C M Spier, T M Grogan, M LeBlanc, S Carlin, E Chase, R I Fisher
雑誌名: N Engl J Med. 1998 Jul 2;339(1):21-6. doi: 10.1056/NEJM199807023390104.
Abstract/Text BACKGROUND: Patients with clinically localized, intermediate- or high-grade non-Hodgkin's lymphoma usually receive initial treatment with a doxorubicin-containing regimen such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Pilot studies suggest that eight cycles of CHOP alone or three cycles of CHOP followed by involved-field radiotherapy are effective in such patients.
METHODS: We compared these two approaches in a prospective, randomized, multi-institutional study. The end points were progression-free survival, overall survival, and life-threatening or fatal toxic effects. Two hundred eligible patients were randomly assigned to receive CHOP plus radiotherapy, and 201 received CHOP alone.
RESULTS: Patients treated with three cycles of CHOP plus radiotherapy had significantly better progression-free survival (P=0.03) and overall survival (P=0.02) than patients treated with CHOP alone. The five-year estimates of progression-free survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 77 percent and 64 percent, respectively. The five-year estimates of overall survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 82 percent and 72 percent, respectively. The adverse effects included one death in each treatment group. Life-threatening toxic effects of any type were seen in 61 of 200 patients treated with CHOP plus radiotherapy and in 80 of 201 patients treated with CHOP alone (P=0.06). The left ventricular function was decreased in seven patients who received CHOP alone, whereas no cardiac events were recorded in the group receiving CHOP plus radiotherapy (P=0.02).
CONCLUSIONS: Three cycles of CHOP followed by involved-field radiotherapy are superior to eight cycles of CHOP alone for the treatment of localized intermediate- and high-grade non-Hodgkin's lymphoma.

PMID 9647875  N Engl J Med. 1998 Jul 2;339(1):21-6. doi: 10.1056/NEJM・・・
著者: Félix Reyes, Eric Lepage, Gérard Ganem, Thierry J Molina, Pauline Brice, Bertrand Coiffier, Pierre Morel, Christophe Ferme, Andre Bosly, Pierre Lederlin, Guy Laurent, Hervé Tilly, Groupe d'Etude des Lymphomes de l'Adulte (GELA)
雑誌名: N Engl J Med. 2005 Mar 24;352(12):1197-205. doi: 10.1056/NEJMoa042040.
Abstract/Text BACKGROUND: Chemoradiotherapy is standard treatment for localized aggressive lymphoma. To determine the optimal therapy for nonelderly persons with low-risk localized lymphoma, we conducted a randomized trial comparing chemoradiotherapy with chemotherapy alone.
METHODS: Previously untreated patients less than 61 years old with localized stage I or II aggressive lymphoma and no adverse prognostic factors according to the International Prognostic Index were randomly assigned to three cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus involved-field radiotherapy (329 patients) or chemotherapy alone with dose-intensified doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) plus sequential consolidation (318 patients).
RESULTS: With a median follow-up of 7.7 years, event-free and overall survival rates were significantly higher in the group given chemotherapy alone than in the group given CHOP plus radiotherapy (P<0.001 and P=0.001, respectively). The five-year estimates of event-free survival were 82 percent (95 percent confidence interval, 78 to 87 percent) for patients receiving chemotherapy alone and 74 percent (95 percent confidence interval, 69 to 78 percent) for those receiving chemoradiotherapy. The respective five-year estimates of overall survival were 90 percent (95 percent confidence interval, 87 to 93 percent) and 81 percent (95 percent confidence interval, 77 to 86 percent). In a multivariate analysis, event-free and overall survival rates were affected by treatment group, independently of tumor stage and the presence or absence of bulky disease.
CONCLUSIONS: In patients under 61 years of age, chemotherapy with three cycles of ACVBP followed by sequential consolidation is superior to three cycles of CHOP plus radiotherapy for the treatment of low-risk localized lymphoma.

Copyright 2005 Massachusetts Medical Society.
PMID 15788496  N Engl J Med. 2005 Mar 24;352(12):1197-205. doi: 10.105・・・
著者: Christophe Bonnet, Georges Fillet, Nicolas Mounier, Gérard Ganem, Thierry Jo Molina, Catherine Thiéblemont, Christophe Fermé, Bruno Quesnel, Claude Martin, Christian Gisselbrecht, Hervé Tilly, Félix Reyes, Groupe d'Etude des Lymphomes de l'Adulte
雑誌名: J Clin Oncol. 2007 Mar 1;25(7):787-92. doi: 10.1200/JCO.2006.07.0722. Epub 2007 Jan 16.
Abstract/Text PURPOSE: Chemoradiotherapy has been considered standard treatment for patients with limited-stage aggressive lymphoma on the basis of trials conducted before the introduction of the International Prognostic Index. To evaluate this approach in elderly patients with low-risk localized lymphoma, we conducted a trial comparing chemoradiotherapy with chemotherapy alone.
PATIENTS AND METHODS: Previously untreated patients older than 60 years with localized stage I or II histologically aggressive lymphoma and no adverse prognostic factors of the International Prognostic Index were randomly assigned to receive either four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus involved-field radiotherapy (299 patients) or chemotherapy alone with four cycles of CHOP (277 patients).
RESULTS: With a median follow-up time of 7 years, event-free and overall survival did not differ between the two treatment groups (P = .6 and P = .5, respectively). The 5-year estimates of event-free survival were 61% for patients receiving chemotherapy alone and 64% for patients receiving CHOP plus radiotherapy; the 5-year estimates of overall survival were 72% and 68%, respectively. In a multivariate analysis, overall survival was affected by stage II disease (P < .001) and male sex (P = .03).
CONCLUSION: In this large prospective study, CHOP plus radiotherapy did not provide any advantage over CHOP alone for the treatment of low-risk localized aggressive lymphoma in elderly patients.

PMID 17228021  J Clin Oncol. 2007 Mar 1;25(7):787-92. doi: 10.1200/JCO・・・
著者: Daniel O Persky, Joseph M Unger, Catherine M Spier, Baldassarre Stea, Michael LeBlanc, Matthew J McCarty, Lisa M Rimsza, Richard I Fisher, Thomas P Miller, Southwest Oncology Group
雑誌名: J Clin Oncol. 2008 May 10;26(14):2258-63. doi: 10.1200/JCO.2007.13.6929. Epub 2008 Apr 14.
Abstract/Text PURPOSE: To evaluate the effect of rituximab in limited-stage diffuse large B-cell lymphoma (DLBCL), we conducted a multicenter phase II trial combining rituximab with three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone; R-CHOP) followed by involved-field radiation therapy (IFRT).
PATIENTS AND METHODS: Southwest Oncology Group (SWOG) study S0014 enrolled patients with newly diagnosed, aggressive, CD20-expressing non-Hodgkin's lymphoma (NHL). Patients had limited-stage disease and at least one adverse risk factor as defined by the stage-modified International Prognostic Index (nonbulky stage II disease, age > 60 years, WHO performance status of 2, or elevated serum lactate dehydrogenase). Four doses of rituximab were infused on days -7, 1, 22, and 43, and CHOP was administered on days 3, 24, and 45, followed 3 weeks later by 40 to 46 Gy of IFRT.
RESULTS: Sixty patients with aggressive NHL were eligible. With the median follow-up of 5.3 years, treatment resulted in a progression-free survival (PFS) of 93% at 2 years and 88% at 4 years. Overall survival (OS) was 95% at 2 years and 92% at 4 years. These results were compared with those from a historic group of patients treated without rituximab on S8736, demonstrating PFS of 78% and OS of 88% at 4 years.
CONCLUSION: In limited-stage DLBCL, the addition of rituximab to three cycles of CHOP plus IFRT met prespecified study criteria of efficacy, with 2-year PFS of at least 84%, meriting further investigation. There is a pattern of continuing relapse with modest survival gains. We hypothesize that such a pattern may be the result of biologic differences between limited- and advanced-stage lymphoma.

PMID 18413640  J Clin Oncol. 2008 May 10;26(14):2258-63. doi: 10.1200/・・・
著者: Stefan K Barta, Jeannette Y Lee, Lawrence D Kaplan, Ariela Noy, Joseph A Sparano
雑誌名: Cancer. 2012 Aug 15;118(16):3977-83. doi: 10.1002/cncr.26723. Epub 2011 Dec 16.
Abstract/Text BACKGROUND: Improved outcomes have recently been reported for rituximab (R) plus rituximab plus infusional etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH) chemotherapy in patients with human immunodeficiency virus (HIV)-associated, aggressive B-cell, non-Hodgkin lymphoma (NHL). The objective of the current analysis was to assess whether patient selection or other factors contributed to this improvement and to identify patients who are at the greatest risk for lethal toxicity.
METHODS: The authors performed a pooled analysis of 2 consecutive trials that included 150 patients with HIV-associated NHL who received either R-CHOP (n = 99; Acquired Immunodeficiency Syndrome [AIDS] Malignancy Consortium Trial 010 [AMC010]) or R-EPOCH (n = 51; AMC034). Age-adjusted International Prognostic Index (aaIPI), CD4 count at lymphoma diagnosis (<100/μL vs ≥100/μL), and treatment (R-CHOP vs R-EPOCH) were included as variables in a multivariate logistic regression model for complete response (CR) and in a Cox proportional hazards regression models for event-free survival (EFS) and overall survival (OS).
RESULTS: Features that were associated significantly with an improved CR rate and improved EFS and OS included a low aaIPI score and a baseline CD4 count ≥100/μL. When the analysis was adjusted for aaIPI and CD4 count, patients who received concurrent R-EPOCH had improved EFS (hazard ratio [HR] 0.40; 95% confidence intervals [CI], 0.23, 0.69; P < .001) and OS (HR, 0.38; 95% CI, 0.21, 0.69; P < .01). Treatment-associated death occurred significantly more often in patients with CD4 counts <50/μL (37% vs 6%; P < .01).
CONCLUSIONS: The current analysis provided additional level 2 evidence supporting the use of concurrent R-EPOCH in patients with HIV-associated lymphoma and a CD4 count >50/μL, and the results support the design of an ongoing phase 3 trial comparing concurrent R-EPOCH with R-CHOP in immunocompetent patients with diffuse large B-cell lymphoma (National Clinical Trial no. NCT00118209).

Copyright © 2011 American Cancer Society.
PMID 22180164  Cancer. 2012 Aug 15;118(16):3977-83. doi: 10.1002/cncr.・・・
著者: Stefan K Barta, Xiaonan Xue, Dan Wang, Roni Tamari, Jeannette Y Lee, Nicolas Mounier, Lawrence D Kaplan, Josep-Maria Ribera, Michele Spina, Umberto Tirelli, Rudolf Weiss, Lionel Galicier, Francois Boue, Wyndham H Wilson, Christoph Wyen, Albert Oriol, José-Tomás Navarro, Kieron Dunleavy, Richard F Little, Lee Ratner, Olga Garcia, Mireia Morgades, Scot C Remick, Ariela Noy, Joseph A Sparano
雑誌名: Blood. 2013 Nov 7;122(19):3251-62. doi: 10.1182/blood-2013-04-498964. Epub 2013 Sep 6.
Abstract/Text Limited comparative data exist for the treatment of HIV-associated non-Hodgkin lymphoma. We analyzed pooled individual patient data for 1546 patients from 19 prospective clinical trials to assess treatment-specific factors (type of chemotherapy, rituximab, and concurrent combination antiretroviral [cART] use) and their influence on the outcomes complete response (CR), progression free survival (PFS), and overall survival (OS). In our analysis, rituximab was associated with a higher CR rate (odds ratio [OR] 2.89; P < .001), improved PFS (hazard ratio [HR] 0.50; P < .001), and OS (HR 0.51; P < .0001). Compared with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), initial therapy with more dose-intense regimens resulted in better CR rates (ACVBP [doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisolone]: OR 1.70; P < .04), PFS (ACVBP: HR 0.72; P = .049; "intensive regimens": HR 0.35; P < .001) and OS ("intensive regimens": HR 0.54; P < .001). Infusional etoposide, prednisone, infusional vincristine, infusional doxorubicin, and cyclophosphamide (EPOCH) was associated with significantly better OS in diffuse large B-cell lymphoma (HR 0.33; P = .03). Concurrent use of cART was associated with improved CR rates (OR 1.89; P = .005) and trended toward improved OS (HR 0.78; P = .07). These findings provide supporting evidence for current patterns of care where definitive evidence is unavailable.

PMID 24014242  Blood. 2013 Nov 7;122(19):3251-62. doi: 10.1182/blood-2・・・
著者: François Boué, Jean Gabarre, Christian Gisselbrecht, Jacques Reynes, Antoine Cheret, Fabrice Bonnet, Eric Billaud, Martine Raphael, Remi Lancar, Dominique Costagliola
雑誌名: J Clin Oncol. 2006 Sep 1;24(25):4123-8. doi: 10.1200/JCO.2005.05.4684. Epub 2006 Aug 8.
Abstract/Text PURPOSE: To evaluate the safety and efficacy of rituximab adjunction to the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen in patients with newly diagnosed AIDS-related non-Hodgkin's lymphoma.
PATIENTS AND METHODS: HIV-seropositive patients with high-grade lymphoma of B-cell origin were eligible if they had no more than one of the following characteristics: CD4 cell count less than 100/microL, prior AIDS, or performance status less than 2. This multicenter phase II trial evaluated the response rate and disease-free survival after six courses of rituximab plus CHOP. Results Sixty-one patients were enrolled. All the patients were assessable for safety and 52 were assessable for the tumor response after treatment completion. Characteristics of patients were median age, 41 years; median CD4 cells, 172/microL; histology, diffuse large B-cell lymphoma (n = 42), immunoblastic (n = 2), Burkitt lymphoma (n = 16), and plasmablastic (n = 1); 42 patients with stage III to IV; International Prognostic Index 0 to 1 (n=31), and 2 to 3 (n = 27). Grade 3 or 4 toxicity consisted of febrile neutropenia in nine patients, anemia in 16 patients, and thrombocytopenia in five patients. Complete remission (CR) or unconfirmed CR was achieved in 40 of the 52 assessable patients, partial remission was achieved in five patients, and seven patients experienced progression. Forty-three patients were alive after a median follow-up of 33 months. The estimated 2-year overall survival rate was 75% (95% CI, 64% to 86%). Eighteen patients died: 16 as a result of lymphoma, one as a result of infection, and one as a result of encephalitis.
CONCLUSION: Rituximab adjunction to CHOP produced a CR rate of 77% and a 2-year survival rate of 75% in patients with AIDS-related non-Hodgkin's lymphoma, without increasing the risk of life-threatening infections.

PMID 16896005  J Clin Oncol. 2006 Sep 1;24(25):4123-8. doi: 10.1200/JC・・・
著者: Joseph A Sparano, Jeannette Y Lee, Lawrence D Kaplan, Alexandra M Levine, Juan Carlos Ramos, Richard F Ambinder, William Wachsman, David Aboulafia, Ariela Noy, David H Henry, Jamie Von Roenn, Bruce J Dezube, Scot C Remick, Manisha H Shah, Lawrence Leichman, Lee Ratner, Ethel Cesarman, Amy Chadburn, Ronald Mitsuyasu, AIDS Malignancy Consortium
雑誌名: Blood. 2010 Apr 15;115(15):3008-16. doi: 10.1182/blood-2009-08-231613. Epub 2009 Dec 18.
Abstract/Text Rituximab plus intravenous bolus chemotherapy is a standard treatment for immunocompetent patients with B-cell non-Hodgkin lymphoma (NHL). Some studies have suggested that rituximab is associated with excessive toxicity in HIV-associated NHL, and that infusional chemotherapy may be more effective. We performed a randomized phase 2 trial of rituximab (375 mg/m(2)) given either concurrently before each infusional etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone (EPOCH) chemotherapy cycle or sequentially (weekly for 6 weeks) after completion of all chemotherapy in HIV-associated NHL. EPOCH consisted of a 96-hour intravenous infusion of etoposide, doxorubicin, and vincristine plus oral prednisone followed by intravenous bolus cyclophosphamide given every 21 days for 4 to 6 cycles. In the concurrent arm, 35 of 48 evaluable patients (73%; 95% confidence interval, 58%-85%) had a complete response. In the sequential arm, 29 of 53 evaluable patients (55%; 95% confidence interval, 41%-68%) had a complete response. The primary efficacy endpoint was met for the concurrent arm only. Toxicity was comparable in the 2 arms, although patients with a baseline CD4 count less than 50/microL had a high infectious death rate in the concurrent arm. We conclude that concurrent rituximab plus infusional EPOCH is an effective regimen for HIV-associated lymphoma.

PMID 20023215  Blood. 2010 Apr 15;115(15):3008-16. doi: 10.1182/blood-・・・
著者: M P Mac Manus, R T Hoppe
雑誌名: J Clin Oncol. 1996 Apr;14(4):1282-90.
Abstract/Text PURPOSE: To evaluate retrospectively the results of radiotherapy for 177 patients with stage I (n = 73 [41%]) and II (n = 104 [59%]) follicular small cleaved-cell and follicular mixed small cleaved-cell and large-cell non-Hodgkin's lymphoma (NHL) treated in the Department of Radiation Oncology, Stanford University between 1961 and 1994.
PATIENTS AND METHODS: Histology was follicular small cleaved-cell in 101 (57%) cases and follicular mixed small cleaved-cell and large-cell in 76 (43%). Forty-five patients (25%) had staging laparotomy; 34 (19%) had extranodal involvement. All patients had received radiotherapy, either to one side of the diaphragm (involved or extended field) or to both sides (total lymphoid irradiation [TLI] or subtotal lymphoid irradiation [STLI]. Radiotherapy doses ranged from 35 to 50 Gy.
RESULTS: The median follow-up duration was 7.7 years. The longest follow-up duration was 31 years. Actuarial survival rates at 5, 10, 15, and 20 years were 82%, 64%, 44%, and 35%, respectively. The median survival time was 13.8 years. At 5, 10, 15, and 20 years, 55%, 44%, 40%, and 37% of patients, respectively, were relapse-free. Only five of 47 patients who reached 10 years without relapse subsequently developed recurrence. Survival and freedom from relapse (FFR) were significantly worse for older patients. Relapse rates were lower following treatment on both sides of the diaphragm or staging laparotomy. Univariate analysis showed that youth and staging laparotomy were associated with significantly better survival and that FFR was better following treatment on both sides of the diaphragm or laparotomy.
CONCLUSION: Radiotherapy remains the treatment of choice for early-stage low-grade follicular lymphomas. Patients who have remained free of disease for 10 years are unlikely to relapse.

PMID 8648385  J Clin Oncol. 1996 Apr;14(4):1282-90.
著者: B Vaughan Hudson, G Vaughan Hudson, K A MacLennan, L Anderson, D C Linch
雑誌名: Br J Cancer. 1994 Jun;69(6):1088-93.
Abstract/Text A retrospective analysis was performed of 451 adult patients with clinical stage 1/1E non-Hodgkin's lymphoma treated initially with radiotherapy alone. Histopathologically 208 patients had low-grade disease and 243 patients high-grade disease. The complete remission (CR) rate was higher in patients with low-grade disease (98%) than in those with high-grade disease (84%) (P < 0.0001). The relapse rate was similar in both histological categories, and relapse usually occurred within 5 years. The resulting overall actuarial percentage of patients achieving CR and remaining disease free (at 10 years) was 47% in patients with low-grade disease and 45% for those with high-grade disease. Salvage therapy was frequently successful in younger patients, and the overall cause-specific survival at 10 years was 71% for low-grade disease and 67% for high-grade disease. In those patients under 60 years of age at diagnosis, the overall cause-specific survival at 10 years was 84% and 80% for those with low-grade and high-grade disease respectively. These long-term results in young patients with clinical stage 1 disease are encouraging, and it will be difficult to demonstrate improved survival with initial chemotherapy either with or without radiotherapy, until new prognostic factors are found to identify poor-risk patients.

PMID 8198975  Br J Cancer. 1994 Jun;69(6):1088-93.
著者: M K Gospodarowicz, R S Bush, T C Brown, T Chua
雑誌名: Int J Radiat Oncol Biol Phys. 1984 Apr;10(4):489-97.
Abstract/Text A total of 1,394 patients with non-Hodgkin's lymphoma were treated at the Princess Margaret Hospital between January 1, 1967 and December 31, 1978. Overall actuarial survival of 525 patients with nodular lymphomas was 40% at 12 years; survival of patients with localized (Stage I & III) nodular lymphomas treated with radical radiation therapy was 58%. Significant prognostic factors defined by multivariate analysis included patient's age, stage, histology, tumor bulk, and presence of B symptoms. By combining prognostic factors we have identified distinct prognostic groups within the overall population. Patients with Stage I & II disease, small or medium bulk, less than 70 years of age achieved 92% 12 year actuarial survival and a 73% relapse-free rate in 12 years of follow-up. These patients represent groups highly curable with irradiation.

PMID 6725039  Int J Radiat Oncol Biol Phys. 1984 Apr;10(4):489-97.
著者: S Pendlebury, M el Awadi, S Ashley, M Brada, A Horwich
雑誌名: Radiother Oncol. 1995 Sep;36(3):167-71.
Abstract/Text This is a retrospective review of stages I and II low grade nodal non-Hodgkin's lymphoma (NHL) seen at the Royal Marsden Hospital and treated with radiotherapy alone. From January 1970 to December 1989, 58 patients were treated. The Ann Arbor staging system was modified to subdivide stage II into localised and extensive disease, with localised disease representing no more than two contiguous regions. There were 40 stage I patients and 18 stage II patients (eight localised and 10 extensive). Volume of the radiotherapy was involved field only in 30 patients and extended fields in 28 patients. The median dose was 40 Gy in 20 fractions. The pattern of relapse was assessed as being systemic or within the standard volume. Survival and progression-free survival (PFS) were calculated. Prognostic variables of age, histology, stage and radiotherapy volume were analysed by multivariate analysis. The 5- and 10-year PFS for the total group were 59 and 43%, and corresponding OS figures were 93 and 79%. Age less than 60 years was a predictor of improved survival but not for PFS and we found no significance in histology, stage or extent of radiotherapy field for the other variables. All relapses occurred with disease outside the original volume, with three patients also relapsing in-field. Treatment of this disease produced an OS at 10 years of 79%. The plateau on the PFS plot suggested that some patients are cured. Young age was the only prognostic factor found for survival. Relapse is most frequently outside the treated volume. Our current treatment policy for stage I and II low grade NHL is involved field radiotherapy to a dose of 35 Gy in 20 fraction over 4 weeks.

PMID 8532901  Radiother Oncol. 1995 Sep;36(3):167-71.
著者: Thomas J Pugh, Ari Ballonoff, Francis Newman, Rachel Rabinovitch
雑誌名: Cancer. 2010 Aug 15;116(16):3843-51. doi: 10.1002/cncr.25149.
Abstract/Text BACKGROUND: External beam radiation therapy (RT) is the standard treatment for stage I-II, grade 1-2 follicular lymphoma. Because of an indolent natural history, some advocate alternative management strategies, including watchful waiting for this disease. The relative improvement in outcomes for patients treated with and without RT has never been tested in randomized trials.
METHODS: The Surveillance, Epidemiology, and End Results database was queried for adult patients with stage I-II, grade 1-2 follicular lymphoma diagnosed from 1973 to 2004. Retrievable patient data included age, sex, race, stage, extranodal disease, and treatment with RT within the first year after diagnosis. Actuarial overall survival (OS) and disease-specific survival (DSS) were analyzed.
RESULTS: A total of 6568 patients were identified. DSS at 5, 10, 15, and 20 years in the RT group was 90%, 79%, 68%, and 63% versus 81%, 66%, 57%, and 51% in the no RT group (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.55-0.68; P<.0001). OS at 5, 10, 15, and 20 years in the RT group was 81%, 62%, 45%, and 35% versus 71%, 48%, 34%, and 23% in patients not receiving RT (HR, 0.68; 95% CI, 0.63-0.73; P<.0001). On multivariate analysis, upfront RT remained independently associated with improved DSS (P<.0001, Cox HR, 0.65; 95% CI, 0.57-0.72) and OS (P<.0001; Cox HR, 0.73; 95% CI, 0.67-0.79). Lymphoma was the most common cause of death (52%). Only 34% of patients received upfront RT.
CONCLUSIONS: Upfront RT was associated with improved DSS and OS compared with alternate management approaches, a benefit that persisted over time. This benefit suggests that watchful waiting with administration of salvage therapies on progression/relapse do not compensate for inadequate initial definitive treatment. Although it is the standard of care for this disease, RT for early stage low-grade follicular lymphoma is greatly underused in the US population; increased use of upfront RT could prevent thousands of deaths from lymphoma in these patients.

Copyright (c) 2010 American Cancer Society.
PMID 20564102  Cancer. 2010 Aug 15;116(16):3843-51. doi: 10.1002/cncr.・・・
著者: P Brice, Y Bastion, E Lepage, N Brousse, C Haïoun, P Moreau, N Straetmans, H Tilly, I Tabah, P Solal-Céligny
雑誌名: J Clin Oncol. 1997 Mar;15(3):1110-7.
Abstract/Text PURPOSE: To evaluate prospectively in patients with follicular lymphoma and a low tumor burden three therapeutic options: delay of any treatment until clinically meaningful progression, immediate treatment with an oral alkylating agent, or treatment with a biologic response modifier, interferon alfa-2b.
PATIENTS AND METHODS: Newly diagnosed follicular lymphoma patients with a low tumor burden (n = 193) were randomly assigned to one of three arms: arm 1, no initial treatment (n = 66); arm 2, prednimustine 200 mg/m2/d for 5 days per month for 18 months (n = 64); or arm 3, interferon alfa 5 MU/d for 3 months then 5 MU three times per week for 15 months (n = 63). Clinical characteristics were similar in the three arms.
RESULTS: Overall response rates with prednimustine and interferon alfa were 78% and 70%, respectively. The overall response to therapy, when deferred, was similar at 70%. With a median follow-up duration of 45 months after randomization, the median freedom-from-treatment (FFT) interval was 24 months in arm 1 and the interval of freedom from treatment failure (FFTF) was 40 months in arm 2 and 35 months in arm 3. The median overall survival time was not reached and the overall survival rate at 5 years was 78% in arm 1, 70% in arm 2, and 84% in arm 3. Therefore, deferred treatment does not adversely influence survival at 5 years. Patients who progressed within 1 year had a significantly shorter survival duration (median, 48 months).
CONCLUSION: Delayed treatment is feasible in patients with follicular lymphoma and a low tumor burden. For patients with early progression, more intensive therapy should be considered. For others, because delay of treatment until significant clinical progression does not seem to hamper the prognosis or subsequent response to treatment, the long-term toxicity of alkylating agents can be reduced.

PMID 9060552  J Clin Oncol. 1997 Mar;15(3):1110-7.
著者: K M Ardeshna, P Smith, A Norton, B W Hancock, P J Hoskin, K A MacLennan, R E Marcus, A Jelliffe, G Vaughan, Hudson, D C Linch, British National Lymphoma Investigation
雑誌名: Lancet. 2003 Aug 16;362(9383):516-22.
Abstract/Text BACKGROUND: Neither chemotherapy with a single-alkylating agent nor aggressive combination chemotherapy cures advanced stage low-grade non-Hodgkin lymphomas, even when combined with radiotherapy. Our aim was to compare administration of immediate chlorambucil treatment with a policy of delaying chlorambucil until clinical progression necessitated its use, in asymptomatic patients with advanced-stage, low-grade non-Hodgkin lymphoma.
METHODS: 309 patients with asymptomatic, advanced-stage, low-grade non-Hodgkin lymphomas were recruited from 44 UK centres between Feb 1, 1981, and July 31, 1990. 158 patients were randomised to receive immediate systemic therapy with oral chlorambucil 10 mg per day continuously. The remaining 151 were randomised to an initial policy of observation, with systemic therapy delayed until disease progression. In both groups, local radiotherapy to symptomatic nodes was allowed.
FINDINGS: Median length of follow-up was 16 years. Overall survival or cause-specific survival did not differ between the two groups (median overall survival for oral chlorambucil 5.9 [range 0-17.8] years and for observation 6.7 [0.5-18.9] years, p=0.84; median cause-specific survival 9 [0-17.8] years and 9.1 [0.67-18.9] years, respectively p=0.44). In a multivariate analysis, age younger than 60 years, erythrocyte sedimentation rate (ESR) 20 mm/h or less, and stage III disease, conferred significant advantages in both overall survival (p<0.0001, 0.03, and 0.03, respectively) and cause-specific survival (p=0.002, 0.008, and 0.001, respectively). In the observation group, at 10 years' follow-up, 19 patients were alive and had not received chemotherapy. The actuarial chance of not needing chemotherapy (non-lymphoma deaths censored) at 10 years was 19% (40% if older than 70 years).
INTERPRETATION: An initial policy of watchful waiting in patients with asymptomatic, advanced stage low-grade non-Hodgkin lymphoma is appropriate, especially in patients older than age 70 years.

PMID 12932382  Lancet. 2003 Aug 16;362(9383):516-22.
著者: C S Portlock, S A Rosenberg
雑誌名: Ann Intern Med. 1979 Jan;90(1):10-3.
Abstract/Text The question of whether initial treatment is necessary in relatively asymptomatic patients with stage III and IV non-Hodgkin's lymphomas of favorable histologic types was studied by retrospective analysis. Two groups of patients were studied: [1] 44 nonprotocol patients, followed since 1963, in whom initial treatment was withheld until required to evaluate the pace of disease and the necessity of treatment; and [2] 112 previously untreated patients who have participated in prospectively randomized clinical trials since 1971. For all 44 "deferred" patients, the median time before requiring treatment was 31 months, and there have been 19 patients who have not yet required therapy for periods of 3 to 104 months. The median actuarial survival for all 44 patients was 121 months. At 4 years, the actuarial survival of the 44 patients with deferred treatment is 77.3%, compared with 83.2% for the 112 protocol patients (P = 0.60). Careful observation without initiation of therapy is an appropriate option in the management of patients with relatively asymptomatic advanced non-Hodgkin's lymphomas of favorable histologic types.

PMID 369420  Ann Intern Med. 1979 Jan;90(1):10-3.
著者: S J Horning, S A Rosenberg
雑誌名: N Engl J Med. 1984 Dec 6;311(23):1471-5. doi: 10.1056/NEJM198412063112303.
Abstract/Text To learn more about the natural history of low-grade non-Hodgkin's lymphoma, we have studied 83 patients in whom the advanced disease was initially managed without therapy. Actuarial survival was 82 per cent at 5 years and 73 per cent at 10 years. The median time until therapy was required was three years. Spontaneous regressions occurred in 19 untreated patients (23 per cent), including 30 per cent of patients with nodular, poorly differentiated lymphocytic lymphoma. Histologic transformation to an intermediate-grade or high-grade lymphoma occurred both before and after primary therapy. The actuarial risk of transformation among the initially untreated patients was similar to that in a group of patients treated at this institution immediately after diagnosis. Neither the time to histologic transformation nor the incidence of transformation was influenced by when therapy was started.

PMID 6548796  N Engl J Med. 1984 Dec 6;311(23):1471-5. doi: 10.1056/N・・・
著者: Wolfgang Hiddemann, Michael Kneba, Martin Dreyling, Norbert Schmitz, Eva Lengfelder, Rudolf Schmits, Marcel Reiser, Bernd Metzner, Harriet Harder, Susanna Hegewisch-Becker, Thomas Fischer, Martin Kropff, Hans-Edgar Reis, Mathias Freund, Bernhard Wörmann, Roland Fuchs, Manfred Planker, Jörg Schimke, Hartmut Eimermacher, Lorenz Trümper, Ali Aldaoud, Reza Parwaresch, Michael Unterhalt
雑誌名: Blood. 2005 Dec 1;106(12):3725-32. doi: 10.1182/blood-2005-01-0016. Epub 2005 Aug 25.
Abstract/Text Phase 2 studies suggest that the monoclonal antibody rituximab may improve the prognosis of patients with follicular lymphoma (FL) when it is added to chemotherapy. In the current study, 428 patients with untreated, advanced-stage FL were randomly assigned for therapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) alone (n = 205) or CHOP combined with rituximab (R-CHOP) (n = 223). R-CHOP reduced the relative risk for treatment failure by 60% and significantly prolonged the time to treatment failure (P < .001). In addition, a significantly higher overall response rate (96% vs 90%; P = .011) and a prolonged duration of remission (P = .001) were achieved. In spite of a relatively short observation time, these beneficial effects even translated to superior overall survival (P = .016), with 6 deaths in the R-CHOP group compared with 17 deaths in the CHOP group within the first 3 years. The predominant treatment-related adverse effect was myelosuppression. Severe granulocytopenia was more frequently observed after R-CHOP (63% vs 53%; P = .01). However, severe infections were rare and of similar frequency after R-CHOP and CHOP (5% and 7%). Hence, adding rituximab to CHOP significantly improves the outcome for patients with previously untreated advanced-stage FL and does not induce major adverse effects.

PMID 16123223  Blood. 2005 Dec 1;106(12):3725-32. doi: 10.1182/blood-2・・・
著者: Robert Marcus, Kevin Imrie, Philippe Solal-Celigny, John V Catalano, Anna Dmoszynska, João C Raposo, Fritz C Offner, José Gomez-Codina, Andrew Belch, David Cunningham, Elisabeth Wassner-Fritsch, George Stein
雑誌名: J Clin Oncol. 2008 Oct 1;26(28):4579-86. doi: 10.1200/JCO.2007.13.5376. Epub 2008 Jul 28.
Abstract/Text PURPOSE: To compare the long-term outcome of patients with previously untreated follicular lymphoma (FL) needing therapy, after treatment with cyclophosphamide, vincristine and prednisone (CVP) versus CVP plus rituximab (R-CVP) and to evaluate the predictive value of known prognostic factors after treatment with R-CVP.
PATIENTS AND METHODS: Patients with previously untreated CD20-positive stage III/IV FL were randomly assigned to eight cycles of R-CVP (n = 159) or CVP alone (n = 162). The median follow-up period was 53 months.
RESULTS: The primary end point-time to treatment failure (TTF), which included patients without a response after four cycles as an event-was significantly prolonged in patients receiving R-CVP versus CVP (P < .0001). Improvements in all other end points, including overall and complete response rates (P < .0001), time to progression (TTP; P < .0001), response duration (P < .0001), time to next antilymphoma treatment (P < .0001), and overall survival (OS; P = .029; 4-year OS: 83% v 77%;) were achieved with R-CVP versus CVP alone. Univariate analyses demonstrated an improvement in TTP with R-CVP versus CVP irrespective of the Follicular Lymphoma International Prognostic Index (FLIPI) subgroup, the International Prognostic Index (IPI) subgroup, baseline histology, and the presence or absence of B symptoms or bulky disease. By multivariate analysis, FLIPI retains a strong predictive power for TTP in the presence of the trial treatment effect.
CONCLUSION: Analysis of all outcome measures, including OS, confirm the benefit of adding R to CVP in the front-line treatment of FL.

PMID 18662969  J Clin Oncol. 2008 Oct 1;26(28):4579-86. doi: 10.1200/J・・・
著者: Richard I Fisher, Michael LeBlanc, Oliver W Press, David G Maloney, Joseph M Unger, Thomas P Miller
雑誌名: J Clin Oncol. 2005 Nov 20;23(33):8447-52. doi: 10.1200/JCO.2005.03.1674. Epub 2005 Oct 17.
Abstract/Text BACKGROUND: The natural history of follicular lymphoma is believed not to have changed over the last 30 years. Median survivals have ranged from 7 to 10 years, and the disease is considered incurable. However, multiple new treatment options have been developed in the last decade, and their impact on survival of follicular lymphoma remains unknown.
PATIENTS AND METHODS: In the current analysis, we identified all previously untreated, advanced-stage, follicular lymphoma patients treated with the following three sequential treatment approaches: cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy +/- nonspecific immunostimulants (Southwest Oncology Group [SWOG] 7426 and 7713: 1974 to 1983); prednisone, methotrexate, doxorubicin, cyclophosphamide, and etoposide (ProMACE) plus mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) +/- interferon (SWOG 8809: 1988 to 1994); and CHOP followed by monoclonal antibody (MoAb) therapy (SWOG 9800 and 9911: 1998 to 2000). We assessed the patients' progression-free survival (PFS) and overall survival (OS). The MoAb trials included CHOP followed by rituximab (SWOG 9800) and CHOP followed by (131)I-tositumomab (SWOG 9911).
RESULTS: The PFS curves for the CHOP and ProMACE-MOPP studies are overlapping, with 4-year PFS estimates of 46% and 48%, respectively. However, the PFS rate of the CHOP + MoAb studies is significantly improved at 61% (P = .005). The OS curves show improvement with each succeeding study. The 4-year estimate of OS is 69% for the CHOP regimens, 79% for the ProMACE-MOPP study, and 91% for the CHOP + MoAb regimens (P < .001). These conclusions were retained after adjusting for differences in prognostic factors between the study groups.
CONCLUSION: The results of this study suggest that OS for patients with follicular lymphoma has improved over time and that the choice of initial therapy may matter.

PMID 16230674  J Clin Oncol. 2005 Nov 20;23(33):8447-52. doi: 10.1200/・・・
著者: Holger Schulz, Julia F Bohlius, Sven Trelle, Nicole Skoetz, Marcel Reiser, Thilo Kober, Guido Schwarzer, Michael Herold, Martin Dreyling, Michael Hallek, Andreas Engert
雑誌名: J Natl Cancer Inst. 2007 May 2;99(9):706-14. doi: 10.1093/jnci/djk152.
Abstract/Text BACKGROUND: Addition of the anti-CD20 monoclonal antibody rituximab to chemotherapy (R-chemo) has been shown to improve response rates and progression-free survival in patients with indolent or mantle cell lymphoma. However, the impact of R-chemo on overall survival is unclear. We performed a comprehensive systematic review and meta-analysis to examine the efficacy of combined immunochemotherapy using R-chemo compared with the identical chemotherapy alone with respect to overall survival in patients with advanced indolent lymphoma or mantle cell lymphoma.
METHODS: Medical databases and conference proceedings were searched for randomized controlled trials published from January 1990 through December 2005 that compared R-chemo with chemotherapy alone in patients with newly diagnosed or relapsed indolent lymphoma or mantle cell lymphoma. We included full-text and abstract publications. Endpoints were overall survival, disease control, overall response, and toxicity. A fixed-effects model was assumed in all meta-analyses. For binary data, the relative risk was used as an indicator of treatment effect, and the Mantel-Haenszel method was used to pool relative risks. Statistical tests for heterogeneity were one-sided; statistical tests for effect estimates were two-sided.
RESULTS: Seven randomized controlled trials involving 1943 patients with follicular lymphoma, mantle cell lymphoma, or other indolent lymphomas were included in the meta-analysis. Five studies were published as full-text articles, and two were in abstract form. Patients treated with R-chemo had better overall survival (hazard ratio [HR] for mortality = 0.65; 95% confidence interval [CI] = 0.54 to 0.78), overall response (relative risk of tumor response = 1.21; 95% CI = 1.16 to 1.27), and disease control (HR of disease event = 0.62; 95% CI = 0.55 to 0.71) than patients treated with chemotherapy alone. R-chemo improved overall survival in patients with follicular lymphoma (HR for mortality = 0.63; 95% CI = 0.51 to 0.79) and in patients with mantle cell lymphoma (HR for mortality = 0.60; 95% CI = 0.37 to 0.98). However, in the latter case, there was heterogeneity among the trials (P = .07), making the survival benefit less reliable.
CONCLUSION: In patients with indolent or mantle cell lymphoma, R-chemo is superior to chemotherapy alone with respect to overall survival.

PMID 17470738  J Natl Cancer Inst. 2007 May 2;99(9):706-14. doi: 10.10・・・
著者: Massimo Federico, Stefano Luminari, Alessandra Dondi, Alessandra Tucci, Umberto Vitolo, Luigi Rigacci, Francesco Di Raimondo, Angelo Michele Carella, Alessandro Pulsoni, Francesco Merli, Luca Arcaini, Francesco Angrilli, Caterina Stelitano, Gianluca Gaidano, Matteo Dell'olio, Luigi Marcheselli, Vito Franco, Sara Galimberti, Stefano Sacchi, Maura Brugiatelli
雑誌名: J Clin Oncol. 2013 Apr 20;31(12):1506-13. doi: 10.1200/JCO.2012.45.0866. Epub 2013 Mar 25.
Abstract/Text PURPOSE: Although rituximab (R) is commonly used for patients with advanced follicular lymphoma (FL) requiring treatment, the optimal associated chemotherapy regimen has yet to be clarified.
PATIENTS AND METHODS: We conducted an open-label, multicenter, randomized trial among adult patients with previously untreated stages II to IV FL to compare efficacy of eight doses of R associated with eight cycles of cyclophosphamide, vincristine, and prednisone (CVP) or six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or six cycles of fludarabine and mitoxantrone (FM). The principal end point of the study was time to treatment failure (TTF).
RESULTS: There were 534 patients enrolled onto the study. Overall response rates were 88%, 93%, and 91% for R-CVP, R-CHOP, and R-FM, respectively (P=.247). After a median follow-up of 34 months, 3-year TTFs were 46%, 62%, and 59% for the respective treatment groups (R-CHOP v R-CVP, P=.003; R-FM v R-CVP, P=.006; R-FM v R-CHOP, P=.763). Three-year progression-free survival (PFS) rates were 52%, 68%, and 63% (overall P=.011), respectively, and 3-year overall survival was 95% for the whole series. R-FM resulted in higher rates of grade 3 to 4 neutropenia (64%) compared with R-CVP (28%) and R-CHOP (50%; P< .001). Overall, 23 second malignancies were registered during follow-up: four in R-CVP, five in R-CHOP, and 14 in R-FM.
CONCLUSION: In this study, R-CHOP and R-FM were superior to R-CVP in terms of 3-year TTF and PFS. In addition, R-CHOP had a better risk-benefit ratio compared with R-FM.

PMID 23530110  J Clin Oncol. 2013 Apr 20;31(12):1506-13. doi: 10.1200/・・・
著者: Mathias J Rummel, Norbert Niederle, Georg Maschmeyer, G Andre Banat, Ulrich von Grünhagen, Christoph Losem, Dorothea Kofahl-Krause, Gerhard Heil, Manfred Welslau, Christina Balser, Ulrich Kaiser, Eckhart Weidmann, Heinz Dürk, Harald Ballo, Martina Stauch, Fritz Roller, Juergen Barth, Dieter Hoelzer, Axel Hinke, Wolfram Brugger, Study group indolent Lymphomas (StiL)
雑誌名: Lancet. 2013 Apr 6;381(9873):1203-10. doi: 10.1016/S0140-6736(12)61763-2. Epub 2013 Feb 20.
Abstract/Text BACKGROUND: Rituximab plus chemotherapy, most often CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is the first-line standard of care for patients with advanced indolent lymphoma, and for elderly patients with mantle-cell lymphoma. Bendamustine plus rituximab is effective for relapsed or refractory disease. We compared bendamustine plus rituximab with CHOP plus rituximab (R-CHOP) as first-line treatment for patients with indolent and mantle-cell lymphomas.
METHODS: We did a prospective, multicentre, randomised, open-label, non-inferiority trial at 81 centres in Germany between Sept 1, 2003, and Aug 31, 2008. Patients aged 18 years or older with a WHO performance status of 2 or less were eligible if they had newly diagnosed stage III or IV indolent or mantle-cell lymphoma. Patients were stratified by histological lymphoma subtype, then randomly assigned according to a prespecified randomisation list to receive either intravenous bendamustine (90 mg/m(2) on days 1 and 2 of a 4-week cycle) or CHOP (cycles every 3 weeks of cyclophosphamide 750 mg/m(2), doxorubicin 50 mg/m(2), and vincristine 1.4 mg/m(2) on day 1, and prednisone 100 mg/day for 5 days) for a maximum of six cycles. Patients in both groups received rituximab 375 mg/m(2) on day 1 of each cycle. Patients and treating physicians were not masked to treatment allocation. The primary endpoint was progression-free survival, with a non-inferiority margin of 10%. Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00991211, and the Federal Institute for Drugs and Medical Devices of Germany, BfArM 4021335.
FINDINGS: 274 patients were assigned to bendamustine plus rituximab (261 assessed) and 275 to R-CHOP (253 assessed). At median follow-up of 45 months (IQR 25-57), median progression-free survival was significantly longer in the bendamustine plus rituximab group than in the R-CHOP group (69.5 months [26.1 to not yet reached] vs 31.2 months [15.2-65.7]; hazard ratio 0.58, 95% CI 0.44-0.74; p<0.0001). Bendamustine plus rituximab was better tolerated than R-CHOP, with lower rates of alopecia (0 patients vs 245 (100%) of 245 patients who recieved ≥3 cycles; p<0.0001), haematological toxicity (77 [30%] vs 173 [68%]; p<0.0001), infections (96 [37%] vs 127 [50%]); p=0.0025), peripheral neuropathy (18 [7%] vs 73 [29%]; p<0.0001), and stomatitis (16 [6%] vs 47 [19%]; p<0.0001). Erythematous skin reactions were more common in patients in the bendamustine plus rituximab group than in those in the R-CHOP group (42 [16%] vs 23 [9%]; p=0.024).
INTERPRETATION: In patients with previously untreated indolent lymphoma, bendamustine plus rituximab can be considered as a preferred first-line treatment approach to R-CHOP because of increased progression-free survival and fewer toxic effects.
FUNDING: Roche Pharma AG, Ribosepharm/Mundipharma GmbH.

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 23433739  Lancet. 2013 Apr 6;381(9873):1203-10. doi: 10.1016/S014・・・
著者: Ian W Flinn, Richard van der Jagt, Brad S Kahl, Peter Wood, Tim E Hawkins, David Macdonald, Mark Hertzberg, Yiu-Lam Kwan, David Simpson, Michael Craig, Kathryn Kolibaba, Samar Issa, Regina Clementi, Doreen M Hallman, Mihaela Munteanu, Ling Chen, John M Burke
雑誌名: Blood. 2014 May 8;123(19):2944-52. doi: 10.1182/blood-2013-11-531327. Epub 2014 Mar 3.
Abstract/Text This randomized, noninferiority (NI), global, phase 3 study evaluated the efficacy and safety of bendamustine plus rituximab (BR) vs a standard rituximab-chemotherapy regimen (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or rituximab plus cyclophosphamide, vincristine, and prednisone [R-CVP]) for treatment-naive patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Investigators preassigned the standard treatment regimen they considered most appropriate for each patient; patients were randomized to receive BR (n = 224) or standard therapy (R-CHOP/R-CVP, n = 223) for 6 cycles; 2 additional cycles were permitted at investigator discretion. Response was assessed by a blinded independent review committee. BR was noninferior to R-CHOP/R-CVP, as assessed by the primary end point of complete response rate (31% vs 25%, respectively; P = .0225 for NI [0.88 margin]). The overall response rates for BR and R-CHOP/R-CVP were 97% and 91%, respectively (P = .0102). Incidences of vomiting and drug-hypersensitivity reactions were significantly higher in patients treated with BR (P < .05), and incidences of peripheral neuropathy/paresthesia and alopecia were significantly higher in patients treated with standard-therapy regimens (P < .05). These data indicate BR is noninferior to standard therapy with regard to clinical response with an acceptable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT00877006.

PMID 24591201  Blood. 2014 May 8;123(19):2944-52. doi: 10.1182/blood-2・・・
著者: Ian W Flinn, Richard van der Jagt, Brad Kahl, Peter Wood, Tim Hawkins, David MacDonald, David Simpson, Kathryn Kolibaba, Samar Issa, Julie Chang, Judith Trotman, Doreen Hallman, Ling Chen, John M Burke
雑誌名: J Clin Oncol. 2019 Apr 20;37(12):984-991. doi: 10.1200/JCO.18.00605. Epub 2019 Feb 27.
Abstract/Text PURPOSE: The BRIGHT study ( ClinicalTrials.gov identifier: NCT00877006) was initiated to compare the efficacy and safety of bendamustine plus rituximab (BR) with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP) for treatment-naive patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma. This publication provides long-term follow-up data.
PATIENTS AND METHODS: Patients were monitored for a minimum of 5 years after completion of study treatment for the time-to-event end points of progression-free survival (PFS), event-free survival, duration of response, and overall survival per investigator assessment. Data on the number of patients who received second-line anticancer treatment and the occurrence of other malignancies were also collected.
RESULTS: The medians were not reached for any of the time-to event end points for either the BR or R-CHOP/R-CVP study treatment groups by study completion. PFS rates at 5 years were 65.5% in the BR treatment group and 55.8% in the R-CHOP/R-CVP group. The difference in PFS was considered significant with a hazard ratio of 0.61 (95% CI, 0.45 to 0.85; P = .0025). The hazard ratio for event-free survival and duration of response (P = .0020 and .0134, respectively) also favored the BR regimen over R-CHOP/R-CVP. However, no significant difference in overall survival was observed. The overall safety profiles of BR, R-CHOP, and R-CVP were as expected; no new safety data were collected during long-term follow-up. A higher number of secondary malignancies was noted in the BR treatment group.
CONCLUSION: Overall, BR demonstrated better long-term disease control than R-CHOP/R-CVP and should be considered as a first-line treatment option for patients with indolent and mantle-cell lymphoma.

PMID 30811293  J Clin Oncol. 2019 Apr 20;37(12):984-991. doi: 10.1200/・・・
著者: Catherine Sebban, Nicolas Mounier, Nicole Brousse, Coralie Belanger, Pauline Brice, Corinne Haioun, Herve Tilly, Pierre Feugier, Redah Bouabdallah, Chantal Doyen, Gilles Salles, Bertrand Coiffier
雑誌名: Blood. 2006 Oct 15;108(8):2540-4. doi: 10.1182/blood-2006-03-013193. Epub 2006 Jul 11.
Abstract/Text The purpose of this study is to compare our standard chemotherapy regimen (CHVP [cyclophosphamide, doxorubicin, teniposide, and prednisone]) plus interferon with 4 courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by high-dose therapy with autologous stem cell transplantation (ASCT) in treatment-naive patients with advanced follicular lymphoma. Four hundred one patients were included from July 1994 to March 2001: 209 received 12 cycles of CHVP plus interferon alpha for 18 months (CHVP-I arm) and 192 received 4 cycles of CHOP followed by high-dose therapy (HDT) with total body irradiation and ASCT (CHOP-HDT arm). Overall response rates were similar in both groups (79% and 78% after induction chemotherapy, respectively). One hundred thirty-one of the 150 patients eligible for HDT underwent transplantation (87%). Intent-to-treat analysis after a median follow-up of 7.5 years showed that there was no difference between the 2 arms for overall survival (P = .53) or event-free survival (P = .11). Patients with a complete response at the end of the induction therapy had a statistically longer event-free survival and overall survival (P = .02 and < .001, respectively). After long-term follow-up, our study showed that there was no statistically significant benefit in favor of first-line high-dose therapy in patients with follicular lymphoma. High-dose therapy should be reserved for relapsing patients.

PMID 16835383  Blood. 2006 Oct 15;108(8):2540-4. doi: 10.1182/blood-20・・・
著者: Eric Deconinck, Charles Foussard, Noel Milpied, Philippe Bertrand, Patrick Michenet, Pascale Cornillet-LeFebvre, Martine Escoffre-Barbe, Herve Maisonneuve, Vincent Delwail, Remy Gressin, Eric Legouffe, Jean-Pierre Vilque, Bernard Desablens, Jerome Jaubert, Jean-François Ramee, Arash Jenabian, Antoine Thyss, Annick Le Pourhiet-Le Mevel, Philippe Travade, Roselyne Delepine, Philippe Colombat, GOELAMS
雑誌名: Blood. 2005 May 15;105(10):3817-23. doi: 10.1182/blood-2004-10-3920. Epub 2005 Feb 1.
Abstract/Text Doxorubicin-based immunochemotherapy, with interferon, has been shown to improve survival in patients with advanced follicular lymphoma. High-dose chemotherapy with stem-cell support is effective in follicular lymphoma in relapse but remains controversial as a first-line therapy. In a randomized study using a purged autologous stem-cell support, we compared these 2 approaches in patients with advanced follicular lymphoma. Newly diagnosed advanced follicular lymphoma patients (172 patients) were randomly assigned either to an immunochemotherapy regimen (cyclophosphamide, doxorubicin, teniposide, prednisone, and interferon) or to a high-dose therapy followed by purged autologous stem-cell transplantation. Compared with the patients who received chemotherapy and interferon, patients treated with high-dose therapy had a higher response rate (69% vs 81%, P = .045) and a longer median event-free survival (not reached vs 45 months). This did not translate into a better survival rate due to an excess of secondary malignancies after transplantation. The Follicular Lymphoma Prognostic Index identified a subgroup of patients with a significantly higher event-free survival rate after high-dose therapy. Autologous stem-cell transplantation cannot be considered as the standard first-line treatment of follicular lymphoma for patients younger than 60 years old with a high tumor burden.

PMID 15687232  Blood. 2005 May 15;105(10):3817-23. doi: 10.1182/blood-・・・
著者: Georg Lenz, Martin Dreyling, Eva Schiegnitz, Roswitha Forstpointner, Hannes Wandt, Mathias Freund, Georg Hess, Lorenz Truemper, Volker Diehl, Martin Kropff, Michael Kneba, Norbert Schmitz, Bernd Metzner, Markus Pfirrmann, Michael Unterhalt, Wolfgang Hiddemann, German Low-Grade Lymphoma Study Group
雑誌名: Blood. 2004 Nov 1;104(9):2667-74. doi: 10.1182/blood-2004-03-0982. Epub 2004 Jul 6.
Abstract/Text Conventional chemotherapy has failed to substantially prolong survival for patients with advanced follicular lymphoma. To improve outcomes, the German Low-Grade Lymphoma Study Group (GLSG) initiated a randomized trial to compare the effect of potentially curative myeloablative radiochemotherapy followed by autologous stem cell transplantation (ASCT) with interferon-alpha (IFN-alpha) maintenance therapy in first remission. Three hundred seven patients (younger than 60 years) with follicular lymphoma were recruited into the trial from 130 institutions. After 2 cycles of cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) or mitoxantrone-chlorambucil-prednisone (MCP) induction chemotherapy, patients were randomly assigned to either the ASCT or the IFN-alpha group. The respective therapy was started when patients achieved complete or partial remission after induction chemotherapy. Two hundred forty patients with follicular lymphoma are evaluable for the comparison of ASCT and IFN-alpha. In patients who underwent ASCT, the 5-year progression-free survival (PFS) rate was 64.7%, and in the IFN-alpha arm it was 33.3% (P < .0001). As expected, acute toxicity was higher in the ASCT group, but early mortality was below 2.5% in both study arms. In this randomized, multicenter trial, high-dose radiochemotherapy followed by ASCT significantly improved PFS compared with IFN-alpha in patients with follicular lymphoma when applied as consolidation in first remission. Longer follow-up is necessary to determine the effect of ASCT on overall survival.

PMID 15238420  Blood. 2004 Nov 1;104(9):2667-74. doi: 10.1182/blood-20・・・
著者: Marco Ladetto, Federica De Marco, Fabio Benedetti, Umberto Vitolo, Caterina Patti, Alessandro Rambaldi, Alessandro Pulsoni, Maurizio Musso, Anna M Liberati, Attilio Olivieri, Andrea Gallamini, Enrico Pogliani, Delia Rota Scalabrini, Vincenzo Callea, Francesco Di Raimondo, Vincenzo Pavone, Alessandra Tucci, Sergio Cortelazzo, Alessandro Levis, Mario Boccadoro, Ignazio Majolino, Alessandro Pileri, Alessandro M Gianni, Roberto Passera, Paolo Corradini, Corrado Tarella, Gruppo Italiano Trapianto di Midollo Osseo (GITMO), Intergruppo Italiano Linfomi (IIL)
雑誌名: Blood. 2008 Apr 15;111(8):4004-13. doi: 10.1182/blood-2007-10-116749. Epub 2008 Jan 31.
Abstract/Text In this randomized multicenter study of 136 patients, 6 courses of CHOP (cyclo-phosphamide/doxorubicin/vincristine/prednisone) followed by rituximab (CHOP-R) were compared with rituximab-supplemented high-dose sequential chemotherapy with autografting (R-HDS) to assess the value of intensified chemo-therapy as a first-line treatment for high-risk follicular lymphoma (FL) after the introduction of monoclonal antibodies. The analysis was intention to treat with event-free survival (EFS) as the primary endpoint. Complete remission (CR) was 62% with CHOP-R and 85% with R-HDS (P < .001). At a median follow-up (MFU) of 51 months, the 4-year EFS was 28% and 61%, respectively (P < .001), with no difference in overall survival (OS). Molecular remission (MR) was achieved in 44% of CHOP-R and 80% of R-HDS patients (P < .001), and was the strongest independent outcome predictor. Patients relapsing after CHOP-R underwent salvage R-HDS in 71% of cases. Salvage R-HDS had an 85% CR rate and a 68% 3-year EFS (MFU, 30 months). We conclude that (1) achieving MR is critical for effective disease control, regardless of which treatment is used; (2) R-HDS ensures superior disease control and molecular outcome than CHOP-R, but no OS improvement; and (3) CHOP-R failures have a good outcome after salvage R-HDS, suggesting that relapsed/refractory FL could be the most appropriate setting for R-HDS-like treatments. This trial was registered at www.clinicaltrials.gov as no. NCT00435955.

PMID 18239086  Blood. 2008 Apr 15;111(8):4004-13. doi: 10.1182/blood-2・・・
著者: Emmanuel Gyan, Charles Foussard, Philippe Bertrand, Patrick Michenet, Steven Le Gouill, Christian Berthou, Hervé Maisonneuve, Vincent Delwail, Rémi Gressin, Philippe Quittet, Jean-Pierre Vilque, Bernard Desablens, Jérôme Jaubert, Jean-François Ramée, Nina Arakelyan, Antoine Thyss, Cécile Moluçon-Chabrot, Roselyne Delépine, Noël Milpied, Philippe Colombat, Eric Deconinck, Groupe Ouest-Est des Leucémies et des Autres Maladies du Sang (GOELAMS)
雑誌名: Blood. 2009 Jan 29;113(5):995-1001. doi: 10.1182/blood-2008-05-160200. Epub 2008 Oct 27.
Abstract/Text Autologous stem cell transplantation (ASCT) as first-line therapy for follicular lymphoma (FL) remains controversial. The multicenter study randomized 172 patients with untreated FL for either immunochemotherapy or high-dose therapy (HDT) followed by purged ASCT. Conditioning was performed with total body irradiation (TBI) and cyclophosphamide. The 9-year overall survival (OS) was similar in the HDT and conventional chemotherapy groups (76% and 80%, respectively). The 9-year progression-free survival (PFS) was higher in the ASCT than the chemotherapy group (64% vs 39%; P = .004). A PFS plateau was observed in the HDT group after 7 years. On multivariate analysis, OS and PFS were independently affected by the per-formance status score, the number of nodal areas involved, and the treatment group. Secondary malignancies were more frequent in the HDT than in the chemotherapy group (6 secondary myelodysplastic syndrome/acute myeloid leukemia and 6 second solid tumor cancers vs 1 acute myeloid leukemia, P = .01). The occurrence of a PFS plateau suggests that a subgroup of patients might have their FL cured by ASCT. However, the increased rate of secondary malignancies may discourage the use of purged ASCT in combination with TBI as first-line treatment for FL. This trial has been registered with ClinicalTrials.gov under identifier NCT00696735.

PMID 18955565  Blood. 2009 Jan 29;113(5):995-1001. doi: 10.1182/blood-・・・
著者: Francesco Bertoni, Annarita Conconi, Carlo Capella, Teresio Motta, Roberto Giardini, Maurilio Ponzoni, Ennio Pedrinis, Domenico Novero, Paolo Rinaldi, Giovanni Cazzaniga, Andrea Biondi, Andrew Wotherspoon, Barry William Hancock, Paul Smith, Robert Souhami, Finbarr E Cotter, Franco Cavalli, Emanuele Zucca, International Extranodal Lymphoma Study Group, United Kingdom Lymphoma Group
雑誌名: Blood. 2002 Apr 1;99(7):2541-4.
Abstract/Text Gastric marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT)-type can regress after anti-Helicobacter pylori treatment. The International Extranodal Lymphoma Study Group, the United Kingdom Lymphoma Group, and the Groupe d'Etude des Lymphomes de l'Adulte have conducted a trial to ascertain whether the addition of chlorambucil is of benefit after anti-H pylori therapy. At the last interim analysis, 105 (55%) of 189 patients had achieved a complete histologic remission after anti-Helicobacter therapy. To further assess the ability of treatment to eradicate the lymphoma clone, we analyzed the gastric biopsies from a subset of the patients by polymerase chain reaction (PCR) targeted to the immunoglobulin heavy chain genes as a molecular marker for minimal residual disease. Sixty-two cases were examined at diagnosis. Fifty-four cases were monoclonal by PCR. Forty-two of these patients achieved histologic complete remission (hCR) after anti-Helicobacter treatment: 34 cases underwent molecular follow-up analysis. Fifteen patients (44%) were in molecular remission with a median follow-up of 2 years after antibiotic treatment and of 1 year after the achievement of hCR. Less than half of the patients with MALT lymphoma can achieve sustained molecular remission after anti-Helicobacter therapy. The presence of molecular disease in the absence of histologic disease does not appear to be associated with histologic relapse, but, given the indolent nature of MALT lymphomas, a longer follow-up is needed.

PMID 11895791  Blood. 2002 Apr 1;99(7):2541-4.
著者: Shotaro Nakamura, Toshiro Sugiyama, Takayuki Matsumoto, Katsunori Iijima, Shouko Ono, Masahiro Tajika, Akira Tari, Yasuhiko Kitadai, Hiroshi Matsumoto, Tadanobu Nagaya, Toshiro Kamoshida, Norihiko Watanabe, Toshimi Chiba, Hideki Origasa, Masahiro Asaka, JAPAN GAST Study Group
雑誌名: Gut. 2012 Apr;61(4):507-13. doi: 10.1136/gutjnl-2011-300495. Epub 2011 Sep 2.
Abstract/Text OBJECTIVE: A multicentre cohort follow-up study of a large number of patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma was conducted to elucidate the long-term outcome of the disease after Helicobacter pylori eradication.
METHODS: 420 patients with gastric low-grade MALT lymphoma who had undergone successful H pylori eradication and been followed up for at least 3 years were registered from 21 participating institutes. Responders to treatment were defined as patients whose post-treatment biopsies showed complete histological response (ChR) or probable minimal residual disease (pMRD). Treatment failure was defined as the status of progressive disease or lymphoma relapse after ChR/pMRD.
RESULTS: 323 patients (77%) responded to H pylori eradication. A logistic regression analysis showed that absence of H pylori, submucosal invasion determined by endoscopic ultrasonography and t(11;18)/API2-MALT1 were independent predictors of resistance to H pylori eradication. During the follow-up periods ranging from 3.0 to 14.6 years (mean 6.5 years, median 6.04 years), the disease relapsed in 10 of 323 responders (3.1%) while progressive disease was found in 27 of 97 non-responders (27%). Thus, 37 of 420 patients (8.8%) were regarded as treatment failures. Of these 37 patients, transformation into diffuse large B cell lymphoma occurred in nine patients. Among the non-responders and relapsed patients, 17 patients were subjected to a 'watch and wait' strategy while 90 patients underwent second-line treatments including radiotherapy (n=49), chemotherapy (n=26), surgical resection (n=6), chemoradiotherapy (n=5), antibiotic treatment (n=2), rituximab monotherapy (n=1) or endoscopic resection (n=1). Probabilities of freedom from treatment failure, overall survival and event-free survival after 10 years were 90%, 95% and 86%, respectively. Cox multivariate analysis revealed endoscopic non-superficial type to be an independent prognostic factor for adverse freedom from treatment failure, overall survival and event-free survival.
CONCLUSIONS: The excellent long-term outcome of gastric MALT lymphoma after H pylori eradication was confirmed by this large-scale follow-up study.

PMID 21890816  Gut. 2012 Apr;61(4):507-13. doi: 10.1136/gutjnl-2011-30・・・
著者: N R Schechter, C S Portlock, J Yahalom
雑誌名: J Clin Oncol. 1998 May;16(5):1916-21.
Abstract/Text PURPOSE: Mucosa-associated lymphoid tissue (MALT) lymphoma of the stomach (MLS) has recently been defined as a distinct clinicopathologic entity, often associated with Helicobacter pylori infection. Many regard antibiotic therapy as the primary treatment of MLS, but in the absence of H pylori infection, or when salvage of antibiotic failures is required, gastrectomy and/or chemotherapy have frequently been used. This study evaluates the efficacy of low-dose radiotherapy alone as an alternative to surgery.
PATIENTS AND METHODS: Seventeen patients with stage I to II(2) low-grade MLS without evidence of H pylori infection or with persistent lymphoma after antibiotic therapy of associated H pylori infection were included in this series. Median age was 69 years (range, 39 to 84). Median total radiation dose was 30 Gy (range, 28.5 to 43.5 Gy) delivered in 1.5-Gy fractions within 4 weeks to the stomach and adjacent lymph nodes. Following treatment, all patients underwent endoscopic evaluation and biopsy at a median of 4 months, at 6-month intervals to 2 years, and annually thereafter.
RESULTS: All obtained a biopsy-confirmed complete response. At a median follow-up time of 27 months (range, 11 to 68) from completion of radiotherapy, event-free survival was 100%. Treatment was well tolerated, with no significant acute side effects. All remained asymptomatic at last follow-up.
CONCLUSION: These results suggest that effective treatment of MLS with low-dose radiation therapy alone is feasible and safe, and allows stomach preservation. Longer follow-up evaluation is required to determine the long-term efficacy of this treatment approach and its side effects. Further studies should clarify the indications for radiotherapy in H pylori-negative or antibiotic-resistant cases of MLS.

PMID 9586910  J Clin Oncol. 1998 May;16(5):1916-21.
著者: Conny Vrieling, Daphne de Jong, Henk Boot, Jan Paul de Boer, Froukje Wegman, Berthe M P Aleman
雑誌名: Radiother Oncol. 2008 Jun;87(3):405-11. doi: 10.1016/j.radonc.2008.02.012. Epub 2008 Mar 17.
Abstract/Text PURPOSE: To evaluate long-term results of stomach-conserving therapy and to assess the value of histological probable minimal residual disease (pMRD) in predicting outcome in patients with gastric MALT lymphoma.
MATERIALS AND METHODS: We studied 115 patients with stage I-II(2) gastric MALT lymphoma treated between 1975 and 2002. Initially, first-line treatment consisted of radiotherapy only. Since 1994 most patients were primarily treated with Helicobacter pylori eradication; radiotherapy was used in case of eradication failure. To assess the value of pMRD, first follow-up biopsy samples classified as compete remission (CR) according to classical clinico-pathological criteria and biopsy samples 1 year after assessment of histological CR were reviewed; results were related to outcome.
RESULTS: Following radiotherapy only (n=56) 96% achieved a clinical CR; 10-year cancer-specific survival rate was 94%. Following H. pylori eradication only (n=35) CR-rate was 43% and after additional treatment 89%; 5-year cause-specific survival was 93%. There was no difference in relapse rate following initial histological CR or pMRD.
CONCLUSIONS: Patients with early stage gastric MALT lymphoma have a favorable long-term outcome following conservative treatment. Outcome after H. pylori eradication followed by delayed radiotherapy on indication was excellent. In our series pMRD was not associated with increased risk of recurrence.

PMID 18343513  Radiother Oncol. 2008 Jun;87(3):405-11. doi: 10.1016/j.・・・
著者: Angelo Zullo, Cesare Hassan, Alessandro Andriani, Francesca Cristofari, Chiara Bassanelli, Gian Paolo Spinelli, Silverio Tomao, Sergio Morini
雑誌名: Med Oncol. 2010 Jun;27(2):291-5. doi: 10.1007/s12032-009-9207-y. Epub 2009 Mar 24.
Abstract/Text The most favourable therapeutic strategy for gastric MALT-lymphoma not responding to Helicobacter pylori eradication still remains unclear, neither official guidelines nor randomised studies being available. We therefore performed a systematic review of the literature to evaluate the efficacy of different therapeutic approaches in these patients. Data regarding 315 patients were valuable, and lymphoma remission following the first therapeutic attempt was achieved in 90.1% cases. The most used therapy was radiotherapy (112 patients), followed by surgery (80 patients) and chemotherapy (68 patients), whilst a combination therapy was less frequent. Radiotherapy achieved a higher remission rate as compared to chemotherapy (97.3 vs. 85.3%; P = 0.007), being similar to surgery (97.3 vs. 92.5%; P = 0.2). No difference emerged when comparing lymphoma remission rate achieved by a single therapy with that of combined treatments (89.6 vs. 96.4%; P = 0.6). This is the first pooled-data analysis assessing the efficacy of different oncologic therapeutic approaches to treat gastric MALT-lymphoma unresponsive to H. pylori eradication. Radiotherapy seems to be the most suitable treatment in these patients.

PMID 19308737  Med Oncol. 2010 Jun;27(2):291-5. doi: 10.1007/s12032-00・・・
著者: M Raderer, B Streubel, S Wöhrer, M Häfner, A Chott
雑誌名: Gut. 2006 May;55(5):616-8. doi: 10.1136/gut.2005.083022. Epub 2005 Nov 18.
Abstract/Text BACKGROUND AND AIMS: The role of antibiotic treatment in early stage gastric mucosa associated lymphoid tissue (MALT) lymphoma not associated with Helicobacter pylori infection has not been investigated.
PATIENTS AND METHODS: Six patients with localised gastric MALT lymphoma underwent antibiotic treatment with clarithromycin, metronidazole, and pantoprazole. Staging, including endosonography plus gastroscopy, computed tomography of the thorax and abdomen, colonoscopy, magnetic resonance imaging of the salivary glands, and bone marrow biopsy were performed to rule out distant spread of the disease. In addition, MALT specific genetic changes, including reverse transcriptase-polymerase chain reaction for t(11;18)(q21;q21), were tested in all patients. H pylori infection was ruled out by histology, urease breath test, serology, and stool antigen testing.
RESULTS: All six patients had MALT lymphoma restricted to the stomach, and no evidence of infection with H pylori was found. Only one patient tested positive for t(11;18)(q21;q21) while the remaining five displayed no genetic aberrations. Following antibiotic treatment, endoscopic controls were performed every three months. Five patients responded with lymphoma regression between three and nine months following antibiotic treatment (one partial remission and four complete responses). One patient had stable disease for 12 months and was then referred for chemotherapy.
CONCLUSIONS: Patients with early stage gastric MALT lymphoma negative for H pylori might still benefit from antibiotic treatment as the sole treatment modality.

PMID 16299027  Gut. 2006 May;55(5):616-8. doi: 10.1136/gut.2005.083022・・・
著者: Jayant S Goda, Mary Gospodarowicz, Melania Pintilie, Woodrow Wells, David C Hodgson, Alexander Sun, Micheal Crump, Richard W Tsang
雑誌名: Cancer. 2010 Aug 15;116(16):3815-24. doi: 10.1002/cncr.25226.
Abstract/Text BACKGROUND: This study was conducted to evaluate the long-term outcomes in patients with stage IE and IIE mucosa-associated lymphoid tissue (MALT) lymphomas treated with involved field radiotherapy (RT).
METHODS: Between 1989 and 2004, 192 patients with stage I and II MALT lymphomas were treated. The report focuses on 167 patients who received RT. The median age of patients was 58 years with a female predominance (2:1). Presenting sites were as follows: orbital adnexa in 71 patients, salivary glands in 28 patients, stomach in 25 patients, thyroid in 21 patients, and other sites in 22 patients. The median dose to nonorbital sites was 30 grays (Gy) (range, 17.5-35 Gy) and was 25 Gy for the orbit (range, 25-35 Gy). The median follow-up was 7.4 years (range, 0.67-16.20 years).
RESULTS: Complete response and complete response, unconfirmed (CR/CRu) was noted in 166 (99%) patients. The 10-year recurrence-free rate (RFR) was 76%, the disease-free survival (DFS) rate was 68%, the overall survival (OS) rate was 87%, and the cause-specific survival rate was 98%. According to presenting site, the 10-year RFR was 95% for thyroid, 92% for stomach, 68% for salivary glands, and 67% for orbit. Patients with thyroid and gastric MALTs had better outcome compared with patients with MALTs diagnosed at other sites (P=.004). Among those patients who achieved CR, 19% developed disease recurrence (n=31), chiefly in distant sites or untreated contralateral-paired organs. At the time of disease recurrence, 7 patients (23%) had transformed to diffuse large B-cell lymphoma, 2 of whom died of lymphoma. The 5-year OS rate after treatment failure was 83%.
CONCLUSIONS: Patients with localized MALT lymphomas are reported to have excellent clinical outcome after moderate-dose RT, and some are likely cured. In the current study, thyroid and gastric MALTs were found to have significantly less risk of distant recurrence. Despite disease recurrence, the overall survival remains excellent in these patients.

Copyright (c) 2010 American Cancer Society.
PMID 20564130  Cancer. 2010 Aug 15;116(16):3815-24. doi: 10.1002/cncr.・・・
著者: C Thieblemont, F Berger, C Dumontet, I Moullet, F Bouafia, P Felman, G Salles, B Coiffier
雑誌名: Blood. 2000 Feb 1;95(3):802-6.
Abstract/Text Mucosa-associated lymphoid tissue-derived lymphoma (MALT lymphoma) is usually a very indolent lymphoma, described as localized at diagnosis and remaining localized for a prolonged period; dissemination occurs only after a long course of evolution. In our database, out of 158 patients with MALT lymphoma, 54 patients presented with a disseminated disease at diagnosis. Of these 54 patients, 17 patients (30%) presented with multiple involved mucosal sites; 37 patients (70%) presented with 1 involved mucosal site, but in 23 of these patients (44%), dissemination of the disease was due to bone marrow involvement; 12 patients (22%) had multiple lymph node involvement; and 2 patients (4%) had nonmucosal site involvement. No significant difference in clinical characteristics (sex, age, performance status, B symptoms) and biological parameters (hemoglobin [Hb] and lactate dehydrogenase levels) was observed between localized or disseminated MALT-lymphoma patients. Only beta2-microglobulin level was significantly more elevated in disseminated disease patients than in localized disease patients. Complete response after the first treatment was achieved in 74% of the patients, and there was no difference between the 2 groups. With a median follow-up of 4 years, the estimated 5- and 10-year overall survival rates were similar in the 2 groups, 86% and 80%, respectively. The median freedom-from-progression survival was 5.6 years for all patients, surprisingly without any difference between localized and disseminated MALT-lymphoma patients. In conclusion, MALT lymphoma is an indolent disease but presents as a disseminated disease in one-third of the cases at diagnosis. The dissemination does not change the outcome of the patients.

PMID 10648389  Blood. 2000 Feb 1;95(3):802-6.
著者: Emanuele Zucca, Annarita Conconi, Ennio Pedrinis, Sergio Cortelazzo, Teresio Motta, Mary K Gospodarowicz, Bruce J Patterson, Andrés J M Ferreri, Maurilio Ponzoni, Liliana Devizzi, Roberto Giardini, Graziella Pinotti, Carlo Capella, Pier Luigi Zinzani, Stefano Pileri, Armando López-Guillermo, Elias Campo, Achille Ambrosetti, Luca Baldini, Franco Cavalli, International Extranodal Lymphoma Study Group
雑誌名: Blood. 2003 Apr 1;101(7):2489-95. doi: 10.1182/blood-2002-04-1279. Epub 2002 Nov 27.
Abstract/Text A retrospective survey of patients with pathologically reviewed extragastric mucosa-associated lymphoma tissue (MALT) lymphomas from 20 institutions was performed. A total of 180 patients with histologically confirmed diagnosis of extragastric MALT lymphomas were studied. Their median age was 59 years (range, 21-92 years). Ann Arbor stage I disease was present in 115 patients (64%) and stage II disease in 16 (9%). Most cases were in the low or low-intermediate risk groups according to the International Prognostic Index (IPI). Forty-one (23%) patients had involvement of more than one extranodal site at diagnosis and in 24 cases (13%) the lymphoma presented at multiple mucosal sites (9 of them with only mucosal involvement, without bone marrow or nodal disease). Lymph node involvement was present in 21%. Patients were treated with a variety of therapeutic strategies, including chemotherapy in 78 cases. The median overall survival (OS) was not reached; the 5-year OS rate was 90% (95% CI, 82%-94%), the 5-year cause-specific survival (CSS) was 94% (95% CI, 87%-97%), and the 5-year progression-free survival (PFS) was 60% (95% CI, 50%-70%). Multivariate analysis showed that Ann Arbor stage was significantly associated with longer OS, nodal involvement with longer CSS, and favorable IPI score with better PFS. At a median follow-up of 3.4 years, 48 patients (27%; 95% CI, 20%-34%) had a relapse, 6 (3%; 95% CI, 1%-7%) showed histologic transformation, and 18 (10%; 95% CI, 6%-15%) experienced the development of a second tumor. Our data confirm the indolent nature of nongastric MALT lymphomas and the high rate of patients presenting with disseminated disease, which, when limited to mucosal sites, was not associated with a poorer outcome.

PMID 12456507  Blood. 2003 Apr 1;101(7):2489-95. doi: 10.1182/blood-20・・・
著者: Richard W Tsang, Mary K Gospodarowicz, Melania Pintilie, Woodrow Wells, David C Hodgson, Alexander Sun, Michael Crump, Bruce J Patterson
雑誌名: J Clin Oncol. 2003 Nov 15;21(22):4157-64. doi: 10.1200/JCO.2003.06.085.
Abstract/Text PURPOSE: Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) is a distinct lymphoma with unique clinicopathologic features. We report the clinical outcome of stage I and II MALT lymphoma treated with involved field radiation therapy (RT).
PATIENTS AND METHODS: From 1989 to 2000, 103 patients with stage IE and IIE disease were referred. Their median age was 60 years, with a 2:1 female predominance. Presenting sites were stomach (17 patients), orbital adnexa (31 patients), salivary glands (24 patients), thyroid gland (13 patients), and other sites (18 patients). Ninety-three patients received RT--85 received RT alone, and eight received chemotherapy and RT--with a median dose of 30 Gy. The median follow-up time was 5.1 years.
RESULTS: A complete response (CR) to RT alone was achieved in 84 of 85 patients. Among CR patients, 14 experienced relapse. Relapse sites were mostly contralateral paired-organ or distant MALT locations and, infrequently, lymph nodes. The crude local control rate with RT was 95.3% (81 of 85 patients). No relapses were observed in patients with stomach or thyroid lymphoma, whereas 14 of 63 patients (22%) experienced relapse in the other sites. The overall 5-year survival rate was 98%, and the disease-free survival rate was 77%. Transformed lymphoma was observed in 14% of patients (two of 14) experiencing relapse.
CONCLUSION: Moderate-dose RT achieved excellent local control in localized MALT lymphomas and had curative potential for three fourths of the patients. Gastric and thyroid MALT lymphomas had better outcome, whereas distant failures were common for other sites. Despite relapse, the disease often maintained an indolent course.

PMID 14615444  J Clin Oncol. 2003 Nov 15;21(22):4157-64. doi: 10.1200/・・・
著者: G E Kim, J H Cho, W I Yang, E J Chung, C O Suh, K R Park, W P Hong, I Y Park, J S Hahn, J K Roh, B S Kim
雑誌名: J Clin Oncol. 2000 Jan;18(1):54-63.
Abstract/Text PURPOSE: To investigate the patterns of systemic failure and the clinical outcome in patients with angiocentric lymphoma of the head and neck who were treated with radiation alone, and to discuss the optimal mode of treatment for these patients.
PATIENTS AND METHODS: We reviewed the records of 92 patients with stage I or II angiocentric lymphoma who were treated at Yonsei Cancer Center between 1976 and 1994. All patients were treated with involved-field irradiation. Radiation doses ranged from 40 to 60 Gy (median dose, 50.4 Gy). Treatment response, patterns of treatment failure including systemic failure, and clinical outcome after radiation treatment were analyzed.
RESULTS: The most frequently involved site was the nasal cavity, either alone or in conjunction with other sites. In 16 patients (17.4%), angiocentric lymphoma was accompanied by cervical lymphadenopathy. Disease was classified as stage I in 62 patients (67.4%) and stage II in 30 patients (32.6%). After completion of radiation treatment, 61 patients (66.3%) achieved a complete response and 16 (17.4%) a partial response. Half of the patients (50.0%) ultimately experienced local recurrence with or without other components of failure, whereas regional failure was relatively uncommon (10.9%). Systemic failure occurred in 25.0% of patients during follow-up. Six patients had histologic findings identical to those at the time of the original disease (group I), whereas four patients exhibited morphologic features of frank lymphomas (group II). The majority of patients with systemic relapse had the predilection sites for widespread extranodal involvement, such as the skin, brain, lung, gastrointestinal tract, or testes. In addition, seven patients died from various medical illnesses or immunologic disorders, including hemophagocytic syndrome and second primary cancers (group III). After a median follow-up of 56 months, the overall survival and disease-free survival rates for all patients were 40.1% and 37.8%, respectively. All patients except one with systemic failure died within 1 year.
CONCLUSION: Treatment with radiation alone had suboptimal results, partly because of the occurrence of a variety of systemic failure with diverse clinicopathologic features. Given the frequent occurrence of systemic failure after radiation treatment, we believe that the multimodality treatment approach containing more effective chemotherapeutic agents should be incorporated in the treatment of angiocentric lymphoma confined to the head and neck.

PMID 10623693  J Clin Oncol. 2000 Jan;18(1):54-63.
著者: Mei-Juan Huang, Yu Jiang, Wei-Ping Liu, Zhi-Ping Li, Mei Li, Lin Zhou, Yong Xu, Chun-Hua Yu, Qiu Li, Feng Peng, Ji-Yan Liu, Feng Luo, You Lu
雑誌名: Int J Radiat Oncol Biol Phys. 2008 Jan 1;70(1):166-74. doi: 10.1016/j.ijrobp.2007.05.073. Epub 2007 Oct 24.
Abstract/Text PURPOSE: To investigate the role of early or up-front radiotherapy (RT), the optimal RT dose required to achieve appropriate treatment outcome and prognostic factors for patients with localized extranodal NK/T-cell lymphoma, nasal-type, in the upper aerodigestive tract.
METHODS AND MATERIALS: Eighty-two patients were reviewed. Eight patients were treated with chemotherapy (CT) alone, 9 patients received RT alone, and 65 patients were given combined modality treatment of CT and RT (CMT). Of those 74 patients receiving RT, 31 patients were given up-front RT, whereas CT was the initial therapy for 43 patients and 41 of those 43 patients received early RT.
RESULTS: Five-year overall survival (OS) and disease-free survival (DFS) were 52.3% and 39.2%, respectively. RT was the only independent prognostic factor for both OS and DFS at both the univariate and multivariate level. The 5-year OS and DFS were better in patients receiving >or=54 Gy of RT as compared with that of <54 Gy (5-year OS 75.5% vs. 46.1%, p = 0.019; 5-year DFS 60.3% vs. 33.4%, p = 0.004). Up-front RT presented better survival in Stage I patients when compared with that of initial CT followed by early RT (5-year OS 90.0% vs. 48.9%, p = 0.012; 5-year DFS 78.7% vs. 39.9%, p = 0.021).
CONCLUSION: Early or up-front RT had an essential role in improved OS and DFS in patients with localized extranodal NK/T-cell lymphoma, nasal-type, in the upper aerodigestive tract. The recommended tumor dose was at least 54 Gy. Up-front RT may yield more benefits on survival in patients with Stage I disease.

PMID 17919841  Int J Radiat Oncol Biol Phys. 2008 Jan 1;70(1):166-74. ・・・
著者: Chi-Cheng Li, Hwei-Fang Tien, Jih-Luh Tang, Ming Yao, Yao-Chang Chen, Ih-Jen Su, Su-Ming Hsu, Ruey-Long Hong
雑誌名: Cancer. 2004 Jan 15;100(2):366-75. doi: 10.1002/cncr.11908.
Abstract/Text BACKGROUND: Sinonasal natural killer (NK)/T-cell or T-cell lymphoma behaves quite differently from other lymphomas. The objective of this study was to investigate clinical features, treatment outcomes, and failure patterns in patients with this type of sinonasal lymphoma.
METHODS: From September, 1977 to December, 2000, 77 patients with sinonasal NK/T-cell lymphoma or T-cell lymphoma who had received radiotherapy (R/T), chemotherapy (C/T), or both (R/T and C/T) were evaluated retrospectively.
RESULTS: Fifty-six patients (73%) had locoregional disease only, and 21 patients (27%) had systemic involvement. Forty-four patients (57%) achieved a complete remission (CR). The 5-year overall survival rate was 36% (median follow-up, 89 months). Achievement of CR was the only prognostic factor for survival in multivariate analysis. Among patients with locoregional disease, the CR rate was 63%, and the 5-year overall survival rate was 42%. Combined R/T and C/T or R/T alone resulted in better survival compared with C/T alone (5-year survival rates, 59%, 50%, and 15%, respectively; P = 0.01). Incidences of locoregional and systemic failure were 43% and 30%, respectively. Outcome was dismal for patients with systemic disease, with a CR rate of 43% and a 5-year survival rate of 25%. Only 2 of 21 patients had sustained remissions. The locoregional and systemic failure rates were 57% and 71%, respectively.
CONCLUSIONS: Treatment outcomes were unsatisfactory for patients with locoregional and systemic sinonasal NK/T-cell or T-cell lymphoma. R/T could not control locoregional disease satisfactorily, and C/T was unable to eradicate systemic disease in many patients. High-dose therapy may be worth studying in these patients. New treatments should be investigated to increase remission rates, prevent failure, and improve survival.

Copyright 2003 American Cancer Society.
PMID 14716773  Cancer. 2004 Jan 15;100(2):366-75. doi: 10.1002/cncr.11・・・
著者: Ye-Xiong Li, Bo Yao, Jing Jin, Wei-Hu Wang, Yue-Ping Liu, Yong-Wen Song, Shu-Lian Wang, Xin-Fan Liu, Li-Qiang Zhou, Xiao-Hui He, Ning Lu, Zi-Hao Yu
雑誌名: J Clin Oncol. 2006 Jan 1;24(1):181-9. doi: 10.1200/JCO.2005.03.2573.
Abstract/Text UNLABELLED: PURPOSE The optimal therapy remains unclear for nasal natural killer (NK)/T-cell lymphoma. The purpose of this study is to analyze the outcome of radiotherapy as the primary treatment for localized stage IE and IIE diseases.
PATIENTS AND METHODS: One hundred five patient cases were reviewed. There were 83 stage IE and 22 stage IIE patients. All except three patients received radiotherapy (RT) alone or RT combined with chemotherapy (CT; combined-modality therapy [CMT]). Overall, 31 patients were treated with RT alone, 34 with RT followed by CT, 37 with CT followed by RT, and three with CT alone.
RESULTS: Five-year overall survival (OS) and progression-free survival (PFS) for all patients were 71% and 59%, respectively. The 5-year OS and PFS were 78% and 63% for stage IE, and 46% and 40% for stage IIE, respectively. Complete response (CR) was achieved in 91 patients (87%) after RT and/or CT. Initial RT resulted in a superior CR as compared with initial CT, with 54 (83%) of 65 patients achieving CR with initial RT, versus only eight (20%) of 40 after initial CT. For 102 patients who received RT with or without CT, the outcome of primary treatment with RT alone was compared with that of CMT. Five-year OS and PFS was 66% and 61% for RT alone, and 76% and 61%% for CMT, respectively (OS, P = .6433; PFS, P = .8391).
CONCLUSION: RT as primary therapy resulted in good outcome in early-stage disease, and the addition of CT to RT was not accompanied by an improvement in survival.

PMID 16382127  J Clin Oncol. 2006 Jan 1;24(1):181-9. doi: 10.1200/JCO.・・・
著者: J-Y You, K-H Chi, M-H Yang, C-C Chen, C-H Ho, W-K Chau, H-C Hsu, J-P Gau, C-H Tzeng, J-H Liu, P-M Chen, T-J Chiou
雑誌名: Ann Oncol. 2004 Apr;15(4):618-25.
Abstract/Text BACKGROUND: To clarify the role of intention to treat for patients with localized nasal natural killer (NK)/T-cell lymphoma, and to determine the prognostic factors for these patients.
PATIENTS AND METHODS: We conducted a retrospective review of 46 patients with localized nasal NK/T-cell lymphomas treated at a single institute between January 1988 and July 2002.
RESULTS: The type of intended treatment was a significant factor for overall survival (OS) (5-year OS: RT versus CT = 83.3% versus 28.6%, P = 0.0269) or failure-free survival (FFS) (5-year FFS: RT versus CT = 83.3% versus 27.1%, P = 0.0247). In the intended chemotherapy group, salvage with radiotherapy was superior to chemotherapy alone for OS (5-year OS: 42.2% versus 20.0%, P = 0.0252) or FFS (5-year FFS: 41.0% versus 20.0%, P = 0.0352). On multivariate analysis, both N stage and serum lactate dehydrogenase level were independent factors for OS and FFS. No radiotherapy was an independent adverse factor for OS; advanced T stage and more than one extranodal involvement were independent adverse factors for FFS.
CONCLUSIONS: Patients with localized nasal NK/T-cell lymphomas were better managed with radiotherapy as front-line therapy. The advantage of radiotherapy persisted even as palliative therapy after chemotherapy.

PMID 15033670  Ann Oncol. 2004 Apr;15(4):618-25.
著者: Steven Horwitz, Owen A O'Connor, Barbara Pro, Tim Illidge, Michelle Fanale, Ranjana Advani, Nancy L Bartlett, Jacob Haaber Christensen, Franck Morschhauser, Eva Domingo-Domenech, Giuseppe Rossi, Won Seog Kim, Tatyana Feldman, Anne Lennard, David Belada, Árpád Illés, Kensei Tobinai, Kunihiro Tsukasaki, Su-Peng Yeh, Andrei Shustov, Andreas Hüttmann, Kerry J Savage, Sam Yuen, Swaminathan Iyer, Pier Luigi Zinzani, Zhaowei Hua, Meredith Little, Shangbang Rao, Joseph Woolery, Thomas Manley, Lorenz Trümper, ECHELON-2 Study Group
雑誌名: Lancet. 2019 Jan 19;393(10168):229-240. doi: 10.1016/S0140-6736(18)32984-2. Epub 2018 Dec 4.
Abstract/Text BACKGROUND: Based on the encouraging activity and manageable safety profile observed in a phase 1 study, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for the treatment of CD30-positive peripheral T-cell lymphomas.
METHODS: ECHELON-2 is a double-blind, double-dummy, randomised, placebo-controlled, active-comparator phase 3 study. Eligible adults from 132 sites in 17 countries with previously untreated CD30-positive peripheral T-cell lymphomas (targeting 75% with systemic anaplastic large cell lymphoma) were randomly assigned 1:1 to receive either A+CHP or CHOP for six or eight 21-day cycles. Randomisation was stratified by histological subtype according to local pathology assessment and by international prognostic index score. All patients received cyclophosphamide 750 mg/m2 and doxorubicin 50 mg/m2 on day 1 of each cycle intravenously and prednisone 100 mg once daily on days 1 to 5 of each cycle orally, followed by either brentuximab vedotin 1·8 mg/kg and a placebo form of vincristine intravenously (A+CHP group) or vincristine 1·4 mg/m2 and a placebo form of brentuximab vedotin intravenously (CHOP group) on day 1 of each cycle. The primary endpoint, progression-free survival according to blinded independent central review, was analysed by intent-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01777152.
FINDINGS: Between Jan 24, 2013, and Nov 7, 2016, 601 patients assessed for eligibility, of whom 452 patients were enrolled and 226 were randomly assigned to both the A+CHP group and the CHOP group. Median progression-free survival was 48·2 months (95% CI 35·2-not evaluable) in the A+CHP group and 20·8 months (12·7-47·6) in the CHOP group (hazard ratio 0·71 [95% CI 0·54-0·93], p=0·0110). Adverse events, including incidence and severity of febrile neutropenia (41 [18%] patients in the A+CHP group and 33 [15%] in the CHOP group) and peripheral neuropathy (117 [52%] in the A+CHP group and 124 [55%] in the CHOP group), were similar between groups. Fatal adverse events occurred in seven (3%) patients in the A+CHP group and nine (4%) in the CHOP group.
INTERPRETATION: Front-line treatment with A+CHP is superior to CHOP for patients with CD30-positive peripheral T-cell lymphomas as shown by a significant improvement in progression-free survival and overall survival with a manageable safety profile.
FUNDING: Seattle Genetics Inc, Millennium Pharmaceuticals Inc, a wholly owned subsidiary of Takeda Pharmacuetical Company Limited, and National Institutes of Health National Cancer Institute Cancer Center.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 30522922  Lancet. 2019 Jan 19;393(10168):229-240. doi: 10.1016/S0・・・
著者: Peter Reimer, Thomas Rüdiger, Eva Geissinger, Florian Weissinger, Christoph Nerl, Norbert Schmitz, Andreas Engert, Hermann Einsele, Hans Konrad Müller-Hermelink, Martin Wilhelm
雑誌名: J Clin Oncol. 2009 Jan 1;27(1):106-13. doi: 10.1200/JCO.2008.17.4870. Epub 2008 Nov 24.
Abstract/Text PURPOSE: Peripheral T-cell lymphomas (PTCLs) are rare malignancies with poor outcome after conventional chemotherapy. The role of myeloablative therapy and autologous stem-cell transplantation (autoSCT) is still unclear. Therefore, we initiated the first prospective multicenter study on upfront autoSCT in PTCL and recently reported good feasibility and efficacy of this approach. Here, we present the final analysis of the study.
PATIENTS AND METHODS: The treatment regimen consisted of four to six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone followed by mobilizing therapy with either the dexamethasone, carmustine, melphalan, etoposide, and cytarabine protocol or the etoposide, methylprednisolone, cytarabine, and cisplatin protocol and stem-cell collection. Patients in complete remission (CR) or partial remission (PR) underwent myeloablative chemoradiotherapy (fractionated total-body irradiation and high-dose cyclophosphamide) and autoSCT.
RESULTS: From June 2000 to April 2006, 83 patients were enrolled onto the study. Main subgroups were PTCL not specified (n = 32) and angioimmunoblastic T-cell lymphoma (n = 27). Fifty-five (66%) of the 83 patients received transplantation. The main reason for not receiving autoSCT was progressive disease. In an intent-to-treat analysis, the overall response rate after myeloablative therapy was 66% (56% CR and 8% PR). With a median follow-up time of 33 months, 43 patients are alive; the estimated 3-year overall and disease-free survival rates for patients in CR (calculated from CR to the date of relapse) and 3-year progression-free survival rate were 48%, 53%, and 36%, respectively.
CONCLUSION: The results of this prospective study suggest a substantial impact on outcome for upfront autoSCT in PTCL and should be further evaluated in randomized trials. Pretransplantation treatment needs to be improved to increase the transplantation rate.

PMID 19029417  J Clin Oncol. 2009 Jan 1;27(1):106-13. doi: 10.1200/JCO・・・
著者: Francesco d'Amore, Thomas Relander, Grete F Lauritzsen, Esa Jantunen, Hans Hagberg, Harald Anderson, Harald Holte, Anders Österborg, Mats Merup, Peter Brown, Outi Kuittinen, Martin Erlanson, Bjørn Østenstad, Unn-Merete Fagerli, Ole V Gadeberg, Christer Sundström, Jan Delabie, Elisabeth Ralfkiaer, Martine Vornanen, Helle E Toldbod
雑誌名: J Clin Oncol. 2012 Sep 1;30(25):3093-9. doi: 10.1200/JCO.2011.40.2719. Epub 2012 Jul 30.
Abstract/Text PURPOSE: Systemic peripheral T-cell lymphomas (PTCLs) respond poorly to conventional therapy. To evaluate the efficacy of a dose-dense approach consolidated by up-front high-dose chemotherapy (HDT) and autologous stem-cell transplantation (ASCT) in PTCL, the Nordic Lymphoma Group (NLG) conducted a large prospective phase II study in untreated systemic PTCL. This is the final report, with a 5-year median follow-up, of the NLG-T-01 study.
PATIENTS AND METHODS: Treatment-naive patients with PTCL age 18 to 67 years (median, 57 years) were included. Anaplastic lymphoma kinase (ALK) -positive anaplastic large-cell lymphoma (ALCL) was excluded. An induction regimen of six cycles of biweekly CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) was administered (in patients age > 60 years, etoposide was omitted). If in complete or partial remission, patients proceeded to consolidation with HDT/ASCT.
RESULTS: Of 166 enrolled patients, 160 had histopathologically confirmed PTCL. The majority presented with advanced-stage disease, B symptoms, and elevated serum lactate dehydrogenase. A total of 115 underwent HDT/ASCT, with 90 in complete remission at 3 months post-transplantation. Early failures occurred in 26%. Treatment-related mortality was 4%. At 60.5 months of median follow-up, 83 patients were alive. Consolidated 5-year overall and progression-free survival (PFS) were 51% (95% CI, 43% to 59%) and 44% (95% CI, 36% to 52%), respectively. Best results were obtained in ALK-negative ALCL.
CONCLUSION: Dose-dense induction followed by HDT/ASCT was well tolerated and led to long-term PFS in 44% of treatment-naive patients with PTCL. This represents an encouraging outcome, particularly considering the high median age and adverse risk profile of the study population. Therefore, dose-dense induction and HDT/ASCT are a rational up-front strategy in transplantation-eligible patients with PTCL.

PMID 22851556  J Clin Oncol. 2012 Sep 1;30(25):3093-9. doi: 10.1200/JC・・・
著者: P Corradini, U Vitolo, A Rambaldi, R Miceli, F Patriarca, A Gallamini, A Olivieri, F Benedetti, G Todeschini, G Rossi, F Salvi, B Bruno, L Baldini, A Ferreri, C Patti, C Tarella, S Pileri, A Dodero
雑誌名: Leukemia. 2014 Sep;28(9):1885-91. doi: 10.1038/leu.2014.79. Epub 2014 Feb 20.
Abstract/Text Peripheral T-cell lymphomas (PTCLs) receiving conventional treatment have a poor clinical outcome. We conducted a phase II study to evaluate the feasibility and efficacy of chemo-immunotherapy in young (⩽60 years old, Clin A study) and elderly (>60 and < or =75 years old, Clin B study) patients with newly diagnosed PTCL. Clin A patients (n=61) received two courses of CHOP (cyclophosphamide, adriamycin, vincristine, prednisone)-21 with alemtuzumab (AL, 30 mg) followed by two courses of high-dose chemotherapy. On the basis of donor availability, patients in response received allogeneic (allo) or autologous (auto) stem cell transplantation (SCT). Clin B patients (n=25) received six courses of CHOP-21 and AL (10 mg). Clin A responding patients were 38 of 61 (62%) and received alloSCT (n=23) or autoSCT (n=14); one complete remission (CR) patient was not transplanted. At a median follow-up of 40 months, the 4-year overall survival (OS), progression-free survival (PFS) and disease-free survival (DFS) rates were 49, 44 and 65%, respectively. In Clin B study, the response rate was 72%. At a median follow-up of 48 months, the 4-year OS, PFS and DFS rates were 31, 26 and 44%, respectively. In conclusion, front-line alloSCT or autoSCT is effective in prolonging DFS in young patients; AL in elderly improved response with no survival benefit.

PMID 24662801  Leukemia. 2014 Sep;28(9):1885-91. doi: 10.1038/leu.2014・・・
著者: Sonali M Smith, Linda J Burns, Koen van Besien, Jennifer Lerademacher, Wensheng He, Timothy S Fenske, Ritsuro Suzuki, Jack W Hsu, Harry C Schouten, Gregory A Hale, Leona A Holmberg, Anna Sureda, Cesar O Freytes, Richard Thomas Maziarz, David J Inwards, Robert Peter Gale, Thomas G Gross, Mitchell S Cairo, Luciano J Costa, Hillard M Lazarus, Peter H Wiernik, Dipnarine Maharaj, Ginna G Laport, Silvia Montoto, Parameswaran N Hari
雑誌名: J Clin Oncol. 2013 Sep 1;31(25):3100-9. doi: 10.1200/JCO.2012.46.0188. Epub 2013 Jul 29.
Abstract/Text PURPOSE: To analyze outcomes of hematopoietic cell transplantation (HCT) in T-cell non-Hodgkin lymphoma.
PATIENTS AND METHODS: Outcomes of 241 patients (112 anaplastic large-cell lymphoma, 102 peripheral T-cell lymphoma not otherwise specified, 27 angioimmunoblastic T-cell lymphoma) undergoing autologous HCT (autoHCT; n = 115; median age, 43 years) or allogeneic HCT (alloHCT; n = 126; median age, 38 years) were analyzed. Primary outcomes were nonrelapse mortality (NRM), relapse/progression, progression-free survival (PFS), and overall survival (OS). Patient, disease, and HCT-related variables were analyzed in multivariate Cox proportional hazard models to determine association with outcomes.
RESULTS: AutoHCT recipients were more likely in first complete remission (CR1; 35% v 14%; P = .001) and with chemotherapy-sensitive disease (86% v 60%; P < .001), anaplastic large-cell histology (53% v 40%; P = .04), and two or fewer lines of prior therapy (65% v 44%; P < .001) compared with alloHCT recipients. Three-year PFS and OS of autoHCT recipients beyond CR1 were 42% and 53%, respectively. Among alloHCT recipients who received transplantations beyond CR1, 31% remained progression-free at 3 years, despite being more heavily pretreated and with more refractory disease. NRM was 3.5-fold higher (95% CI, 1.80 to 6.99; P < .001) for alloHCT. In multivariate analysis, chemotherapy sensitivity (hazard ratio [HR], 1.8; 95% CI, 1.16 to 2.87) and two or fewer lines of pretransplantation therapy (HR, 5.02; 95% CI, 2.15 to 11.72) were prognostic of survival.
CONCLUSION: These data describe the roles of autoHCT and alloHCT in T-cell non-Hodgkin lymphoma and suggest greater effectiveness earlier in the disease course, and limited utility in multiply relapsed disease. Notably, autoHCT at relapse may be a potential option for select patients, particularly those with anaplastic large-cell lymphoma histology.

PMID 23897963  J Clin Oncol. 2013 Sep 1;31(25):3100-9. doi: 10.1200/JC・・・
著者: H C Kluin-Nelemans, E Hoster, O Hermine, J Walewski, M Trneny, C H Geisler, S Stilgenbauer, C Thieblemont, U Vehling-Kaiser, J K Doorduijn, B Coiffier, R Forstpointner, H Tilly, L Kanz, P Feugier, M Szymczyk, M Hallek, S Kremers, G Lepeu, L Sanhes, J M Zijlstra, R Bouabdallah, P J Lugtenburg, M Macro, M Pfreundschuh, V Procházka, F Di Raimondo, V Ribrag, M Uppenkamp, M André, W Klapper, W Hiddemann, M Unterhalt, M H Dreyling
雑誌名: N Engl J Med. 2012 Aug 9;367(6):520-31. doi: 10.1056/NEJMoa1200920.
Abstract/Text BACKGROUND: The long-term prognosis for older patients with mantle-cell lymphoma is poor. Chemoimmunotherapy results in low rates of complete remission, and most patients have a relapse. We investigated whether a fludarabine-containing induction regimen improved the complete-remission rate and whether maintenance therapy with rituximab prolonged remission.
METHODS: We randomly assigned patients 60 years of age or older with mantle-cell lymphoma, stage II to IV, who were not eligible for high-dose therapy to six cycles of rituximab, fludarabine, and cyclophosphamide (R-FC) every 28 days or to eight cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days. Patients who had a response underwent a second randomization to maintenance therapy with rituximab or interferon alfa, each given until progression.
RESULTS: Of the 560 patients enrolled, 532 were included in the intention-to-treat analysis for response, and 485 in the primary analysis for response. The median age was 70 years. Although complete-remission rates were similar with R-FC and R-CHOP (40% and 34%, respectively; P=0.10), progressive disease was more frequent with R-FC (14%, vs. 5% with R-CHOP). Overall survival was significantly shorter with R-FC than with R-CHOP (4-year survival rate, 47% vs. 62%; P=0.005), and more patients in the R-FC group died during the first remission (10% vs. 4%). Hematologic toxic effects occurred more frequently in the R-FC group than in the R-CHOP group, but the frequency of grade 3 or 4 infections was balanced (17% and 14%, respectively). In 274 of the 316 patients who were randomly assigned to maintenance therapy, rituximab reduced the risk of progression or death by 45% (in remission after 4 years, 58%, vs. 29% with interferon alfa; hazard ratio for progression or death, 0.55; 95% confidence interval, 0.36 to 0.87; P=0.01). Among patients who had a response to R-CHOP, maintenance therapy with rituximab significantly improved overall survival (4-year survival rate, 87%, vs. 63% with interferon alfa; P=0.005).
CONCLUSIONS: R-CHOP induction followed by maintenance therapy with rituximab is effective for older patients with mantle-cell lymphoma. (Funded by the European Commission and others; ClinicalTrials.gov number, NCT00209209.).

PMID 22873532  N Engl J Med. 2012 Aug 9;367(6):520-31. doi: 10.1056/NE・・・
著者: Tadeusz Robak, Huiqiang Huang, Jie Jin, Jun Zhu, Ting Liu, Olga Samoilova, Halyna Pylypenko, Gregor Verhoef, Noppadol Siritanaratkul, Evgenii Osmanov, Julia Alexeeva, Juliana Pereira, Johannes Drach, Jiri Mayer, Xiaonan Hong, Rumiko Okamoto, Lixia Pei, Brendan Rooney, Helgi van de Velde, Franco Cavalli, LYM-3002 Investigators
雑誌名: N Engl J Med. 2015 Mar 5;372(10):944-53. doi: 10.1056/NEJMoa1412096.
Abstract/Text BACKGROUND: The proteasome inhibitor bortezomib was initially approved for the treatment of relapsed mantle-cell lymphoma. We investigated whether substituting bortezomib for vincristine in frontline therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) could improve outcomes in patients with newly diagnosed mantle-cell lymphoma.
METHODS: In this phase 3 trial, we randomly assigned 487 adults with newly diagnosed mantle-cell lymphoma who were ineligible or not considered for stem-cell transplantation to receive six to eight 21-day cycles of R-CHOP intravenously on day 1 (with prednisone administered orally on days 1 to 5) or VR-CAP (R-CHOP regimen, but replacing vincristine with bortezomib at a dose of 1.3 mg per square meter of body-surface area on days 1, 4, 8, and 11). The primary end point was progression-free survival.
RESULTS: After a median follow-up of 40 months, median progression-free survival (according to independent radiologic review) was 14.4 months in the R-CHOP group versus 24.7 months in the VR-CAP group (hazard ratio favoring the VR-CAP group, 0.63; P<0.001), a relative improvement of 59%. On the basis of investigator assessment, the median durations of progression-free survival were 16.1 months and 30.7 months, respectively (hazard ratio, 0.51; P<0.001), a relative improvement of 96%. Secondary end points were consistently improved in the VR-CAP group, including the complete response rate (42% vs. 53%), the median duration of complete response (18.0 months vs. 42.1 months), the median treatment-free interval (20.5 months vs. 40.6 months), and the 4-year overall survival rate (54% vs. 64%). Rates of neutropenia and thrombocytopenia were higher in the VR-CAP group.
CONCLUSIONS: VR-CAP was more effective than R-CHOP in patients with newly diagnosed mantle-cell lymphoma but at the cost of increased hematologic toxicity. (Funded by Janssen Research and Development and Millennium Pharmaceuticals; LYM-3002 ClinicalTrials.gov number, NCT00722137.).

PMID 25738670  N Engl J Med. 2015 Mar 5;372(10):944-53. doi: 10.1056/N・・・
著者: Tadeusz Robak, Jie Jin, Halyna Pylypenko, Gregor Verhoef, Noppadol Siritanaratkul, Johannes Drach, Markus Raderer, Jiri Mayer, Juliana Pereira, Gayane Tumyan, Rumiko Okamoto, Susumu Nakahara, Peter Hu, Carlos Appiani, Sepideh Nemat, Franco Cavalli, LYM-3002 investigators
雑誌名: Lancet Oncol. 2018 Nov;19(11):1449-1458. doi: 10.1016/S1470-2045(18)30685-5. Epub 2018 Oct 19.
Abstract/Text BACKGROUND: In the LYM-3002 study, the efficacy and safety of frontline bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were compared in transplant-ineligible patients with untreated, newly diagnosed, mantle cell lymphoma. We report the final overall survival and safety outcomes for patients in the long-term follow-up phase after the primary progression-free-survival endpoint was met.
METHODS: LYM-3002 was a randomised, open-label, phase 3 study done at 128 clinical centres in 28 countries in Asia, Europe, North America, and South America. Adult patients with confirmed stage II-IV previously untreated mantle cell lymphoma, Eastern Cooperative Oncology Group performance status score of 2 or less, who were ineligible for bone marrow transplantation, were randomly assigned (1:1) to receive six or eight 21-day cycles of VR-CAP (intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and bortezomib 1·3 mg/m2, plus oral prednisone 100 mg/m2) or R-CHOP (intravenous vincristine 1·4 mg/m2 [2 mg maximum], rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2, plus oral prednisone 100 mg/m2). Randomisation was done according to a computer-generated randomisation schedule prepared by the sponsor; permuted blocks central randomisation was used (block size of 4), and was stratified by International Prognostic Index score and disease stage at diagnosis. The primary endpoint of this final analysis was overall survival, which was analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00722137, and is closed to new participants with follow-up completed.
FINDINGS: Between May 22, 2008, and Dec 5, 2011, 487 patients were enrolled and randomly assigned. 268 patients (140 in the VR-CAP group and 128 in the R-CHOP group) were included in the follow-up analysis, which included patients with data available after the primary analysis clinical cutoff date of Dec 2, 2013. After median follow-up of 82·0 months (IQR 74·1-94·2), median overall survival was significantly longer in the VR-CAP group than in the R-CHOP group (90·7 months [95% CI 71·4 to not estimable] vs 55·7 months [47·2 to 68·9]; hazard ratio 0·66 [95% CI 0·51-0·85]; p=0·001). Three new adverse events were reported since the primary analysis cutoff (one each of grade 4 lung adenocarcinoma and grade 4 gastric cancer in the VR-CAP group, and one case of grade 2 pneumonia in the R-CHOP group). 103 (42%) of 243 patients in the VR-CAP group, and 138 (57%) of 244 in the R-CHOP group died; the most common cause of death was progressive disease.
INTERPRETATIONS: Compared with R-CHOP, VR-CAP was associated with significantly longer survival, and had a manageable and expected safety profile. Our results support further assessment of VR-CAP in patients with previously untreated mantle cell lymphoma.
FUNDING: Janssen Research & Development.

Copyright © 2018 Elsevier Ltd. All rights reserved.
PMID 30348538  Lancet Oncol. 2018 Nov;19(11):1449-1458. doi: 10.1016/S・・・
著者: Christian H Geisler, Arne Kolstad, Anna Laurell, Niels S Andersen, Lone B Pedersen, Mats Jerkeman, Mikael Eriksson, Marie Nordström, Eva Kimby, Anne Marie Boesen, Outi Kuittinen, Grete F Lauritzsen, Herman Nilsson-Ehle, Elisabeth Ralfkiaer, Måns Akerman, Mats Ehinger, Christer Sundström, Ruth Langholm, Jan Delabie, Marja-Liisa Karjalainen-Lindsberg, Peter Brown, Erkki Elonen, Nordic Lymphoma Group
雑誌名: Blood. 2008 Oct 1;112(7):2687-93. doi: 10.1182/blood-2008-03-147025. Epub 2008 Jul 14.
Abstract/Text Mantle cell lymphoma (MCL) is considered incurable. Intensive immunochemotherapy with stem cell support has not been tested in large, prospective series. In the 2nd Nordic MCL trial, we treated 160 consecutive, untreated patients younger than 66 years in a phase 2 protocol with dose-intensified induction immunochemotherapy with rituximab (R) + cyclophosphamide, vincristine, doxorubicin, prednisone (maxi-CHOP), alternating with R + high-dose cytarabine. Responders received high-dose chemotherapy with BEAM or BEAC (carmustine, etoposide, cytarabine, and melphalan/cyclophosphamide) with R-in vivo purged autologous stem cell support. Overall and complete response was achieved in 96% and 54%, respectively. The 6-year overall, event-free, and progression-free survival were 70%, 56%, and 66%, respectively, with no relapses occurring after 5 years. Multivariate analysis showed Ki-67 to be the sole independent predictor of event-free survival. The nonrelapse mortality was 5%. The majority of stem cell products and patients assessed with polymerase chain reaction (PCR) after transplantation were negative. Compared with our historical control, the Nordic MCL-1 trial, the event-free, overall, and progression-free survival, the duration of molecular remission, and the proportion of PCR-negative stem cell products were significantly increased (P < .001). Intensive immunochemotherapy with in vivo purged stem cell support can lead to long-term progression-free survival of MCL and perhaps cure. Registered at www.isrctn.org as #ISRCTN 87866680.

PMID 18625886  Blood. 2008 Oct 1;112(7):2687-93. doi: 10.1182/blood-20・・・
著者: Lloyd E Damon, Jeffrey L Johnson, Donna Niedzwiecki, Bruce D Cheson, David D Hurd, Nancy L Bartlett, Ann S Lacasce, Kristie A Blum, John C Byrd, Michael Kelly, Wendy Stock, Charles A Linker, George P Canellos
雑誌名: J Clin Oncol. 2009 Dec 20;27(36):6101-8. doi: 10.1200/JCO.2009.22.2554. Epub 2009 Nov 16.
Abstract/Text PURPOSE Mantle-cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with a poor prognosis. We explored the feasibility, safety, and effectiveness of an aggressive immunochemotherapy treatment program that included autologous stem-cell transplantation (ASCT) for patients up to age 69 years with newly diagnosed MCL. PATIENTS AND METHODS The primary end point was 2-year progression-free survival (PFS). A successful trial would yield a 2-year PFS of at least 50% and an event rate (early progression plus nonrelapse mortality) less than 20% at day +100 following ASCT. Seventy-eight patients were treated with two or three cycles of rituximab combined with methotrexate and augmented CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). This treatment was followed by intensification with high doses of cytarabine and etoposide combined with rituximab and filgrastim to mobilize autologous peripheral-blood stem cells. Patients then received high doses of carmustine, etoposide, and cyclophosphamide followed by ASCT and two doses of rituximab. Results There were two nonrelapse mortalities, neither during ASCT. With a median follow-up of 4.7 years, the 2-year PFS was 76% (95% CI, 64% to 85%), and the 5-year PFS was 56% (95% CI, 43% to 68%). The 5-year overall survival was 64% (95% CI, 50% to 75%). The event rate by day +100 of ASCT was 5.1%. CONCLUSION The Cancer and Leukemia Group B 59909 regimen is feasible, safe, and effective in patients with newly diagnosed MCL. The incorporation of rituximab with aggressive chemotherapy and ASCT may be responsible for the encouraging outcomes demonstrated in this study, which produced results comparable to similar treatment regimens.

PMID 19917845  J Clin Oncol. 2009 Dec 20;27(36):6101-8. doi: 10.1200/J・・・
著者: Steven Le Gouill, Catherine Thieblemont, Lucie Oberic, Anne Moreau, Krimo Bouabdallah, Caroline Dartigeas, Gandhi Damaj, Thomas Gastinne, Vincent Ribrag, Pierre Feugier, Olivier Casasnovas, Hacène Zerazhi, Corinne Haioun, Hervé Maisonneuve, Roch Houot, Fabrice Jardin, Eric Van Den Neste, Olivier Tournilhac, Katell Le Dû, Franck Morschhauser, Guillaume Cartron, Luc-Matthieu Fornecker, Danielle Canioni, Mary Callanan, Marie C Béné, Gilles Salles, Hervé Tilly, Thierry Lamy, Remy Gressin, Olivier Hermine, LYSA Group
雑誌名: N Engl J Med. 2017 Sep 28;377(13):1250-1260. doi: 10.1056/NEJMoa1701769.
Abstract/Text BACKGROUND: Mantle-cell lymphoma is generally incurable. Despite high rates of complete response after initial immunochemotherapy followed by autologous stem-cell transplantation, patients have relapses. We investigated whether rituximab maintenance therapy at a dose of 375 mg per square meter of body-surface area administered every 2 months for 3 years after transplantation would prolong the duration of response.
METHODS: In a phase 3 trial involving 299 patients who were younger than 66 years of age at diagnosis, we randomly assigned 240 patients to receive rituximab maintenance therapy or to undergo observation after autologous stem-cell transplantation (120 patients per group); 59 patients did not undergo randomization. The primary end point was event-free survival (with an event defined as disease progression, relapse, death, allergy to rituximab, or severe infection) after transplantation among patients who underwent randomization.
RESULTS: After four courses of immunochemotherapy induction (rituximab, dexamethasone, cytarabine, and a platinum derivative [R-DHAP]), the overall response rate was 89%, and the complete response rate 77%. Transplantation was performed in 257 patients. The median follow-up from randomization after transplantation was 50.2 months (range, 46.4 to 54.2). Starting from randomization, the rate of event-free survival at 4 years was 79% (95% confidence interval [CI], 70 to 86) in the rituximab group versus 61% (95% CI, 51 to 70) in the observation group (P=0.001). The rate of progression-free survival at 4 years was 83% (95% CI, 73 to 88) in the rituximab group versus 64% (95% CI, 55 to 73) in the observation group (P<0.001). The rate of overall survival was 89% (95% CI, 81 to 94) in the rituximab group versus 80% (95% CI, 72 to 88) in the observation group (P=0.04). According to a Cox regression unadjusted analysis, the rate of overall survival at 4 years was higher in the rituximab group than in the observation group (hazard ratio for death, 0.50; 95% CI, 0.26 to 0.99; P=0.04).
CONCLUSIONS: Rituximab maintenance therapy after transplantation prolonged event-free survival, progression-free survival, and overall survival among patients with mantle-cell lymphoma who were younger than 66 years of age at diagnosis. (Funded by Roche and Amgen; LyMa ClinicalTrials.gov number, NCT00921414 .).

PMID 28953447  N Engl J Med. 2017 Sep 28;377(13):1250-1260. doi: 10.10・・・
著者: Olivier Hermine, Eva Hoster, Jan Walewski, André Bosly, Stephan Stilgenbauer, Catherine Thieblemont, Michal Szymczyk, Reda Bouabdallah, Michael Kneba, Michael Hallek, Gilles Salles, Pierre Feugier, Vincent Ribrag, Josef Birkmann, Roswitha Forstpointner, Corinne Haioun, Mathias Hänel, René Olivier Casasnovas, Jürgen Finke, Norma Peter, Kamal Bouabdallah, Catherine Sebban, Thomas Fischer, Ulrich Dührsen, Bernd Metzner, Georg Maschmeyer, Lothar Kanz, Christian Schmidt, Richard Delarue, Nicole Brousse, Wolfram Klapper, Elizabeth Macintyre, Marie-Hélène Delfau-Larue, Christiane Pott, Wolfgang Hiddemann, Michael Unterhalt, Martin Dreyling, European Mantle Cell Lymphoma Network
雑誌名: Lancet. 2016 Aug 6;388(10044):565-75. doi: 10.1016/S0140-6736(16)00739-X. Epub 2016 Jun 14.
Abstract/Text BACKGROUND: Mantle cell lymphoma is characterised by a poor long-term prognosis. The European Mantle Cell Lymphoma Network aimed to investigate whether the introduction of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation (ASCT) improves outcome.
METHODS: This randomised, open-label, parallel-group, phase 3 trial was done in 128 haemato-oncological hospital departments or private practices in Germany, France, Belgium, and Poland. Patients aged 65 years or younger with untreated stage II-IV mantle cell lymphoma were centrally randomised (1:1), with computer-assisted random block selection, to receive either six courses of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by myeloablative radiochemotherapy and ASCT (control group), or six courses of alternating R-CHOP or R-DHAP (rituximab plus dexamethasone, high-dose cytarabine, and cisplatin) followed by a high-dose cytarabine-containing conditioning regimen and ASCT (cytarabine group). Patients were stratified by study group and international prognostic index. The primary outcome was time to treatment failure from randomisation to stable disease after at least four induction cycles, progression, or death from any cause. Patients with stage II-IV mantle cell lymphoma were included in the primary analysis if treatment was started according to randomisation. For safety analyses, patients were assessed according to the treatment actually started. This study is registered with ClinicalTrials.gov, number NCT00209222.
FINDINGS: Of 497 patients (median age 55 years [IQR 49-60]) randomised from July 20, 2004, to March 18, 2010, 234 of 249 in the control group and 232 of 248 in the cytarabine group were included in the primary analysis. After a median follow-up of 6.1 years (95% CI 5.4-6.4), time to treatment failure was significantly longer in the cytarabine group (median 9.1 years [95% CI 6.3-not reached], 5 year rate 65% [95% CI 57-71]) than in the control group (3.9 years [3.2-4.4], 40% [33-46]; hazard ratio 0.56; p=0.038). During induction immunochemotherapy, patients who received high-dose cytarabine had increased grade 3 or 4 haematological toxicity (haemoglobin 71 [29%] of 241m vs 19 [8%] of 227 controls; platelets 176 [73%] of 240 vs 21 [9%] of 225), grade 3 or 4 febrile neutropenia (39 [17%] of 230 vs 19 [8%] of 224), and grade 1 or 2 renal toxicity (creatinine 102 [43%] of 236 vs 22 [10%] of 224). The number of ASCT-related deaths was similar (eight [3.4%]) in both groups.
INTERPRETATION: Immunochemotherapy containing high-dose cytarabine followed by ASCT should be considered standard of care in patients aged 65 years or younger with mantle cell lymphoma.
FUNDING: European Commission, Lymphoma Research Foundation, and Roche.

Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID 27313086  Lancet. 2016 Aug 6;388(10044):565-75. doi: 10.1016/S014・・・
著者: James N Gerson, Elizabeth Handorf, Diego Villa, Alina S Gerrie, Parv Chapani, Shaoying Li, L Jeffrey Medeiros, Michael I Wang, Jonathon B Cohen, Oscar Calzada, Michael C Churnetski, Brian T Hill, Yazeed Sawalha, Francisco J Hernandez-Ilizaliturri, Shalin Kothari, Julie M Vose, Martin A Bast, Timothy S Fenske, Swapna Narayana Rao Gari, Kami J Maddocks, David Bond, Veronika Bachanova, Bhaskar Kolla, Julio Chavez, Bijal Shah, Frederick Lansigan, Timothy F Burns, Alexandra M Donovan, Nina Wagner-Johnston, Marcus Messmer, Amitkumar Mehta, Jennifer K Anderson, Nishitha Reddy, Alexandra E Kovach, Daniel J Landsburg, Martha Glenn, David J Inwards, Reem Karmali, Jason B Kaplan, Paolo F Caimi, Saurabh Rajguru, Andrew Evens, Andreas Klein, Elvira Umyarova, Bhargavi Pulluri, Jennifer E Amengual, Jennifer K Lue, Catherine Diefenbach, Richard I Fisher, Stefan K Barta
雑誌名: J Clin Oncol. 2019 Feb 20;37(6):471-480. doi: 10.1200/JCO.18.00690. Epub 2019 Jan 7.
Abstract/Text PURPOSE: Mantle cell lymphoma (MCL) is a B-cell lymphoma characterized by cyclin D1 expression. Autologous hematopoietic cell transplantation (AHCT) consolidation after induction chemotherapy is often used for eligible patients; however, the benefit remains uncertain in the rituximab era. Herein we retrospectively assessed the impact of AHCT consolidation on survival in a large cohort of transplantation-eligible patients age 65 years or younger.
PATIENTS AND METHODS: We retrospectively studied transplantation-eligible adults age 65 years or younger with newly diagnosed MCL treated between 2000 and 2015. The primary objective was to assess for improved progression-free survival (PFS) with AHCT consolidation and secondarily to assess for improved overall survival (OS). Cox multivariable regression analysis and propensity score-weighted (PSW) analysis were performed.
RESULTS: Data were collected from 25 medical centers for 1,254 patients; 1,029 met inclusion criteria. Median follow-up for the cohort was 76 months. Median PFS and OS were 62 and 139 months, respectively. On unadjusted analysis, AHCT was associated with improved PFS (75 v 44 months with v without AHCT, respectively; P < .01) and OS (147 v 115 months with v without AHCT, respectively; P < .05). On multivariable regression analysis, AHCT was associated with improved PFS (hazard ratio [HR], 0.54; 95% CI, 0.44 to 0.66; P < .01) and a trend toward improved OS (HR, 0.77; 95% CI, 0.59 to 1.01; P = .06). After PSW analysis, AHCT remained associated with improved PFS (HR, 0.70; 95% CI, 0.59 to 0.84; P < .05) but not improved OS (HR, 0.87; 95% CI, 0.69 to 1.1; P = .2).
CONCLUSION: In this large cohort of younger, transplantation-eligible patients with MCL, AHCT consolidation after induction was associated with significantly improved PFS but not OS after PSW analysis. Within the limitations of a retrospective analysis, our findings suggest that in younger, fit patients, AHCT consolidation may improve PFS.

PMID 30615550  J Clin Oncol. 2019 Feb 20;37(6):471-480. doi: 10.1200/J・・・
著者: Sattva S Neelapu, Frederick L Locke, Nancy L Bartlett, Lazaros J Lekakis, David B Miklos, Caron A Jacobson, Ira Braunschweig, Olalekan O Oluwole, Tanya Siddiqi, Yi Lin, John M Timmerman, Patrick J Stiff, Jonathan W Friedberg, Ian W Flinn, Andre Goy, Brian T Hill, Mitchell R Smith, Abhinav Deol, Umar Farooq, Peter McSweeney, Javier Munoz, Irit Avivi, Januario E Castro, Jason R Westin, Julio C Chavez, Armin Ghobadi, Krishna V Komanduri, Ronald Levy, Eric D Jacobsen, Thomas E Witzig, Patrick Reagan, Adrian Bot, John Rossi, Lynn Navale, Yizhou Jiang, Jeff Aycock, Meg Elias, David Chang, Jeff Wiezorek, William Y Go
雑誌名: N Engl J Med. 2017 Dec 28;377(26):2531-2544. doi: 10.1056/NEJMoa1707447. Epub 2017 Dec 10.
Abstract/Text BACKGROUND: In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy.
METHODS: In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments.
RESULTS: Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response.
CONCLUSIONS: In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).

PMID 29226797  N Engl J Med. 2017 Dec 28;377(26):2531-2544. doi: 10.10・・・
著者: Frederick L Locke, Armin Ghobadi, Caron A Jacobson, David B Miklos, Lazaros J Lekakis, Olalekan O Oluwole, Yi Lin, Ira Braunschweig, Brian T Hill, John M Timmerman, Abhinav Deol, Patrick M Reagan, Patrick Stiff, Ian W Flinn, Umar Farooq, Andre Goy, Peter A McSweeney, Javier Munoz, Tanya Siddiqi, Julio C Chavez, Alex F Herrera, Nancy L Bartlett, Jeffrey S Wiezorek, Lynn Navale, Allen Xue, Yizhou Jiang, Adrian Bot, John M Rossi, Jenny J Kim, William Y Go, Sattva S Neelapu
雑誌名: Lancet Oncol. 2019 Jan;20(1):31-42. doi: 10.1016/S1470-2045(18)30864-7. Epub 2018 Dec 2.
Abstract/Text BACKGROUND: Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7-17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study.
METHODS: ZUMA-1 is a single-arm, multicentre, registrational trial at 22 sites in the USA and Israel. Eligible patients were aged 18 years or older, and had histologically confirmed large B-cell lymphoma-including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma-according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue; refractory disease or relapsed after autologous stem-cell transplantation; an Eastern Cooperative Oncology Group performance status of 0 or 1; and had previously received an anti-CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy. Participants received one dose of axicabtagene ciloleucel on day 0 at a target dose of 2 × 106 CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m2 body-surface area) and cyclophosphamide (500 mg/m2 body-surface area) on days -5, -4, and -3. The primary endpoints were safety for phase 1 and the proportion of patients achieving an objective response for phase 2, and key secondary endpoints were overall survival, progression-free survival, and duration of response. Pre-planned activity and safety analyses were done per protocol. ZUMA-1 is registered with ClinicalTrials.gov, number NCT02348216. Although the registrational cohorts are closed, the trial remains open, and recruitment to extension cohorts with alternative endpoints is underway.
FINDINGS: Between May 19, 2015, and Sept 15, 2016, 119 patients were enrolled and 108 received axicabtagene ciloleucel across phases 1 and 2. As of the cutoff date of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27·1 months (IQR 25·7-28·8), 84 (83%) had an objective response, and 59 (58%) had a complete response. The median duration of response was 11·1 months (4·2-not estimable). The median overall survival was not reached (12·8-not estimable), and the median progression-free survival was 5·9 months (95% CI 3·3-15·0). 52 (48%) of 108 patients assessable for safety in phases 1 and 2 had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11%) patients, and grade 3 or worse neurological events in 35 (32%). Since the previous analysis at 1 year, additional serious adverse events were reported in four patients (grade 3 mental status changes, grade 4 myelodysplastic syndrome, grade 3 lung infection, and two episodes of grade 3 bacteraemia), none of which were judged to be treatment related. Two treatment-related deaths (due to haemophagocytic lymphohistiocytosis and cardiac arrest) were previously reported, but no new treatment-related deaths occurred during the additional follow-up.
INTERPRETATION: These 2-year follow-up data from ZUMA-1 suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma.
FUNDING: Kite and the Leukemia & Lymphoma Society Therapy Acceleration Program.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 30518502  Lancet Oncol. 2019 Jan;20(1):31-42. doi: 10.1016/S1470-・・・
著者: Stephen J Schuster, Michael R Bishop, Constantine S Tam, Edmund K Waller, Peter Borchmann, Joseph P McGuirk, Ulrich Jäger, Samantha Jaglowski, Charalambos Andreadis, Jason R Westin, Isabelle Fleury, Veronika Bachanova, S Ronan Foley, P Joy Ho, Stephan Mielke, John M Magenau, Harald Holte, Serafino Pantano, Lida B Pacaud, Rakesh Awasthi, Jufen Chu, Özlem Anak, Gilles Salles, Richard T Maziarz, JULIET Investigators
雑誌名: N Engl J Med. 2019 Jan 3;380(1):45-56. doi: 10.1056/NEJMoa1804980. Epub 2018 Dec 1.
Abstract/Text BACKGROUND: Patients with diffuse large B-cell lymphoma that is refractory to primary and second-line therapies or that has relapsed after stem-cell transplantation have a poor prognosis. The chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel targets and eliminates CD19-expressing B cells and showed efficacy against B-cell lymphomas in a single-center, phase 2a study.
METHODS: We conducted an international, phase 2, pivotal study of centrally manufactured tisagenlecleucel involving adult patients with relapsed or refractory diffuse large B-cell lymphoma who were ineligible for or had disease progression after autologous hematopoietic stem-cell transplantation. The primary end point was the best overall response rate (i.e., the percentage of patients who had a complete or partial response), as judged by an independent review committee.
RESULTS: A total of 93 patients received an infusion and were included in the evaluation of efficacy. The median time from infusion to data cutoff was 14 months (range, 0.1 to 26). The best overall response rate was 52% (95% confidence interval, 41 to 62); 40% of the patients had complete responses, and 12% had partial responses. Response rates were consistent across prognostic subgroups. At 12 months after the initial response, the rate of relapse-free survival was estimated to be 65% (79% among patients with a complete response). The most common grade 3 or 4 adverse events of special interest included cytokine release syndrome (22%), neurologic events (12%), cytopenias lasting more than 28 days (32%), infections (20%), and febrile neutropenia (14%). Three patients died from disease progression within 30 days after infusion. No deaths were attributed to tisagenlecleucel, cytokine release syndrome, or cerebral edema. No differences between response groups in tumor expression of CD19 or immune checkpoint-related proteins were found.
CONCLUSIONS: In this international study of CAR T-cell therapy in relapsed or refractory diffuse large B-cell lymphoma in adults, high rates of durable responses were produced with the use of tisagenlecleucel. (Funded by Novartis; JULIET ClinicalTrials.gov number, NCT02445248 .).

PMID 30501490  N Engl J Med. 2019 Jan 3;380(1):45-56. doi: 10.1056/NEJ・・・
著者: Bruce D Cheson, Neil Chua, Jiri Mayer, Greg Dueck, Marek Trněný, Kamal Bouabdallah, Nathan Fowler, Vincent Delwail, Oliver Press, Gilles Salles, John G Gribben, Anne Lennard, Pieternella J Lugtenburg, Günter Fingerle-Rowson, Federico Mattiello, Andrea Knapp, Laurie H Sehn
雑誌名: J Clin Oncol. 2018 Aug 1;36(22):2259-2266. doi: 10.1200/JCO.2017.76.3656. Epub 2018 Mar 27.
Abstract/Text Purpose To perform an updated analysis of the randomized phase III GADOLIN trial in patients with rituximab-refractory indolent non-Hodgkin lymphoma treated with obinutuzumab (GA101; G) and bendamustine (B). Patients and Methods Patients with histologically documented, rituximab-refractory CD20+ indolent non-Hodgkin lymphoma received G 1,000 mg (days 1, 8, and 15, cycle 1; day 1, cycles 2 to 6) plus B 90 mg/m2/d (days 1 and 2, all cycles) or B 120 mg/m2/d monotherapy. Patients who did not experience disease progression with G-B received G maintenance (1,000 mg every 2 months) for up to 2 years. The primary end point was progression-free survival (PFS). Results Of 413 randomly assigned patients (intention-to-treat [ITT]: G-B, n = 204; B monotherapy, n = 209), 335 had follicular lymphoma (FL; G-B, n = 164; B monotherapy, n = 171). After a median follow-up of 31.8 months, median PFS in ITT patients was 25.8 months (G-B) and 14.1 months (B monotherapy; hazard ratio [HR], 0.57; 95% CI, 0.44 to 0.73; P < .001). Overall survival (OS) also was prolonged (HR, 0.67; 95% CI, 0.47 to 0.96; P = .027). PFS and OS benefits were similar in patients with FL. Grade 3 to 5 adverse events (AEs) were reported by 148 (72.5%) and 133 (65.5%) patients in the G-B and B monotherapy arms, respectively, most commonly neutropenia (G-B, 34.8%; B monotherapy, 27.1%), thrombocytopenia (10.8% and 15.8%), anemia (7.4% and 10.8%), and infusion-related reactions (9.3% and 3.4%). Serious AEs occurred in 89 G-B patients (43.6%) and 75 B monotherapy patients (36.9%); fatal AEs occurred in 16 (7.8%) and 13 (6.4%), respectively. Conclusion This updated analysis confirms the PFS benefit for G-B shown in the primary analysis. A substantial OS benefit also was demonstrated in the ITT population and in patients with FL. Toxicity was similar for both treatments.

PMID 29584548  J Clin Oncol. 2018 Aug 1;36(22):2259-2266. doi: 10.1200・・・
著者: Laurie H Sehn, Neil Chua, Jiri Mayer, Gregg Dueck, Marek Trněný, Kamal Bouabdallah, Nathan Fowler, Vincent Delwail, Oliver Press, Gilles Salles, John Gribben, Anne Lennard, Pieternella J Lugtenburg, Natalie Dimier, Elisabeth Wassner-Fritsch, Günter Fingerle-Rowson, Bruce D Cheson
雑誌名: Lancet Oncol. 2016 Aug;17(8):1081-1093. doi: 10.1016/S1470-2045(16)30097-3. Epub 2016 Jun 23.
Abstract/Text BACKGROUND: Patients with indolent non-Hodgkin lymphoma who fail to achieve adequate disease control with rituximab-based treatment have few treatment options and a poor prognosis. We aimed to assess a combination of obinutuzumab (GA101), a novel glyco-engineered type II anti-CD20 monoclonal antibody, and bendamustine in this patient population.
METHODS: In this open-label, randomised, phase 3 study (GADOLIN), patients aged 18 years or older with histologically documented, CD20-positive indolent non-Hodgkin lymphoma refractory to rituximab were enrolled at 83 hospital and community sites in 14 countries in Europe, Asia, and North and Central America. Patients were randomly assigned (1:1) using a hierarchical dynamic randomisation scheme stratified by indolent non-Hodgkin lymphoma subtype, rituximab-refractory type, number of previous therapies, and geographical region, to receive induction treatment (six 28-day cycles) with obinutuzumab plus bendamustine or bendamustine monotherapy, both given intravenously. Obinutuzumab plus bendamustine dosing was obinutuzumab 1000 mg (days 1, 8, and 15, cycle 1; day 1, cycles 2-6) plus bendamustine 90 mg/m(2) per day (days 1 and 2, cycles 1-6), and bendamustine monotherapy dosing was 120 mg/m(2) per day (days 1 and 2, all cycles). Non-progressing patients in the obinutuzumab plus bendamustine group received obinutuzumab maintenance (1000 mg every 2 months) for up to 2 years. The primary endpoint was progression-free survival in all randomised patients, as assessed by an independent review committee. Safety was assessed in all patients who received any amount of obinutuzumab or bendamustine. This study is registered with ClinicalTrials.gov, number NCT01059630, and has stopped recruiting patients.
FINDINGS: Between April 15, 2010, and Sept 1, 2014, when the study was stopped after a pre-planned interim analysis, 396 patients were randomly assigned (194 to obinutuzumab plus bendamustine and 202 to bendamustine monotherapy). After a median follow-up time of 21·9 months (IQR 12·1-31·0) in the obinutuzumab plus bendamustine group and 20·3 months (9·5-29·7) in the bendamustine monotherapy group, progression-free survival was significantly longer with obinutuzumab plus bendamustine (median not reached [95% CI 22·5 months-not estimable]) than with bendamustine monotherapy (14·9 months [12·8-16·6]; hazard ratio 0·55 [95% CI 0·40-0·74]; p=0·0001). Grade 3-5 adverse events occurred in 132 (68%) of 194 patients in the obinutuzumab plus bendamustine group and in 123 (62%) of 198 patients in the bendamustine monotherapy group. The most frequent grade 3 or worse adverse events were neutropenia (64 [33%] in the obinutuzumab plus bendamustine group vs 52 [26%] in the bendamustine monotherapy group), thrombocytopenia (21 [11%] vs 32 [16%]), anaemia (15 [8%] vs 20 [10%]) and infusion-related reactions (21 [11%] vs 11 [6%]). Serious adverse events occurred in 74 patients (38%) in the obinutuzumab plus bendamustine group and in 65 patients (33%) in the bendamustine monotherapy group, and deaths due to adverse events occurred in 12 patients (6%) and 12 patients (6%), respectively. Three (25%) of 12 adverse event-related deaths in the obinutuzumab plus bendamustine group and five (42%) of 12 in the bendamustine monotherapy group were treatment related.
INTERPRETATION: Obinutuzumab plus bendamustine followed by obinutuzumab maintenance has improved efficacy over bendamustine monotherapy in rituximab-refractory patients with indolent non-Hodgkin lymphoma, with manageable toxicity, and is a new treatment option for patients who have relapsed after or are no longer responding to rituximab-based therapy.
FUNDING: F Hoffmann-La Roche Ltd.

Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID 27345636  Lancet Oncol. 2016 Aug;17(8):1081-1093. doi: 10.1016/S1・・・
著者: John P Leonard, Marek Trneny, Koji Izutsu, Nathan H Fowler, Xiaonan Hong, Jun Zhu, Huilai Zhang, Fritz Offner, Adriana Scheliga, Grzegorz S Nowakowski, Antonio Pinto, Francesca Re, Laura Maria Fogliatto, Phillip Scheinberg, Ian W Flinn, Claudia Moreira, José Cabeçadas, David Liu, Stacey Kalambakas, Pierre Fustier, Chengqing Wu, John G Gribben, AUGMENT Trial Investigators
雑誌名: J Clin Oncol. 2019 May 10;37(14):1188-1199. doi: 10.1200/JCO.19.00010. Epub 2019 Mar 21.
Abstract/Text PURPOSE: Patients with indolent non-Hodgkin lymphoma typically respond well to first-line immunochemotherapy. At relapse, single-agent rituximab is commonly administered. Data suggest the immunomodulatory agent lenalidomide could increase the activity of rituximab.
METHODS: A phase III, multicenter, randomized trial of lenalidomide plus rituximab versus placebo plus rituximab was conducted in patients with relapsed and/or refractory follicular or marginal zone lymphoma. Patients received lenalidomide or placebo for 12 cycles plus rituximab once per week for 4 weeks in cycle 1 and day 1 of cycles 2 through 5. The primary end point was progression-free survival per independent radiology review.
RESULTS: A total of 358 patients were randomly assigned to lenalidomide plus rituximab (n = 178) or placebo plus rituximab (n = 180). Infections (63% v 49%), neutropenia (58% v 23%), and cutaneous reactions (32% v 12%) were more common with lenalidomide plus rituximab. Grade 3 or 4 neutropenia (50% v 13%) and leukopenia (7% v 2%) were higher with lenalidomide plus rituximab; no other grade 3 or 4 adverse event differed by 5% or more between groups. Progression-free survival was significantly improved for lenalidomide plus rituximab versus placebo plus rituximab, with a hazard ratio of 0.46 (95% CI, 0.34 to 0.62; P < .001) and median duration of 39.4 months (95% CI, 22.9 months to not reached) versus 14.1 months (95% CI, 11.4 to 16.7 months), respectively.
CONCLUSION: Lenalidomide improved efficacy of rituximab in patients with recurrent indolent lymphoma, with an acceptable safety profile.

PMID 30897038  J Clin Oncol. 2019 May 10;37(14):1188-1199. doi: 10.120・・・
著者: Martin Dreyling, Wojciech Jurczak, Mats Jerkeman, Rodrigo Santucci Silva, Chiara Rusconi, Marek Trneny, Fritz Offner, Dolores Caballero, Cristina Joao, Mathias Witzens-Harig, Georg Hess, Isabelle Bence-Bruckler, Seok-Goo Cho, John Bothos, Jenna D Goldberg, Christopher Enny, Shana Traina, Sriram Balasubramanian, Nibedita Bandyopadhyay, Steven Sun, Jessica Vermeulen, Aleksandra Rizo, Simon Rule
雑誌名: Lancet. 2016 Feb 20;387(10020):770-8. doi: 10.1016/S0140-6736(15)00667-4. Epub 2015 Dec 7.
Abstract/Text BACKGROUND: Mantle-cell lymphoma is an aggressive B-cell lymphoma with a poor prognosis. Both ibrutinib and temsirolimus have shown single-agent activity in patients with relapsed or refractory mantle-cell lymphoma. We undertook a phase 3 study to assess the efficacy and safety of ibrutinib versus temsirolimus in relapsed or refractory mantle-cell lymphoma.
METHODS: This randomised, open-label, multicentre, phase 3 clinical trial enrolled patients with relapsed or refractory mantle-cell lymphoma confirmed by central pathology in 21 countries who had received one or more rituximab-containing treatments. Patients were stratified by previous therapy and simplified mantle-cell lymphoma international prognostic index score, and were randomly assigned with a computer-generated randomisation schedule to receive daily oral ibrutinib 560 mg or intravenous temsirolimus (175 mg on days 1, 8, and 15 of cycle 1; 75 mg on days 1, 8, and 15 of subsequent 21-day cycles). Randomisation was balanced by using randomly permuted blocks. The primary efficacy endpoint was progression-free survival assessed by a masked independent review committee with the primary hypothesis that ibrutinib compared with temsirolimus significantly improves progression-free survival. The analysis followed the intention-to-treat principle. The trial is ongoing and is registered with ClinicalTrials.gov (number NCT01646021) and with the EU Clinical Trials Register, EudraCT (number 2012-000601-74).
FINDINGS: Between Dec 10, 2012, and Nov 26, 2013, 280 patients were randomised to ibrutinib (n=139) or temsirolimus (n=141). Primary efficacy analysis showed significant improvement in progression-free survival (p<0·0001) for patients treated with ibrutinib versus temsirolimus (hazard ratio 0·43 [95% CI 0·32-0·58]; median progression-free survival 14·6 months [95% CI 10·4-not estimable] vs 6·2 months [4·2-7·9], respectively). Ibrutinib was better tolerated than temsirolimus, with grade 3 or higher treatment-emergent adverse events reported for 94 (68%) versus 121 (87%) patients, and fewer discontinuations of study medication due to adverse events for ibrutinib versus temsirolimus (9 [6%] vs 36 [26%]).
INTERPRETATION: Ibrutinib treatment resulted in significant improvement in progression-free survival and better tolerability versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma. These data lend further support to the positive benefit-risk ratio for ibrutinib in relapsed or refractory mantle-cell lymphoma.
FUNDING: Janssen Research & Development, LLC.

Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID 26673811  Lancet. 2016 Feb 20;387(10020):770-8. doi: 10.1016/S014・・・
著者: John C Byrd, Jennifer R Brown, Susan O'Brien, Jacqueline C Barrientos, Neil E Kay, Nishitha M Reddy, Steven Coutre, Constantine S Tam, Stephen P Mulligan, Ulrich Jaeger, Steve Devereux, Paul M Barr, Richard R Furman, Thomas J Kipps, Florence Cymbalista, Christopher Pocock, Patrick Thornton, Federico Caligaris-Cappio, Tadeusz Robak, Julio Delgado, Stephen J Schuster, Marco Montillo, Anna Schuh, Sven de Vos, Devinder Gill, Adrian Bloor, Claire Dearden, Carol Moreno, Jeffrey J Jones, Alvina D Chu, Maria Fardis, Jesse McGreivy, Fong Clow, Danelle F James, Peter Hillmen, RESONATE Investigators
雑誌名: N Engl J Med. 2014 Jul 17;371(3):213-23. doi: 10.1056/NEJMoa1400376. Epub 2014 May 31.
Abstract/Text BACKGROUND: In patients with chronic lymphoid leukemia (CLL) or small lymphocytic lymphoma (SLL), a short duration of response to therapy or adverse cytogenetic abnormalities are associated with a poor outcome. We evaluated the efficacy of ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, in patients at risk for a poor outcome.
METHODS: In this multicenter, open-label, phase 3 study, we randomly assigned 391 patients with relapsed or refractory CLL or SLL to receive daily ibrutinib or the anti-CD20 antibody ofatumumab. The primary end point was the duration of progression-free survival, with the duration of overall survival and the overall response rate as secondary end points.
RESULTS: At a median follow-up of 9.4 months, ibrutinib significantly improved progression-free survival; the median duration was not reached in the ibrutinib group (with a rate of progression-free survival of 88% at 6 months), as compared with a median of 8.1 months in the ofatumumab group (hazard ratio for progression or death in the ibrutinib group, 0.22; P<0.001). Ibrutinib also significantly improved overall survival (hazard ratio for death, 0.43; P=0.005). At 12 months, the overall survival rate was 90% in the ibrutinib group and 81% in the ofatumumab group. The overall response rate was significantly higher in the ibrutinib group than in the ofatumumab group (42.6% vs. 4.1%, P<0.001). An additional 20% of ibrutinib-treated patients had a partial response with lymphocytosis. Similar effects were observed regardless of whether patients had a chromosome 17p13.1 deletion or resistance to purine analogues. The most frequent nonhematologic adverse events were diarrhea, fatigue, pyrexia, and nausea in the ibrutinib group and fatigue, infusion-related reactions, and cough in the ofatumumab group.
CONCLUSIONS: Ibrutinib, as compared with ofatumumab, significantly improved progression-free survival, overall survival, and response rate among patients with previously treated CLL or SLL. (Funded by Pharmacyclics and Janssen; RESONATE ClinicalTrials.gov number, NCT01578707.).

PMID 24881631  N Engl J Med. 2014 Jul 17;371(3):213-23. doi: 10.1056/N・・・
著者: H Miles Prince, Youn H Kim, Steven M Horwitz, Reinhard Dummer, Julia Scarisbrick, Pietro Quaglino, Pier Luigi Zinzani, Pascal Wolter, Jose A Sanches, Pablo L Ortiz-Romero, Oleg E Akilov, Larisa Geskin, Judith Trotman, Kerry Taylor, Stephane Dalle, Michael Weichenthal, Jan Walewski, David Fisher, Brigitte Dréno, Rudolf Stadler, Tatyana Feldman, Timothy M Kuzel, Yinghui Wang, Maria Corinna Palanca-Wessels, Erin Zagadailov, William L Trepicchio, Wenwen Zhang, Hui-Min Lin, Yi Liu, Dirk Huebner, Meredith Little, Sean Whittaker, Madeleine Duvic, ALCANZA study group
雑誌名: Lancet. 2017 Aug 5;390(10094):555-566. doi: 10.1016/S0140-6736(17)31266-7. Epub 2017 Jun 7.
Abstract/Text BACKGROUND: Cutaneous T-cell lymphomas are rare, generally incurable, and associated with reduced quality of life. Present systemic therapies rarely provide reliable and durable responses. We aimed to assess efficacy and safety of brentuximab vedotin versus conventional therapy for previously treated patients with CD30-positive cutaneous T-cell lymphomas.
METHODS: In this international, open-label, randomised, phase 3, multicentre trial, we enrolled adult patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma who had been previously treated. Patients were enrolled across 52 centres in 13 countries. Patients were randomly assigned (1:1) centrally by an interactive voice and web response system to receive intravenous brentuximab vedotin 1·8 mg/kg once every 3 weeks, for up to 16 3-week cycles, or physician's choice (oral methotrexate 5-50 mg once per week or oral bexarotene 300 mg/m2 once per day) for up to 48 weeks. The primary endpoint was the proportion of patients in the intention-to-treat population achieving an objective global response lasting at least 4 months per independent review facility. Safety analyses were done in all patients who received at least one dose of study drug. This trial was registered with ClinicalTrials.gov, number NCT01578499.
FINDINGS: Between Aug 13, 2012, and July 31, 2015, 131 patients were enrolled and randomly assigned to a group (66 to brentuximab vedotin and 65 to physician's choice), with 128 analysed in the intention-to-treat population (64 in each group). At a median follow-up of 22·9 months (95% CI 18·4-26·1), the proportion of patients achieving an objective global response lasting at least 4 months was 56·3% (36 of 64 patients) with brentuximab vedotin versus 12·5% (eight of 64) with physician's choice, resulting in a between-group difference of 43·8% (95% CI 29·1-58·4; p<0·0001). Grade 3-4 adverse events were reported in 27 (41%) of 66 patients in the brentuximab vedotin group and 29 (47%) of 62 patients in the physician's choice group. Peripheral neuropathy was seen in 44 (67%) of 66 patients in the brentuximab vedotin group (n=21 grade 2, n=6 grade 3) and four (6%) of 62 patients in the physician's choice group. One of the four on-treatment deaths was deemed by the investigator to be treatment-related in the brentuximab vedotin group; no on-treatment deaths were reported in the physician's choice group.
INTERPRETATION: Significant improvement in objective response lasting at least 4 months was seen with brentuximab vedotin versus physician's choice of methotrexate or bexarotene.
FUNDING: Millennium Pharmaceuticals Inc (a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd), Seattle Genetics Inc.

Copyright © 2017 Elsevier Ltd. All rights reserved.
PMID 28600132  Lancet. 2017 Aug 5;390(10094):555-566. doi: 10.1016/S01・・・
著者: Angelo Rosolen, Sherrie L Perkins, C Ross Pinkerton, R Paul Guillerman, John T Sandlund, Catherine Patte, Alfred Reiter, Mitchell S Cairo
雑誌名: J Clin Oncol. 2015 Jun 20;33(18):2112-8. doi: 10.1200/JCO.2014.59.7203. Epub 2015 May 4.
Abstract/Text PURPOSE: Treatment and prognosis of pediatric non-Hodgkin lymphoma (NHL) have improved dramatically in the last 30 years. However, the St Jude NHL staging classification for pediatric NHL was developed more than 35 years ago. The most recent Lugano lymphoma staging classification focused on adult lymphoma. Furthermore, major limitations of the current pediatric NHL staging classification include lack of consideration of new distinct pediatric NHL histologic entities; absence of recognition of frequent skin, bone, kidney, ovarian, and other organ involvement; and lack of newer precise methods to detect bone marrow and CNS involvement, minimal disease quantification, and highly sensitive imaging technologies.
METHODS: An international multidisciplinary expert panel convened in Frankfurt, Germany, in 2009 at the Third International Childhood, Adolescent and Young Adult NHL Symposium to develop a revised international pediatric NHL staging system (IPNHLSS), addressing limitations of the current pediatric NHL staging system and creating a revised classification. Evidence-based disease distribution and behavior were reviewed from multiple pediatric cooperative group NHL studies.
RESULTS: A revised IPNHLSS was developed incorporating new histologic entities, extranodal dissemination, improved diagnostic methods, and advanced imaging technology.
CONCLUSION: This revised IPNHLSS will facilitate more precise staging for children and adolescents with NHL and facilitate comparisons of efficacy across different treatment strategies, various institutions, multicenter trials, and cooperative groups by allowing for reproducible pediatric-based staging at diagnosis and relapse.

© 2015 by American Society of Clinical Oncology.
PMID 25940716  J Clin Oncol. 2015 Jun 20;33(18):2112-8. doi: 10.1200/J・・・
著者: Kazuyuki Shimada, Motoko Yamaguchi, Yoshiko Atsuta, Kosei Matsue, Keijiro Sato, Shigeru Kusumoto, Hirokazu Nagai, Jun Takizawa, Noriko Fukuhara, Koji Nagafuji, Kana Miyazaki, Eiichi Ohtsuka, Masataka Okamoto, Yasumasa Sugita, Toshiki Uchida, Satoshi Kayukawa, Atsushi Wake, Daisuke Ennishi, Yukio Kondo, Tohru Izumi, Yoshihiro Kin, Kunihiro Tsukasaki, Daigo Hashimoto, Masaaki Yuge, Atsumi Yanagisawa, Yachiyo Kuwatsuka, Satoko Shimada, Yasufumi Masaki, Nozomi Niitsu, Hitoshi Kiyoi, Ritsuro Suzuki, Takashi Tokunaga, Shigeo Nakamura, Tomohiro Kinoshita
雑誌名: Lancet Oncol. 2020 Apr;21(4):593-602. doi: 10.1016/S1470-2045(20)30059-0. Epub 2020 Mar 11.
Abstract/Text BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease for which there is no available standard treatment. We aimed to ascertain the safety and activity of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with high-dose methotrexate and intrathecal chemotherapy as CNS-oriented therapy for patients with previously untreated IVLBCL.
METHODS: PRIMEUR-IVL is a multicentre, single-arm, phase 2 trial at 22 hospitals in Japan. Eligible patients had untreated histologically confirmed IVLBCL, were aged 20-79 years, had an Eastern Cooperative Group performance status of 0-3, and had no apparent CNS involvement at diagnosis. Patients received three cycles of R-CHOP (rituximab 375 mg/m2 intravenously on day 1 [except cycle one, which was on day 8]; cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2·0 mg] intravenously on day 1 of cycle one and day 2 of cycles two and three; and prednisolone 100 mg/day orally on days 1-5 of cycle one and days 2-6 of cycles two and three) followed by two cycles of rituximab with high-dose methotrexate (3·5 g/m2 intravenously on day 2 of cycles four and five) every 2 weeks and three additional cycles of R-CHOP. Intrathecal chemotherapy (methotrexate 15 mg, cytarabine 40 mg, and prednisolone 10 mg) was administered four times during the R-CHOP phase. The primary endpoint was 2-year progression-free survival. Efficacy analyses were done in all enrolled patients; safety analyses were done in all enrolled and treated patients. The trial is registered in the UMIN Clinical Trials Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165); the trial is ongoing for long-term follow-up.
FINDINGS: Between June 16, 2011, and July 21, 2016, 38 patients were enrolled, of whom 37 were eligible; one patient was excluded because of a history of testicular lymphoma. Median follow-up was 3·9 years (IQR 2·5-5·5). 2-year progression-free survival was 76% (95% CI 58-87). The most frequent adverse events of grade 3-4 were neutropenia and leucocytopenia, which were reported in all 38 (100%) patients. Serious adverse events were hypokalaemia, febrile neutropenia with hypotension, hypertension, and intracerebral haemorrhage (reported in one [3%] patient each). No treatment-related deaths occurred during protocol treatment.
INTERPRETATION: R-CHOP combined with rituximab and high-dose methotrexate plus intrathecal chemotherapy is a safe and active treatment for patients with IVLBCL without apparent CNS involvement at diagnosis, and this regimen warrants future investigation.
FUNDING: The Japan Agency for Medical Research and Development, the Center for Supporting Hematology-Oncology Trials, and the National Cancer Center.

Copyright © 2020 Elsevier Ltd. All rights reserved.
PMID 32171071  Lancet Oncol. 2020 Apr;21(4):593-602. doi: 10.1016/S147・・・

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