今日の臨床サポート

ホジキンリンパ腫

著者: 山本一仁 愛知県がんセンター

監修: 木崎昌弘 埼玉医科大学総合医療センター

著者校正済:2022/11/24
現在監修レビュー中
参考ガイドライン:
  1. 日本血液学会:造血器腫瘍診療ガイドライン 2018年版補訂版
患者向け説明資料

概要・推奨   

  1. 限局期ホジキンリンパ腫は予後因子の有無により予後良好群と予後不良群に分類する必要がある(推奨度2)
  1. 限局期ホジキンリンパ腫は放射線単独(STLIなどの拡大照射野)で治療するべきではない(推奨度4)
  1. 限局期ホジキンリンパ腫の標準療法は化学療法と放射線療法(IFRT)の併用のCMTである(推奨度1)
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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。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※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、実際の保険適応の査定において保険適応及び保険適応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応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:
山本一仁 : 未申告[2022年]
監修:木崎昌弘 : 講演料(武田薬品工業,ヤンセンファーマ,小野薬品工業,ブリストル・マイヤーズスクイブ),研究費・助成金など(武田薬品工業),奨学(奨励)寄付など(協和キリン,旭化成ファーマ,第一三共,中外製薬,日本新薬,武田薬品工業)[2022年]

改訂のポイント:
  1. 定期的レビューおよび日本血液学会造血器腫瘍ガイドラインに基づき、bulky腫瘤のない限局期古典的ホジキンリンパ腫の治療選択と進行期古典的ホジキンリンパ腫の標準治療の改訂を行った。

病態・疫学・診察

疾患情報  
  1. ホジキンリンパ腫とは、Hodgkin/Reed-Sternberg細胞やlymphocyte predominant細胞などの腫瘍細胞の増生を特徴とするリンパ腫で、全悪性リンパ腫の約8~10%程度を占める疾患である。WHO分類では、結節性リンパ球優位型ホジキンリンパ腫と古典的ホジキンリンパ腫に大別される。腫瘍細胞の起源は両病型ともBリンパ球である。
  1. 臨床症状はリンパ節の腫大が最も頻度として多いが、不明熱、体重減少、寝汗、痒疹なども認められる。
  1. Ann Arbor病期分類で臨床病期(I-IV)が決定される。(表<図表>
  1. 比較的予後は良好であり、I、II期では80%程度、III、IV期においては50%前後の20年生存が期待できる。
  1. I、II期は限局期とされコース数を短縮した化学療法と放射線療法の併用、またはbulky腫瘤がない場合は放射線療法を省略した化学療法を行う。
  1. III、IV期は進行期とされ化学療法を行う。
  1. 長期生存が期待できる疾患であり、化学療法および放射線療法の晩期毒性が問題となる。
問診・診察のポイント  
  1. 病変の評価 ⇒(問診:いつからリンパ節の腫大が認められたか。増大のスピード。診察:全身の表在リンパ節の評価。扁桃腺の腫大の有無。腫大リンパ節による圧迫症状の有無。肝脾腫の有無)
  1. 全身状態 ⇒(問診:38℃を超える発熱、6カ月以内の10%以上の体重減少、寝汗の有無。診察:Performance statusの評価。貧血の有無。痒疹の有無)

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

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文献 

M Tubiana, M Henry-Amar, P Carde, J M Burgers, M Hayat, E Van der Schueren, E M Noordijk, A Tanguy, J H Meerwaldt, J Thomas
Toward comprehensive management tailored to prognostic factors of patients with clinical stages I and II in Hodgkin's disease. The EORTC Lymphoma Group controlled clinical trials: 1964-1987.
Blood. 1989 Jan;73(1):47-56.
Abstract/Text From 1964 to 1987, the EORTC Lymphoma Group conducted four consecutive controlled clinical trials on clinical stages I and II Hodgkin's disease in which 1,579 patients were entered. From the onset the main aim of these trials was to identify the subsets of patients who could be treated safely by regional radiotherapy (RT). Therefore, several prognostic indicators were prospectively registered and progressively used in the trial protocols for the delineation of the favorable and unfavorable subgroups as soon as they were recognized of high predictive value. In the H2 trial (1972 to 1976), the histologic subtype was the only variable taken into account for the therapeutic strategy and the staging laparotomy findings were found to be of prognostic value only in patients with favorable prognostic indicators. In the H5 trial (1977 to 1982), patients were subdivided into two subgroups according to six prognostic indicators. Patients with favorable features were submitted to a staging laparotomy (lap); lap negative patients were randomized between mantle field RT and mantle field plus paraaortic RT. Disease free survival (DFS) and total survival (S) were similar in the two arms. Among patients with unfavorable features, DFS and S were significantly higher in the arm treated by combination of mechlorethamine, vincristine, procarbazine, prednisone (MOPP) chemotherapy (CT) and RT than in the arm treated by total nodal irradiation. Nevertheless, in patients below the age of 40, the overall survival rates were equivalent in the two arms. In the H6 trial, the delineation of the favorable subgroup was based on (a) absence of systemic symptoms and elevated ESR, (b) no more than one or two lymph node areas involved. The aim of the study was to assess the impact on survival of a therapeutic strategy including staging laparotomy. At a 4-year follow-up, no difference in survival was evidenced. In patients with unfavorable prognostic indicators, 3 MOPP-RT-3 MOPP were compared with 3 ABVD-RT-3 ABVD. From H1 to H5 trials, the proportion of patients having received CT during the course of the disease gradually decreased; the data suggest that a further reduction in the proportion of patients aggressively treated is conceptually possible. On the basis of the prognostic factors identified, one can delineate three subsets of patients and modulate toxic cost of the initial treatment according to the characteristics of these subsets. In the most favorable subgroup, RT alone produces high survival and CT is not justified.(ABSTRACT TRUNCATED AT 400 WORDS)

PMID 2462943
Christophe Fermé, Houchingue Eghbali, Jacobus H Meerwaldt, Chantal Rieux, Jacques Bosq, Françoise Berger, Théodore Girinsky, Pauline Brice, Mars B van't Veer, Jan A Walewski, Pierre Lederlin, Umberto Tirelli, Patrice Carde, Eric Van den Neste, Emmanuel Gyan, Mathieu Monconduit, Marine Diviné, John M M Raemaekers, Gilles Salles, Evert M Noordijk, Geert-Jan Creemers, Jean Gabarre, Anton Hagenbeek, Oumédaly Reman, Michel Blanc, José Thomas, Brigitte Vié, Johanna C Kluin-Nelemans, Fernando Viseu, Joke W Baars, Philip Poortmans, Pieternella J Lugtenburg, Christian Carrie, Jérôme Jaubert, Michel Henry-Amar, EORTC-GELA H8 Trial
Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease.
N Engl J Med. 2007 Nov 8;357(19):1916-27. doi: 10.1056/NEJMoa064601.
Abstract/Text BACKGROUND: Treatment of early-stage Hodgkin's disease is usually tailored in line with prognostic factors that allow for reductions in the amount of chemotherapy and extent of radiotherapy required for a possible cure.
METHODS: From 1993 to 1999, we identified 1538 patients (age, 15 to 70 years) who had untreated stage I or II supradiaphragmatic Hodgkin's disease with favorable prognostic features (the H8-F trial) or unfavorable features (the H8-U trial). In the H8-F trial, we compared three cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) combined with doxorubicin, bleomycin, and vinblastine (ABV) plus involved-field radiotherapy with subtotal nodal radiotherapy alone (reference group). In the H8-U trial, we compared three regimens: six cycles of MOPP-ABV plus involved-field radiotherapy (reference group), four cycles of MOPP-ABV plus involved-field radiotherapy, and four cycles of MOPP-ABV plus subtotal nodal radiotherapy.
RESULTS: The median follow-up was 92 months. In the H8-F trial, the estimated 5-year event-free survival rate was significantly higher after three cycles of MOPP-ABV plus involved-field radiotherapy than after subtotal nodal radiotherapy alone (98% vs. 74%, P<0.001). The 10-year overall survival estimates were 97% and 92%, respectively (P=0.001). In the H8-U trial, the estimated 5-year event-free survival rates were similar in the three treatment groups: 84% after six cycles of MOPP-ABV plus involved-field radiotherapy, 88% after four cycles of MOPP-ABV plus involved-field radiotherapy, and 87% after four cycles of MOPP-ABV plus subtotal nodal radiotherapy. The 10-year overall survival estimates were 88%, 85%, and 84%, respectively.
CONCLUSIONS: Chemotherapy plus involved-field radiotherapy should be the standard treatment for Hodgkin's disease with favorable prognostic features. In patients with unfavorable features, four courses of chemotherapy plus involved-field radiotherapy should be the standard treatment. (ClinicalTrials.gov number, NCT00379041 [ClinicalTrials.gov].).

Copyright 2007 Massachusetts Medical Society.
PMID 17989384
Andreas Engert, Jeremy Franklin, Hans Theodor Eich, Corinne Brillant, Susanne Sehlen, Claudio Cartoni, Richard Herrmann, Michael Pfreundschuh, Markus Sieber, Hans Tesch, Astrid Franke, Peter Koch, Maike de Wit, Ursula Paulus, Dirk Hasenclever, Markus Loeffler, Rolf-Peter Müller, Hans Konrad Müller-Hermelink, Eckhart Dühmke, Volker Diehl
Two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine plus extended-field radiotherapy is superior to radiotherapy alone in early favorable Hodgkin's lymphoma: final results of the GHSG HD7 trial.
J Clin Oncol. 2007 Aug 10;25(23):3495-502. doi: 10.1200/JCO.2006.07.0482. Epub 2007 Jul 2.
Abstract/Text PURPOSE: To investigate whether combined-modality treatment (CMT) with two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by extended-field radiotherapy (EF-RT) is superior to EF-RT alone in patients with early favorable Hodgkin's lymphoma (HL).
PATIENTS AND METHODS: Between 1993 and 1998, 650 patients with newly diagnosed, histology-proven HL in clinical stages IA to IIB without risk factors were enrolled onto this multicenter study and randomly assigned to receive 30 Gy EF-RT plus 10 Gy to the involved field (arm A) or two cycles of ABVD followed by the same radiotherapy (arm B). Results At a median observation time of 87 months, there was no difference between treatment arms in terms of complete response rate (arm A, 95%; arm B, 94%) and overall survival (at 7 years: arm A, 92%; arm B, 94%; P = .43). However, freedom from treatment failure was significantly different, with 7-year rates of 67% in arm A (95% CI, 61% to 73%) and 88% in arm B (95% CI, 84% to 92%; P CONCLUSION: CMT consisting of two cycles of ABVD plus EF-RT is more effective than EF-RT alone.

PMID 17606976
Ralph M Meyer, Mary K Gospodarowicz, Joseph M Connors, Robert G Pearcey, Woodrow A Wells, Jane N Winter, Sandra J Horning, A Rashid Dar, Chaim Shustik, Douglas A Stewart, Michael Crump, Marina S Djurfeldt, Bingshu E Chen, Lois E Shepherd, NCIC Clinical Trials Group, Eastern Cooperative Oncology Group
ABVD alone versus radiation-based therapy in limited-stage Hodgkin's lymphoma.
N Engl J Med. 2012 Feb 2;366(5):399-408. doi: 10.1056/NEJMoa1111961. Epub 2011 Dec 11.
Abstract/Text BACKGROUND: Chemotherapy plus radiation treatment is effective in controlling stage IA or IIA nonbulky Hodgkin's lymphoma in 90% of patients but is associated with late treatment-related deaths. Chemotherapy alone may improve survival because it is associated with fewer late deaths.
METHODS: We randomly assigned 405 patients with previously untreated stage IA or IIA nonbulky Hodgkin's lymphoma to treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) alone or to treatment with subtotal nodal radiation therapy, with or without ABVD therapy. Patients in the ABVD-only group, both those with a favorable risk profile and those with an unfavorable risk profile, received four to six cycles of ABVD. Among those assigned to subtotal nodal radiation therapy, patients who had a favorable risk profile received subtotal nodal radiation therapy alone and patients with an unfavorable risk profile received two cycles of ABVD plus subtotal nodal radiation therapy. The primary end point was 12-year overall survival.
RESULTS: The median length of follow-up was 11.3 years. At 12 years, the rate of overall survival was 94% among those receiving ABVD alone, as compared with 87% among those receiving subtotal nodal radiation therapy (hazard ratio for death with ABVD alone, 0.50; 95% confidence interval [CI], 0.25 to 0.99; P=0.04); the rates of freedom from disease progression were 87% and 92% in the two groups, respectively (hazard ratio for disease progression, 1.91; 95% CI, 0.99 to 3.69; P=0.05); and the rates of event-free survival were 85% and 80%, respectively (hazard ratio for event, 0.88; 95% CI, 0.54 to 1.43; P=0.60). Among the patients randomly assigned to ABVD alone, 6 patients died from Hodgkin's lymphoma or an early treatment complication and 6 died from another cause; among those receiving radiation therapy, 4 deaths were related to Hodgkin's lymphoma or early toxic effects from the treatment and 20 were related to another cause.
CONCLUSIONS: Among patients with Hodgkin's lymphoma, ABVD therapy alone, as compared with treatment that included subtotal nodal radiation therapy, was associated with a higher rate of overall survival owing to a lower rate of death from other causes. (Funded by the Canadian Cancer Society and the National Cancer Institute; HD.6 ClinicalTrials.gov number, NCT00002561.).

PMID 22149921
Andrea Gallamini, Martin Hutchings, Luigi Rigacci, Lena Specht, Francesco Merli, Mads Hansen, Caterina Patti, Annika Loft, Francesco Di Raimondo, Francesco D'Amore, Alberto Biggi, Umberto Vitolo, Caterina Stelitano, Rosario Sancetta, Livio Trentin, Stefano Luminari, Emilio Iannitto, Simonetta Viviani, Ivana Pierri, Alessandro Levis
Early interim 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography is prognostically superior to international prognostic score in advanced-stage Hodgkin's lymphoma: a report from a joint Italian-Danish study.
J Clin Oncol. 2007 Aug 20;25(24):3746-52. doi: 10.1200/JCO.2007.11.6525. Epub 2007 Jul 23.
Abstract/Text PURPOSE: Starting from November 2001, 260 newly diagnosed patients with Hodgkin's lymphoma (HL) were consecutively enrolled in parallel Italian and Danish prospective trials to evaluate the prognostic role of an early interim 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) scan and the International Prognostic Score (IPS) in advanced HL, treated with conventional ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) therapy.
PATIENTS AND METHODS: Most patients (n = 190) presented with advanced disease (stages IIB through IVB), whereas 70 presented in stage IIA with adverse prognostic factors. All but 11 patients were treated with standard ABVD therapy followed by consolidation radiotherapy in case of bulky presentation or residual tumor mass. Conventional radiologic staging was performed at baseline. FDG-PET scan was performed at baseline and after two courses of ABVD (PET-2). No treatment change was allowed on the basis of the PET-2 results.
RESULTS: After a median follow-up of 2.19 years (range, 0.32 to 5.18 years), 205 patients were in continued complete remission and two patients were in partial remission. Forty-three patients progressed during therapy or immediately after, whereas 10 patients relapsed. The 2-year progression-free survival for patients with positive PET-2 results was 12.8% and for patients with negative PET-2 results was 95.0% (P < .0001). In univariate analysis, the treatment outcome was significantly associated with PET-2 (P < .0001), stage IV (P < .0001), WBC more than 15,000 (P < .0001), lymphopenia (P < .001), IPS as a continuous variable (P < .0001), extranodal involvement (P < .0001), and bulky disease (P = .012). In multivariate analyses, only PET-2 turned out to be significant (P < .0001).
CONCLUSION: PET-2 overshadows the prognostic value of IPS and emerges as the single most important tool for planning of risk-adapted treatment in advanced HL.

PMID 17646666
Teruhiko Terasawa, Joseph Lau, Stéphane Bardet, Olivier Couturier, Tomomitsu Hotta, Martin Hutchings, Takashi Nihashi, Hirokazu Nagai
Fluorine-18-fluorodeoxyglucose positron emission tomography for interim response assessment of advanced-stage Hodgkin's lymphoma and diffuse large B-cell lymphoma: a systematic review.
J Clin Oncol. 2009 Apr 10;27(11):1906-14. doi: 10.1200/JCO.2008.16.0861. Epub 2009 Mar 9.
Abstract/Text PURPOSE: To systematically review the prognostic accuracy of fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) for interim response assessment of patients with untreated advanced-stage Hodgkin's lymphoma (HL) or diffuse large B-cell lymphoma (DLBCL).
METHODS: MEDLINE, EMBASE, SCOPUS, and Biologic Abstracts were searched for relevant studies. Two assessors independently reviewed studies for inclusion and extracted data. Relevant unpublished data were requested from the investigators if unavailable from publications. A meta-analysis of the prognostic accuracy was performed.
RESULTS: Thirteen studies involving 360 advanced-stage HL patients and 311 DLBCL patients met our inclusion criteria. Advanced-stage HL studies included few unfavorable-risk patients. DLBCL studies were heterogeneous. FDG-PET had an overall sensitivity of 0.81 (95% CI, 0.72 to 0.89) and a specificity of 0.97 (95% CI, 0.94 to 0.99) for advanced-stage HL, and a sensitivity of 0.78 (95% CI, 0.64 to 0.87) and a specificity of 0.87 (95% CI, 0.75 to 0.93) for DLBCL. Meta-regression and subgroup analyses did not identify factors that affect prognostic accuracy.
CONCLUSION: For low- to intermediate-risk advanced-stage HL, FDG-PET performed after a few cycles of standard chemotherapy seems to be a reliable prognostic test to identify poor responders, warranting prospective studies to assess PET-based treatment strategies. For DLBCL, no reliable conclusions can be drawn due to heterogeneity. Interim PET remains an unproven test for routine clinical practice. Its use should be reserved for research settings where treatment regimens and imaging conditions are standardized.

PMID 19273713
Michel Meignan, Andrea Gallamini, Corinne Haioun, Aaron Polliack
Report on the Second International Workshop on interim positron emission tomography in lymphoma held in Menton, France, 8-9 April 2010.
Leuk Lymphoma. 2010 Dec;51(12):2171-80. doi: 10.3109/10428194.2010.529208. Epub 2010 Nov 15.
Abstract/Text One hundred and fifty hemato-oncologists and nuclear medicine specialists from more than 20 countries joined in April 2010 the 2-day Second International Workshop on interim PET in lymphoma. During the nuclear medicine session the advantages of the five-point scale Deauville criteria for interim PET reporting over the other sets of visual criteria were presented. The specific problems of PET reporting in escalation/de-escalation trials in Hodgkin lymphoma (HL) were addressed as well as the limitations of visual analysis for early PET evaluation in non-Hodgkin lymphoma (NHL). The applicability, efficacy, and reproducibility of quantitative criteria (ΔSUV(max) analysis and tumor/liver SUV ratio) for interim PET in NHL were reported. In retrospective and prospective series. Some of the interim PET-based clinical trials ongoing worldwide in HL and NHL were reported. In early-stage HL, three trials aimed at determining the feasibility of omitting radiotherapy in interim PET negative patients, and in advanced-stage HL two PET-based ABVD escalation or BEACOPP de-escalation trials, in NHL two studies reported preliminary results of interim PET in follicular lymphoma, in DLBCL a round-table discussion pointed out the lack of definite criteria for interim PET, and a few observational studies in DLBCL reported the comparison of the various techniques of interim PET reporting (visual versus quantitative). The preliminary results of two international validation studies of the five-point scale criteria in HL and NHL launched in 2009 were reported. The presentations of the meeting are available on http://eitti.free.fr.

PMID 21077737
Sally F Barrington, N George Mikhaeel, Lale Kostakoglu, Michel Meignan, Martin Hutchings, Stefan P Müeller, Lawrence H Schwartz, Emanuele Zucca, Richard I Fisher, Judith Trotman, Otto S Hoekstra, Rodney J Hicks, Michael J O'Doherty, Roland Hustinx, Alberto Biggi, Bruce D Cheson
Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group.
J Clin Oncol. 2014 Sep 20;32(27):3048-58. doi: 10.1200/JCO.2013.53.5229.
Abstract/Text PURPOSE: Recent advances in imaging, use of prognostic indices, and molecular profiling techniques have the potential to improve disease characterization and outcomes in lymphoma. International trials are under way to test image-based response–adapted treatment guided by early interim positron emission tomography (PET)–computed tomography (CT). Progress in imaging is influencing trial design and affecting clinical practice. In particular, a five-point scale to grade response using PET-CT, which can be adapted to suit requirements for early- and late-response assessment with good interobserver agreement, is becoming widely used both in practice- and response-adapted trials. A workshop held at the 11th International Conference on Malignant Lymphomas (ICML) in 2011 concluded that revision to current staging and response criteria was timely.
METHODS: An imaging working group composed of representatives from major international cooperative groups was asked to review the literature, share knowledge about research in progress, and identify key areas for research pertaining to imaging and lymphoma.
RESULTS: A working paper was circulated for comment and presented at the Fourth International Workshop on PET in Lymphoma in Menton, France, and the 12th ICML in Lugano, Switzerland, to update the International Harmonisation Project guidance regarding PET. Recommendations were made to optimize the use of PET-CT in staging and response assessment of lymphoma, including qualitative and quantitative methods.
CONCLUSION: This article comprises the consensus reached to update guidance on the use of PET-CT for staging and response assessment for [18F]fluorodeoxyglucose-avid lymphomas in clinical practice and late-phase trials.

PMID 25113771
Oliver W Press, Hongli Li, Heiko Schöder, David J Straus, Craig H Moskowitz, Michael LeBlanc, Lisa M Rimsza, Nancy L Bartlett, Andrew M Evens, Erik S Mittra, Ann S LaCasce, John W Sweetenham, Paul M Barr, Michelle A Fanale, Michael V Knopp, Ariela Noy, Eric D Hsi, James R Cook, Mary Jo Lechowicz, Randy D Gascoyne, John P Leonard, Brad S Kahl, Bruce D Cheson, Richard I Fisher, Jonathan W Friedberg
US Intergroup Trial of Response-Adapted Therapy for Stage III to IV Hodgkin Lymphoma Using Early Interim Fluorodeoxyglucose-Positron Emission Tomography Imaging: Southwest Oncology Group S0816.
J Clin Oncol. 2016 Jun 10;34(17):2020-7. doi: 10.1200/JCO.2015.63.1119. Epub 2016 Apr 11.
Abstract/Text PURPOSE: Four US National Clinical Trials Network components (Southwest Oncology Group, Cancer and Leukemia Group B/Alliance, Eastern Cooperative Oncology Group, and the AIDS Malignancy Consortium) conducted a phase II Intergroup clinical trial that used early interim fluorodeoxyglucose positron emission tomography (FDG-PET) imaging to determine the utility of response-adapted therapy for stage III to IV classic Hodgkin lymphoma.
PATIENTS AND METHODS: The Southwest Oncology Group S0816 (Fludeoxyglucose F 18-PET/CT Imaging and Combination Chemotherapy With or Without Additional Chemotherapy and G-CSF in Treating Patients With Stage III or Stage IV Hodgkin Lymphoma) trial enrolled 358 HIV-negative patients between July 1, 2009, and December 2, 2012. A PET scan was performed after two initial cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and was labeled PET2. PET2-negative patients (Deauville score 1 to 3) received an additional four cycles of ABVD, whereas PET2-positive patients (Deauville score 4 to 5) were switched to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for six cycles. Among 336 eligible and evaluable patients, the median age was 32 years (range, 18 to 60 years), with 52% stage III, 48% stage IV, 49% International Prognostic Score 0 to 2, and 51% score 3 to 7.
RESULTS: Three hundred thirty-six of the enrolled patients were evaluable. Central review of the interim PET2 scan was performed in 331 evaluable patients, with 271 (82%) PET2-negative and 60 (18%) PET2-positive. Of 60 eligible PET2-positive patients, 49 switched to eBEACOPP as planned and 11 declined. With a median follow-up of 39.7 months, the Kaplan-Meier estimate for 2-year overall survival was 98% (95% CI, 95% to 99%), and the 2-year estimate for progression-free survival (PFS) was 79% (95% CI, 74% to 83%). The 2-year estimate for PFS in the subset of patients who were PET2-positive after two cycles of ABVD was 64% (95% CI, 50% to 75%). Both nonhematologic and hematologic toxicities were greater in the eBEACOPP arm than in the continued ABVD arm.
CONCLUSION: Response-adapted therapy based on interim PET imaging after two cycles of ABVD seems promising with a 2-year PFS of 64% for PET2-positive patients, which is much higher than the expected 2-year PFS of 15% to 30%.

© 2016 by American Society of Clinical Oncology.
PMID 27069074
Andreas Engert, Petra Schiller, Andreas Josting, Richard Herrmann, Peter Koch, Markus Sieber, Friederike Boissevain, Maike De Wit, Jorg Mezger, Eckhart Duhmke, Normann Willich, Rolf-Peter Muller, Bernhard F Schmidt, Helmut Renner, Hans Konrad Muller-Hermelink, Beate Pfistner, Jurgen Wolf, Dirk Hasenclever, Markus Loffler, Volker Diehl, German Hodgkin's Lymphoma Study Group
Involved-field radiotherapy is equally effective and less toxic compared with extended-field radiotherapy after four cycles of chemotherapy in patients with early-stage unfavorable Hodgkin's lymphoma: results of the HD8 trial of the German Hodgkin's Lymphoma Study Group.
J Clin Oncol. 2003 Oct 1;21(19):3601-8. doi: 10.1200/JCO.2003.03.023. Epub 2003 Aug 11.
Abstract/Text PURPOSE: To investigate whether radiotherapy can be reduced without loss of efficacy from extended field (EF) to involved field (IF) after four cycles of chemotherapy.
PATIENTS AND METHODS: Between 1993 and 1998, patients with newly diagnosed early-stage unfavorable HD were enrolled onto this multicenter study. Patients were randomly assigned to receive cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) + doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for two cycles followed by radiotherapy of 30 Gy EF + 10 Gy to bulky disease (arm A) or 30 Gy IF + 10 Gy to bulky disease (arm B).
RESULTS: Of 1,204 patients randomly assigned to treatment, 1,064 patients were informative and eligible for the arm comparison (532 patients in arm A; 532 patients in arm B). The median observation time was 54 months. Five years after random assignment, the overall survival (OSran) for all eligible patients was 91% and freedom from treatment failure (FFTFran) was 83%. Survival rates at 5 years after start of radiotherapy revealed no differences for arms A and B, respectively, in terms of FFTF (85.8% and 84.2%) and OS at 5 years (90.8% and 92.4%). There also were no differences between arms A and B, respectively, in terms of complete remission (98.5% and 97.2%), progressive disease (0.8% and 1.9%), relapse (6.4% and 7.7%), death (8.1% and 6.4%), and secondary neoplasia (4.5% and 2.8%). In contrast, acute side effects including leukopenia, thrombocytopenia, nausea, gastrointestinal toxicity, and pharyngeal toxicity were more frequent in the EF arm.
CONCLUSION: Radiotherapy volume size reduction from EF to IF after COPP + ABVD chemotherapy for two cycles produces similar results and less toxicity in patients with early-stage unfavorable HD.

PMID 12913100
Gianni Bonadonna, Valeria Bonfante, Simonetta Viviani, Anna Di Russo, Fabrizio Villani, Pinuccia Valagussa
ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin's disease: long-term results.
J Clin Oncol. 2004 Jul 15;22(14):2835-41. doi: 10.1200/JCO.2004.12.170. Epub 2004 Jun 15.
Abstract/Text PURPOSE: Radiation therapy (RT) alone can cure more than 80% of all patients with pathologic stage IA, IB, and IIA Hodgkin's disease, but some prognostic factors unfavorably affect treatment outcome. Combined-modality approaches improved results compared with RT, but the optimal extent of RT fields when combined with chemotherapy warranted additional evaluation.
PATIENTS AND METHODS: In February 1990, we activated a prospective trial in patients with early, clinically staged Hodgkin's disease to assess efficacy and tolerability of four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by either subtotal nodal plus spleen irradiation (STNI) or involved-field radiotherapy (IFRT).
RESULTS: Main patient characteristics were fairly well balanced between the two arms. Complete remission was achieved in 100% and in 97% of patients, respectively. The 12-year freedom from progression rates were 93% (95% CI, 83% to 100%) after ABVD and STNI, and 94% (95% CI, 88% to 100%) after ABVD and IFRT, whereas the figures for overall survival were 96% (95% CI, 91% to 100%) and 94% (95% CI, 89% to 100%), respectively. Apart from three patients who developed second malignancies in the STNI arm, treatment-related morbidities were mild.
CONCLUSION: Present long-term findings suggest that, after four cycles of ABVD, IFRT can achieve a worthwhile outcome. The limited size of our patient sample, however, had no adequate statistical power to test for noninferiority of IFRT versus STNI. Despite this, ABVD followed by IFRT can be considered an effective and safe modality in early Hodgkin's disease with both favorable and unfavorable presentation.

PMID 15199092
Andreas Engert, Annette Plütschow, Hans Theodor Eich, Andreas Lohri, Bernd Dörken, Peter Borchmann, Bernhard Berger, Richard Greil, Kay C Willborn, Martin Wilhelm, Jürgen Debus, Michael J Eble, Martin Sökler, Antony Ho, Andreas Rank, Arnold Ganser, Lorenz Trümper, Carsten Bokemeyer, Hartmut Kirchner, Jörg Schubert, Zdenek Král, Michael Fuchs, Hans-Konrad Müller-Hermelink, Rolf-Peter Müller, Volker Diehl
Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma.
N Engl J Med. 2010 Aug 12;363(7):640-52. doi: 10.1056/NEJMoa1000067.
Abstract/Text BACKGROUND: Whether it is possible to reduce the intensity of treatment in early (stage I or II) Hodgkin's lymphoma with a favorable prognosis remains unclear. We therefore conducted a multicenter, randomized trial comparing four treatment groups consisting of a combination chemotherapy regimen of two different intensities followed by involved-field radiation therapy at two different dose levels.
METHODS: We randomly assigned 1370 patients with newly diagnosed early-stage Hodgkin's lymphoma with a favorable prognosis to one of four treatment groups: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gy of radiation therapy (group 1), four cycles of ABVD followed by 20 Gy of radiation therapy (group 2), two cycles of ABVD followed by 30 Gy of radiation therapy (group 3), or two cycles of ABVD followed by 20 Gy of radiation therapy (group 4). The primary end point was freedom from treatment failure; secondary end points included efficacy and toxicity of treatment.
RESULTS: The two chemotherapy regimens did not differ significantly with respect to freedom from treatment failure (P=0.39) or overall survival (P=0.61). At 5 years, the rates of freedom from treatment failure were 93.0% (95% confidence interval [CI], 90.5 to 94.8) with the four-cycle ABVD regimen and 91.1% (95% CI, 88.3 to 93.2) with the two-cycle regimen. When the effects of 20-Gy and 30-Gy doses of radiation therapy were compared, there were also no significant differences in freedom from treatment failure (P=1.00) or overall survival (P=0.61). Adverse events and acute toxic effects of treatment were most common in the patients who received four cycles of ABVD and 30 Gy of radiation therapy (group 1).
CONCLUSIONS: In patients with early-stage Hodgkin's lymphoma and a favorable prognosis, treatment with two cycles of ABVD followed by 20 Gy of involved-field radiation therapy is as effective as, and less toxic than, four cycles of ABVD followed by 30 Gy of involved-field radiation therapy. Long-term effects of these treatments have not yet been fully assessed. (Funded by the Deutsche Krebshilfe and the Swiss Federal Government; ClinicalTrials.gov number, NCT00265018.)

PMID 20818855
Karolin Behringer, Helen Goergen, Felicitas Hitz, Josée M Zijlstra, Richard Greil, Jana Markova, Stephanie Sasse, Michael Fuchs, Max S Topp, Martin Soekler, Stephan Mathas, Julia Meissner, Martin Wilhelm, Peter Koch, Hans-Walter Lindemann, Enrico Schalk, Robert Semrau, Jan Kriz, Tom Vieler, Martin Bentz, Elisabeth Lange, Rolf Mahlberg, Andre Hassler, Martin Vogelhuber, Dennis Hahn, Jörg Mezger, Stefan W Krause, Nicole Skoetz, Boris Böll, Bastian von Tresckow, Volker Diehl, Michael Hallek, Peter Borchmann, Harald Stein, Hans Eich, Andreas Engert, German Hodgkin Study Group, Swiss Group for Clinical Cancer Research, Arbeitsgemeinschaft Medikamentöse Tumortherapie
Omission of dacarbazine or bleomycin, or both, from the ABVD regimen in treatment of early-stage favourable Hodgkin's lymphoma (GHSG HD13): an open-label, randomised, non-inferiority trial.
Lancet. 2015 Apr 11;385(9976):1418-27. doi: 10.1016/S0140-6736(14)61469-0. Epub 2014 Dec 22.
Abstract/Text BACKGROUND: The role of bleomycin and dacarbazine in the ABVD regimen (ie, doxorubicin, bleomycin, vinblastine, and dacarbazine) has been questioned, especially for treatment of early-stage favourable Hodgkin's lymphoma, because of the drugs' toxicity. We aimed to investigate whether omission of either bleomycin or dacarbazine, or both, from ABVD reduced the efficacy of this regimen in treatment of Hodgkin's lymphoma.
METHODS: In this open-label, randomised, multicentre trial (HD13) we compared two cycles of ABVD with two cycles of the reduced-intensity regimen variants ABV (doxorubicin, bleomycin, and vinblastine), AVD (doxorubicin, vinblastine, and dacarbazine), and AV (doxorubicin and vinblastine), in patients with newly diagnosed, histologically proven, classic or nodular, lymphocyte predominant Hodgkin's lymphoma. In each treatment group, 30 Gy involved-field radiotherapy (IFRT) was given after both cycles of chemotherapy were completed. From Jan 28, 2003, patients were centrally randomly assigned (1:1:1:1) with a minimisation method to the four groups. Because of high event rates, assignment to the AV and ABV groups stopped early, on Sept 30, 2005, and Feb 10, 2006; assignment to ABVD and AVD continued (1:1) until Sept 30, 2009. Our primary objective was to show non-inferiority of the experimental variants compared with ABVD in terms of freedom from treatment failure (FFTF), by excluding a difference of 6% after 5 years corresponding to a hazard ratio (HR) of 1.72, via a 95% CI. Analyses reported here include qualified patients only, and between-group comparisons include only patients recruited during the same period. The trial was registered, number ISRCTN63474366.
FINDINGS: Of 1502 qualified patients, 566, 198, 571, and 167 were randomly assigned to receive ABVD, ABV, AVD, or AV, respectively. 5 year FFTF was 93.1%, 81.4%, 89.2%, and 77.1% with ABVD, ABV, AVD, and AV, respectively. Compared with ABVD, inferiority of the dacarbazine-deleted variants was detected with 5 year differences of -11.5% (95% CI -18.3 to -4.7; HR 2.06 [1.21 to 3.52]) for ABV and -15.2% (-23.0 to -7.4; HR 2.57 [1.51 to 4.40]) for AV. Non-inferiority of AVD compared with ABVD could also not be detected (5 year difference -3.9%, -7.7 to -0·1; HR 1.50, 1.00 to 2.26). 178 (33%) of 544 patients given ABVD had WHO grade III or IV toxicity, compared with 53 (28%) of 187 given ABV, 142 (26%) of 539 given AVD, and 40 (26%) of 151 given AV. Leucopenia was the most common event, and highest in the groups given bleomycin.
INTERPRETATION: Dacarbazine cannot be omitted from ABVD without a substantial loss of efficacy. With respect to our predefined non-inferiority margin, bleomycin cannot be safely omitted either, and the standard of care for patients with early-stage favourable Hodgkin's lymphoma should remain ABVD followed by IFRT.
FUNDING: Deutsche Krebshilfe and Swiss State Secretariat for Education and Research.

Copyright © 2015 Elsevier Ltd. All rights reserved.
PMID 25539730
Hans Theodor Eich, Volker Diehl, Helen Görgen, Thomas Pabst, Jana Markova, Jürgen Debus, Anthony Ho, Bernd Dörken, Andreas Rank, Anca-Ligia Grosu, Thomas Wiegel, Johann Hinrich Karstens, Richard Greil, Normann Willich, Heinz Schmidberger, Hartmut Döhner, Peter Borchmann, Hans-Konrad Müller-Hermelink, Rolf-Peter Müller, Andreas Engert
Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial.
J Clin Oncol. 2010 Sep 20;28(27):4199-206. doi: 10.1200/JCO.2010.29.8018. Epub 2010 Aug 16.
Abstract/Text PURPOSE: Combined-modality treatment consisting of four to six cycles of chemotherapy followed by involved-field radiotherapy (IFRT) is the standard of care for patients with early unfavorable Hodgkin's lymphoma (HL). It is unclear whether treatment results can be improved with more intensive chemotherapy and which radiation dose needs to be applied.
PATIENTS AND METHODS: Patients age 16 to 75 years with newly diagnosed early unfavorable HL were randomly assigned in a 2 × 2 factorial design to one of the following treatment arms: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + 30 Gy of IFRT; four cycles of ABVD + 20 Gy of IFRT; four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP(baseline)) + 30 Gy of IFRT; or four cycles of BEACOPP(baseline) + 20 Gy of IFRT.
RESULTS: With a total of 1,395 patients included, the freedom from treatment failure (FFTF) at 5 years was 85.0%, overall survival was 94.5%, and progression-free survival was 86.0%. BEACOPP(baseline) was more effective than ABVD when followed by 20 Gy of IFRT (5-year FFTF difference, 5.7%; 95% CI, 0.1% to 11.3%). However, there was no difference between BEACOPP(baseline) and ABVD when followed by 30 Gy of IFRT (5-year FFTF difference, 1.6%; 95% CI, -3.6% to 6.9%). Similar results were observed for the radiotherapy question; after four cycles of BEACOPP(baseline), 20 Gy was not inferior to 30 Gy (5-year FFTF difference, -0.8%; 95% CI, -5.8% to 4.2%), whereas inferiority of 20 Gy cannot be excluded after four cycles of ABVD (5-year FFTF difference, -4.7%; 95% CI, -10.3% to 0.8%). Treatment-related toxicity occurred more often in the arms with more intensive therapy.
CONCLUSION: Moderate dose escalation using BEACOPP(baseline) did not significantly improve outcome in early unfavorable HL. Four cycles of ABVD should be followed by 30 Gy of IFRT.

PMID 20713848
Ranjana H Advani, Fangxin Hong, Richard I Fisher, Nancy L Bartlett, K Sue Robinson, Randy D Gascoyne, Henry Wagner, Patrick J Stiff, Bruce D Cheson, Douglas A Stewart, Leo I Gordon, Brad S Kahl, Jonathan W Friedberg, Kristie A Blum, Thomas M Habermann, Joseph M Tuscano, Richard T Hoppe, Sandra J Horning
Randomized Phase III Trial Comparing ABVD Plus Radiotherapy With the Stanford V Regimen in Patients With Stages I or II Locally Extensive, Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the North American Intergroup E2496 Trial.
J Clin Oncol. 2015 Jun 10;33(17):1936-42. doi: 10.1200/JCO.2014.57.8138. Epub 2015 Apr 20.
Abstract/Text PURPOSE: The phase III North American Intergroup E2496 Trial (Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Hodgkin's Lymphoma) compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with mechlorethamine, doxorubicin, vincristine, bleomycin, vinblastine, etoposide, and prednisone (Stanford V). We report results of a planned subgroup analysis in patients with stage I or II bulky mediastinal Hodgkin lymphoma (HL).
PATIENTS AND METHODS: Patients were randomly assigned to six to eight cycles of ABVD every 28 days or Stanford V once per week for 12 weeks. Two to 3 weeks after completion of chemotherapy, all patients received 36 Gy of modified involved field radiotherapy (IFRT) to the mediastinum, hila, and supraclavicular regions. Patients on the Stanford V arm received IFRT to additional sites ≥ 5 cm at diagnosis. Primary end points were failure-free survival (FFS) and overall survival (OS).
RESULTS: Of 794 eligible patients, 264 had stage I or II bulky disease, 135 received ABVD, and 129 received Stanford V. Patient characteristics were matched. The overall response rate was 83% with ABVD and 88% with Stanford V. At a median follow-up of 6.5 years, the study excluded a difference of more than 21% in 5-year FFS and more than 16% in 5-year OS between ABVD and Stanford V (5-year FFS: 85% v 79%; HR, 0.68; 95% CI, 0.37 to 1.25; P = .22; 5-year OS: 96% v 92%; HR, 0.49; 95% CI, 0.16 to 1.47; P = .19). In-field relapses occurred in < 10% of the patients in each arm.
CONCLUSION: For patients with stage I or II bulky mediastinal HL, no substantial statistically significant differences were detected between the two regimens, although power was limited. To the best of our knowledge, this is the first prospective trial reporting outcomes specific to this subgroup, and it sets a benchmark for comparison of ongoing and future studies.

© 2015 by American Society of Clinical Oncology.
PMID 25897153
V T DeVita, R M Simon, S M Hubbard, R C Young, C W Berard, J H Moxley, E Frei, P P Carbone, G P Canellos
Curability of advanced Hodgkin's disease with chemotherapy. Long-term follow-up of MOPP-treated patients at the National Cancer Institute.
Ann Intern Med. 1980 May;92(5):587-95.
Abstract/Text The results of treatment of 198 patients with Hodgkin's disease with MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) were analyzed. Eighty percent attained complete remission, and 68% of patients achieving a complete remission have remained disease free beyond 10 years from the end of treatment. Results of autopsy on patients who died of other causes while in clinical complete remission did not show evidence of residual tumors except in one patient. Asymptomatic patients and patients with mixed-cellularity or lymphocytic-depleted Hodgkin's disease do significantly better than symptomatic patients and those with nodular sclerosing histologic type. Advanced Hodgkin's disease appears to be curable by chemotherapy.

PMID 6892984
G P Canellos, J R Anderson, K J Propert, N Nissen, M R Cooper, E S Henderson, M R Green, A Gottlieb, B A Peterson
Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD.
N Engl J Med. 1992 Nov 19;327(21):1478-84. doi: 10.1056/NEJM199211193272102.
Abstract/Text BACKGROUND AND METHODS: MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) has been the standard treatment for Hodgkin's disease for almost 20 years. In a randomized, multicenter trial, we compared three regimens of primary systemic therapy for newly diagnosed advanced Hodgkin's disease in Stages IIIA2, IIIB, and IVA or IVB: (1) MOPP alone given for 6 to 8 cycles, (2) MOPP alternating with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) for 12 cycles, and (3) ABVD alone for 6 to 8 cycles. Patients in a first relapse after radiation therapy were eligible. No additional radiation therapy was given. Patients who did not have a complete response or who had a relapse with either MOPP alone or ABVD alone were switched to the opposite regimen.
RESULTS: Of 361 eligible patients, 123 received MOPP, 123 received MOPP alternating with ABVD, and 115 received ABVD alone. The patients were stratified according to age, stage, previous radiation, histologic features, and performance status. The overall response rate was 93 percent, with complete responses in 77 percent: 67 percent in the MOPP group, 82 percent in the ABVD group, and 83 percent in the MOPP-ABVD group (P = 0.006 for the comparison of MOPP with the other two regimens, both of which contained doxorubicin). The rates of failure-free survival at five years were 50 percent for MOPP, 61 percent for ABVD, and 65 percent for MOPP-ABVD. Age, stage (III vs. IV), and regimen influenced failure-free survival significantly. Overall survival at five years was 66 percent for MOPP, 73 percent for ABVD, and 75 percent for MOPP-ABVD (P = 0.28 for the comparison of MOPP with the doxorubicin regimens). MOPP had more severe toxic effects on bone marrow than ABVD and was associated with greater reductions in the prescribed dose.
CONCLUSIONS: In this trial, ABVD therapy for 6 to 8 months was as effective as 12 months of MOPP alternating with ABVD, and both were superior to MOPP alone in the treatment of advanced Hodgkin's disease. ABVD was less myelotoxic than MOPP or ABVD alternating with MOPP.

PMID 1383821
George P Canellos, Donna Niedzwiecki
Long-term follow-up of Hodgkin's disease trial.
N Engl J Med. 2002 May 2;346(18):1417-8. doi: 10.1056/NEJM200205023461821.
Abstract/Text
PMID 11986425
Peter W M Johnson, John A Radford, Michael H Cullen, Matthew R Sydes, Jan Walewski, Andrew S Jack, Kenneth A MacLennan, Sally P Stenning, Simon Clawson, Paul Smith, David Ryder, Barry W Hancock, United Kingdom Lymphoma Group LY09 Trial (ISRCTN97144519)
Comparison of ABVD and alternating or hybrid multidrug regimens for the treatment of advanced Hodgkin's lymphoma: results of the United Kingdom Lymphoma Group LY09 Trial (ISRCTN97144519).
J Clin Oncol. 2005 Dec 20;23(36):9208-18. doi: 10.1200/JCO.2005.03.2151. Epub 2005 Nov 28.
Abstract/Text PURPOSE: To perform an open-label, randomized, controlled trial comparing treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with two multidrug regimens (MDRs) for advanced Hodgkin's lymphoma (HL).
PATIENTS AND METHODS: Eight hundred seven patients with advanced HL (stage III to IV, or earlier stage with systemic symptoms or bulky disease) were randomly assigned between ABVD and MDR specified before randomization as alternating chlorambucil, vinblastine, procarbazine, and prednisolone (ChlVPP) with prednisolone, doxorubicin, bleomycin, vincristine, and etoposide (PABIOE), or hybrid ChlVPP/etoposide, vincristine, and doxorubicin (EVA). Radiotherapy was planned for incomplete response or initial bulk disease.
RESULTS: At 52 months median follow-up, 212 event-free survival (EFS) events (disease progression or any death) were reported. In the primary comparison, at 3 years EFS was 75% (95% CI, 71% to 79%) for ABVD and 75% (95% CI, 70% to 79%) for MDRs (hazard ratio [HR] = 1.05; 95% CI, 0.8 to 1.37; HR more than 1.0 favors ABVD). The 3-year overall survival (OS) rates were 90% (95% CI, 87% to 93%) in patients allocated ABVD and 88% (95% CI, 84% to 91%) in patients allocated MDRs (HR = 1.22; 95% CI, 0.84 to 1.77). Patients receiving MDRs experienced more grade 3/4 infection, mucositis, and neuropathy. One occurrence of myelodysplastic syndrome was reported, but no acute leukemia was reported. When the two MDRs are compared separately with ABVD, neither the alternating nor the hybrid regimen showed a statistically significant difference from ABVD for EFS or OS. Subgroup analysis suggested that MDRs may be associated with poorer outcomes in older patients (heterogeneity test of OS older or younger than 45 years, P = .020).
CONCLUSION: There was no evidence of significant difference in EFS or OS between ABVD and MDRs in the trial overall or if the two MDR versus ABVD comparisons are considered separately. ABVD remains the standard for treatment of advanced HL.

PMID 16314615
Massimo Federico, Stefano Luminari, Emilio Iannitto, Giuseppe Polimeno, Luigi Marcheselli, Antonella Montanini, Antonio La Sala, Francesco Merli, Caterina Stelitano, Samantha Pozzi, Renato Scalone, Nicola Di Renzo, Pellegrino Musto, Luca Baldini, Giulia Cervetti, Francesco Angrilli, Patrizio Mazza, Maura Brugiatelli, Paolo G Gobbi, HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial
ABVD compared with BEACOPP compared with CEC for the initial treatment of patients with advanced Hodgkin's lymphoma: results from the HD2000 Gruppo Italiano per lo Studio dei Linfomi Trial.
J Clin Oncol. 2009 Feb 10;27(5):805-11. doi: 10.1200/JCO.2008.17.0910. Epub 2009 Jan 5.
Abstract/Text PURPOSE: To compare doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD) versus bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) versus cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxirubicin, vincristine, procarbazine, vinblastine, and bleomycin (COPPEBVCAD; CEC) for advanced Hodgkin's lymphoma (HL).
PATIENTS AND METHODS: Three hundred seven patients with advanced HL (stage IIB, III, and IV) were randomly assigned to receive six courses of ABVD, four escalated plus two standard courses of BEACOPP, or six courses of CEC, plus a limited radiation therapy program.
RESULTS: After a median follow-up of 41 months, BEACOPP resulted in a superior progression-free survival (PFS), with a significant reduction in risk of progression (hazard ratio [HR] = 0.50) compared with ABVD. No differences between BEACOPP and CEC, or CEC and ABVD were observed. The 5-year PFS was 68% (95% CI, 56% to 78%), 81% (95% CI, 70% to 89%), and 78% (95% CI, 68% to 86%), for ABVD, BEACOPP, and CEC, respectively (BEACOPP v ABVD, P = .038; CEC v ABVD and BEACOPP v CEC, P = not significant [NS]). The 5-year overall survival was 84% (95% CI, 69% to 92%), 92% (95% CI, 84% to 96%), and 91% (95% CI, 81% to 96%) for ABVD, BEACOPP, and CEC, respectively (P = NS). BEACOPP and CEC resulted in higher rates of grade 3-4 neutropenia than ABVD (P = .016); BEACOPP was associated with higher rates of severe infections than ABVD and CEC (P = .003).
CONCLUSION: As adopted in this study BEACOPP is associated with a significantly improved PFS compared with ABVD, with a predictable higher acute toxicity.

PMID 19124807
Simonetta Viviani, Pier Luigi Zinzani, Alessandro Rambaldi, Ercole Brusamolino, Alessandro Levis, Valeria Bonfante, Umberto Vitolo, Alessandro Pulsoni, Anna Marina Liberati, Giorgina Specchia, Pinuccia Valagussa, Andrea Rossi, Francesco Zaja, Enrico M Pogliani, Patrizia Pregno, Manuel Gotti, Andrea Gallamini, Delia Rota Scalabrini, Gianni Bonadonna, Alessandro M Gianni, Michelangelo Foundation, Gruppo Italiano di Terapie Innovative nei Linfomi, Intergruppo Italiano Linfomi
ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned.
N Engl J Med. 2011 Jul 21;365(3):203-12. doi: 10.1056/NEJMoa1100340.
Abstract/Text BACKGROUND: BEACOPP, an intensified regimen consisting of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone, has been advocated as the new standard of treatment for advanced Hodgkin's lymphoma, in place of the combination of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).
METHODS: We randomly assigned 331 patients with previously untreated and unfavorable Hodgkin's lymphoma (stage IIB, III, or IV, or an international prognostic score of ≥3 on a scale of 0 to 7, with higher scores indicating increased risk), to receive either BEACOPP or ABVD, each followed by local radiotherapy when indicated. Patients with residual or progressive disease after the initial therapy were to be treated according to a state-of-the-art high-dose salvage program. The median follow-up period was 61 months.
RESULTS: The 7-year rate of freedom from first progression was 85% among patients who had received initial treatment with BEACOPP and 73% among those who had received initial treatment with ABVD (P=0.004), and the 7-year rate of event-free survival was 78% and 71%, respectively (P=0.15). A total of 65 patients (20 in the BEACOPP group, and 45 in the ABVD group) went on to receive the intended high-dose salvage regimen. As of the cutoff date, 3 of the 20 patients in the BEACOPP group and 15 of the 45 in the ABVD group who had had progressive disease or relapse after the initial therapy were alive and free of disease. After completion of the overall planned treatment, including salvage therapy, the 7-year rate of freedom from a second progression was 88% in the BEACOPP group and 82% in the ABVD group (P=0.12), and the 7-year rate of overall survival was 89% and 84%, respectively (P=0.39). Severe adverse events occurred more frequently in the BEACOPP group than in the ABVD group.
CONCLUSIONS: Treatment with BEACOPP, as compared with ABVD, resulted in better initial tumor control, but the long-term clinical outcome did not differ significantly between the two regimens. (Funded by Fondazione Michelangelo; ClinicalTrials.gov number, NCT01251107.).

PMID 21774708
Patrice Carde, Matthias Karrasch, Catherine Fortpied, Pauline Brice, Hussein Khaled, Olivier Casasnovas, Denis Caillot, Isabelle Gaillard, Serge Bologna, Christophe Ferme, Pieternella Johanna Lugtenburg, Frank Morschhauser, Igor Aurer, Bertrand Coiffier, Ralph Meyer, Matthew Seftel, Max Wolf, Bengt Glimelius, Anna Sureda, Nicolas Mounier
Eight Cycles of ABVD Versus Four Cycles of BEACOPPescalated Plus Four Cycles of BEACOPPbaseline in Stage III to IV, International Prognostic Score ≥ 3, High-Risk Hodgkin Lymphoma: First Results of the Phase III EORTC 20012 Intergroup Trial.
J Clin Oncol. 2016 Jun 10;34(17):2028-36. doi: 10.1200/JCO.2015.64.5648. Epub 2016 Apr 25.
Abstract/Text PURPOSE: To compare patients with high-risk stage III to IV Hodgkin lymphoma (HL) in the phase III European Organisation for Research and Treatment of Cancer 20012 Intergroup trial (Comparison of Two Combination Chemotherapy Regimens in Treating Patients With Stage III or Stage IV Hodgkin's Lymphoma) who were randomly assigned to either doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) or to bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP).
PATIENTS AND METHODS: Patients with clinical stage III or IV HL, International Prognostic Score of 3 or higher, and age 60 years or younger received ABVD for eight cycles (ABVD8) or escalated-dose BEACOPP (BEACOPPescalated) for four cycles followed by baseline BEACOPP (BEACOPPbaseline) for four cycles (BEACOPP4+4) without radiotherapy. Primary end points were event-free survival (EFS), treatment discontinuation, no complete response (CR) or unconfirmed complete response (CRu) after eight cycles, progression, relapse, or death. Secondary end points were CR rate, overall survival (OS), quality of life, secondary malignancies, and disease-free survival in CR/CRu patients.
RESULTS: Between 2002 and 2010, 549 patients were randomly assigned to ABVD8 (n = 275) or BEACOPP4+4 (n = 274). Other characteristics included median age, 35 years; male, 75%; stage IV, 74%; "B" symptoms, 81%; and International Prognostic Score ≥ 4, 59%. WHO performance status was 0 (34%), 1 (48%), or 2 (17%). Median follow-up was 3.6 years. CR/CRu was 82.5% in both arms. At 4 years, EFS was 63.7% for ABVD8 versus 69.3% for BEACOPP4+4 (hazard ratio [HR], 0.86; 95% CI, 0.64 to 1.15; P = .312); disease-free survival was 85.8% versus 91.0% (HR, 0.59; 95% CI, 0.33 to 1.06; P = .076), and OS was 86.7% versus 90.3% (HR, 0.71; 95% CI, 0.42 to 1.21; P = .208). Death as a result of toxicity occurred in six and five patients, early discontinuation (before cycle 5) in 12 and 26 patients, treatment crossovers in five and 10 patients, and secondary malignancies in eight and 10 patients in the ABVD8 and BEACOPP4+4 arms, respectively.
CONCLUSION: ABVD8 and BEACOPP4+4 resulted in similar EFS and OS in patients with high-risk advanced-stage HL. Because BEACOPP4+4 did not demonstrate a favorable effectiveness or toxicity ratio compared with ABVD8, treatment burden, immediate and late toxicities, and associated costs must be considered before selecting one of these regimens on which to build future treatment strategies.

© 2016 by American Society of Clinical Oncology.
PMID 27114593
Joseph M Connors, Wojciech Jurczak, David J Straus, Stephen M Ansell, Won S Kim, Andrea Gallamini, Anas Younes, Sergey Alekseev, Árpád Illés, Marco Picardi, Ewa Lech-Maranda, Yasuhiro Oki, Tatyana Feldman, Piotr Smolewski, Kerry J Savage, Nancy L Bartlett, Jan Walewski, Robert Chen, Radhakrishnan Ramchandren, Pier L Zinzani, David Cunningham, Andras Rosta, Neil C Josephson, Eric Song, Jessica Sachs, Rachael Liu, Hina A Jolin, Dirk Huebner, John Radford, ECHELON-1 Study Group
Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's Lymphoma.
N Engl J Med. 2018 Jan 25;378(4):331-344. doi: 10.1056/NEJMoa1708984. Epub 2017 Dec 10.
Abstract/Text BACKGROUND: Brentuximab vedotin is an anti-CD30 antibody-drug conjugate that has been approved for relapsed and refractory Hodgkin's lymphoma.
METHODS: We conducted an open-label, multicenter, randomized phase 3 trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma, in which 664 were assigned to receive brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee. The key secondary end point was overall survival.
RESULTS: At a median follow-up of 24.6 months, 2-year modified progression-free survival rates in the A+AVD and ABVD groups were 82.1% (95% confidence interval [CI], 78.8 to 85.0) and 77.2% (95% CI, 73.7 to 80.4), respectively, a difference of 4.9 percentage points (hazard ratio for an event of progression, death, or modified progression, 0.77; 95% CI, 0.60 to 0.98; P=0.04). There were 28 deaths with A+AVD and 39 with ABVD (hazard ratio for interim overall survival, 0.73 [95% CI, 0.45 to 1.18]; P=0.20) [corrected]. All secondary efficacy end points trended in favor of A+AVD. Neutropenia occurred in 58% of the patients receiving A+AVD and in 45% of those receiving ABVD; in the A+AVD group, the rate of febrile neutropenia was lower among the 83 patients who received primary prophylaxis with granulocyte colony-stimulating factor than among those who did not (11% vs. 21%). Peripheral neuropathy occurred in 67% of patients in the A+AVD group and in 43% of patients in the ABVD group; 67% of patients in the A+AVD group who had peripheral neuropathy had resolution or improvement at the last follow-up visit. Pulmonary toxicity of grade 3 or higher was reported in less than 1% of patients receiving A+AVD and in 3% of those receiving ABVD. Among the deaths that occurred during treatment, 7 of 9 in the A+AVD group were associated with neutropenia and 11 of 13 in the ABVD group were associated with pulmonary-related toxicity.
CONCLUSIONS: A+AVD had superior efficacy to ABVD in the treatment of patients with advanced-stage Hodgkin's lymphoma, with a 4.9 percentage-point lower combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years. (Funded by Millennium Pharmaceuticals and Seattle Genetics; ECHELON-1 ClinicalTrials.gov number, NCT01712490 ; EudraCT number, 2011-005450-60 .).

PMID 29224502
Stephen M Ansell, John Radford, Joseph M Connors, Monika Długosz-Danecka, Won-Seog Kim, Andrea Gallamini, Radhakrishnan Ramchandren, Jonathan W Friedberg, Ranjana Advani, Martin Hutchings, Andrew M Evens, Piotr Smolewski, Kerry J Savage, Nancy L Bartlett, Hyeon-Seok Eom, Jeremy S Abramson, Cassie Dong, Frank Campana, Keenan Fenton, Markus Puhlmann, David J Straus, ECHELON-1 Study Group
Overall Survival with Brentuximab Vedotin in Stage III or IV Hodgkin's Lymphoma.
N Engl J Med. 2022 Jul 28;387(4):310-320. doi: 10.1056/NEJMoa2206125. Epub 2022 Jul 13.
Abstract/Text BACKGROUND: Five-year follow-up in a trial involving patients with previously untreated stage III or IV classic Hodgkin's lymphoma showed long-term progression-free survival benefits with first-line therapy with brentuximab vedotin, a CD30-directed antibody-drug conjugate, plus doxorubicin, vinblastine, and dacarbazine (A+AVD), as compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). A planned interim analysis indicated a potential benefit with regard to overall survival; data from a median of 6 years of follow-up are now available.
METHODS: We randomly assigned patients in a 1:1 ratio to receive up to six cycles of A+AVD or ABVD. The primary end point, modified progression-free survival, has been reported previously. The key secondary end point was overall survival in the intention-to-treat population. Safety was also assessed.
RESULTS: A total of 664 patients were assigned to receive A+AVD and 670 to receive ABVD. At a median follow-up of 73.0 months, 39 patients in the A+AVD group and 64 in the ABVD group had died (hazard ratio, 0.59; 95% confidence interval [CI], 0.40 to 0.88; P = 0.009). The 6-year overall survival estimates were 93.9% (95% CI, 91.6 to 95.5) in the A+AVD group and 89.4% (95% CI, 86.6 to 91.7) in the ABVD group. Progression-free survival was longer with A+AVD than with ABVD (hazard ratio for disease progression or death, 0.68; 95% CI, 0.53 to 0.86). Fewer patients in the A+AVD group than in the ABVD group received subsequent therapy, including transplantation, and fewer second cancers were reported with A+AVD (in 23 vs. 32 patients). Primary prophylaxis with granulocyte colony-stimulating factor was recommended after an increased incidence of febrile neutropenia was observed with A+AVD. More patients had peripheral neuropathy with A+AVD than with ABVD, but most patients in the two groups had resolution or amelioration of the event by the last follow-up.
CONCLUSIONS: Patients who received A+AVD for the treatment of stage III or IV Hodgkin's lymphoma had a survival advantage over those who received ABVD. (Funded by Takeda Development Center Americas and Seagen; ECHELON-1 ClinicalTrials.gov number, NCT01712490; EudraCT number, 2011-005450-60.).

Copyright © 2022 Massachusetts Medical Society.
PMID 35830649
Volker Diehl, Jeremy Franklin, Michael Pfreundschuh, Bernd Lathan, Ursula Paulus, Dirk Hasenclever, Hans Tesch, Richard Herrmann, Bernd Dörken, Hans-Konrad Müller-Hermelink, Eckhardt Dühmke, Markus Loeffler, German Hodgkin's Lymphoma Study Group
Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease.
N Engl J Med. 2003 Jun 12;348(24):2386-95. doi: 10.1056/NEJMoa022473.
Abstract/Text BACKGROUND: Faced with unsatisfactory results of treatment for advanced Hodgkin's disease, we investigated three combinations of chemotherapy.
METHODS: From 1993 to 1998, 1201 eligible patients 15 to 65 years of age who had newly diagnosed Hodgkin's disease in unfavorable stage IIB or IIIA or stage IIIB or IV were randomly assigned to receive eight cycles of cyclophosphamide, vincristine, procarbazine, and prednisone alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (COPP-ABVD); bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP); or increased-dose BEACOPP, each followed by local radiotherapy when indicated. Enrollment in the COPP-ABVD group was stopped in 1996 owing to inferior results.
RESULTS: For the final analysis, 1195 of 1201 patients could be evaluated: 260 in the COPP-ABVD group, 469 in the BEACOPP group, and 466 in the increased-dose BEACOPP group; the median follow-up was 72, 54, and 51 months, respectively. The rate of freedom from treatment failure at five years was 69 percent in the COPP-ABVD group, 76 percent in the BEACOPP group, and 87 percent in the increased-dose BEACOPP group (P=0.04 for the comparison of the COPP-ABVD group with the BEACOPP group and P<0.001 for the comparison of the increased-dose BEACOPP group with the COPP-ABVD group and with the BEACOPP group), and the five-year rates of overall survival were 83 percent, 88 percent, and 91 percent, respectively (P=0.16 for the comparison of the COPP-ABVD group with the BEACOPP group, P=0.06 for the comparison of the BEACOPP group with the increased-dose BEACOPP group, and P=0.002 for the comparison of the COPP-ABVD group with the increased-dose BEACOPP group). Rates of early progression were significantly lower with increased-dose BEACOPP than with COPP-ABVD or standard BEACOPP.
CONCLUSIONS: Increased-dose BEACOPP resulted in better tumor control and overall survival than did COPP-ABVD.

Copyright 2003 Massachusetts Medical Society
PMID 12802024
Andreas Engert, Volker Diehl, Jeremy Franklin, Andreas Lohri, Bernd Dörken, Wolf-Dieter Ludwig, Peter Koch, Mathias Hänel, Michael Pfreundschuh, Martin Wilhelm, Lorenz Trümper, Walter-Erich Aulitzky, Martin Bentz, Mathias Rummel, Orhan Sezer, Hans-Konrad Müller-Hermelink, Dirk Hasenclever, Markus Löffler
Escalated-dose BEACOPP in the treatment of patients with advanced-stage Hodgkin's lymphoma: 10 years of follow-up of the GHSG HD9 study.
J Clin Oncol. 2009 Sep 20;27(27):4548-54. doi: 10.1200/JCO.2008.19.8820. Epub 2009 Aug 24.
Abstract/Text PURPOSE: The HD9 trial of the German Hodgkin Study Group compared two different doses (baseline and escalated) of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) chemotherapy regimen in 1,196 patients with advanced-stage Hodgkin's lymphoma (HL). The previous analysis with 5 years median follow-up had indicated improved tumor control with BEACOPP escalated. Since the long-term safety and efficacy of this regimen has been debated, we report the 10-year follow-up.
PATIENTS AND METHODS: Patients received one of three chemotherapy regimens: eight cycles of cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); eight cycles of BEACOPP baseline; or eight cycles of BEACOPP escalated.
RESULTS: Median follow-up was 111 months. At 10 years, freedom from treatment failure (FFTF) was 64%, 70%, and 82% with OS rates of 75%, 80%, and 86% for patients treated with COPP/ABVD (arm A), BEACOPP baseline (arm B), and BEACOPP escalated (arm C), respectively (P < .001). BEACOPP escalated was significantly better than BEACOPP baseline in terms of FFTF (P < .0001) and OS (P = .0053). A total of 74 second malignancies (6.2%) were documented, including acute myeloid leukemia (0.4%, 1.5%, and 3.0%), non-Hodgkin's lymphoma (2.7%, 1.7%, and 1.0%), and solid tumors (2.7%, 3.4%, and 1.9%). The corresponding overall secondary malignancy rates were 5.7%, 6.6%, and 6.0%, respectively.
CONCLUSION: The 10-year follow-up of the HD9 trial demonstrates a stabilized significant improvement in long-term FFTF and OS for BEACOPP escalated in advanced-stage HL. These results challenge ABVD as standard of care for this patient population.

PMID 19704068
V Ballova, J-U Rüffer, H Haverkamp, B Pfistner, H K Müller-Hermelink, E Dühmke, P Worst, M Wilhelmy, R Naumann, M Hentrich, H T Eich, A Josting, M Löffler, V Diehl, A Engert
A prospectively randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin's disease comparing BEACOPP baseline and COPP-ABVD (study HD9elderly).
Ann Oncol. 2005 Jan;16(1):124-31. doi: 10.1093/annonc/mdi023.
Abstract/Text In contrast to younger patients, the prognosis of elderly patients with advanced Hodgkin's disease (HD) has not improved substantially over the last 20 years. We thus carried out a prospectively randomized study (HD9(elderly)) to compare the BEACOPP regimen in this setting against standard COPP-ABVD. Between February 1993 and 1998, 75 patients aged 66-75 years with newly diagnosed HD in advanced stages were recruited into the HD9 trial as a separate stratum (HD9(elderly)). Patients were assigned to eight alternating cycles of COPP and ABVD or eight cycles of BEACOPP in baseline doses. Radiotherapy was given to initial bulky or residual disease. In total, 68 of 75 registered patients were assessable: 26 were treated with COPP-ABVD and 42 with BEACOPP baseline. There were no significant differences between COPP-ABVD and BEACOPP in terms of complete remission (76%), overall survival (50%) and freedom from treatment failure (FFTF) (46%) at 5 years. At a median follow-up of 80 months, a total of 37 patients died: 14/26 patients (54%) treated with COPP-ABVD and 23/42 patients (55%) with BEACOPP. Two patients (8%) treated with COPP-ABVD and nine patients (21%) treated with BEACOPP died of acute toxicity. Hodgkin-specific FFTF at 5 years was 55% after COPP-ABVD and 74% after BEACOPP (P=0.13). Thus, there are no differences in survival between these regimens in elderly patients.

PMID 15598949
Berthe M P Aleman, John M M Raemaekers, Umberto Tirelli, Roberto Bortolus, Mars B van 't Veer, Marnix L M Lybeert, Jo J Keuning, Patrice Carde, Théodore Girinsky, Richard W M van der Maazen, Radka Tomsic, Marjeta Vovk, Achilles van Hoof, Geertrui Demeestere, Pieternella J Lugtenburg, José Thomas, Wilfried Schroyens, Koenraad De Boeck, Johanna W Baars, Johanna C Kluin-Nelemans, Christian Carrie, Malek Aoudjhane, Dominique Bron, Houchingue Eghbali, Wilma G J M Smit, Jacobus H Meerwaldt, Anton Hagenbeek, Antonella Pinna, Michel Henry-Amar, European Organization for Research and Treatment of Cancer Lymphoma Group
Involved-field radiotherapy for advanced Hodgkin's lymphoma.
N Engl J Med. 2003 Jun 12;348(24):2396-406. doi: 10.1056/NEJMoa022628.
Abstract/Text BACKGROUND: The use of involved-field radiotherapy after chemotherapy for advanced Hodgkin's lymphoma is controversial.
METHODS: We randomly assigned patients with previously untreated stage III or IV Hodgkin's lymphoma who were in complete remission after hybrid chemotherapy with mechlorethamine, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, and vinblastine (MOPP-ABV) to receive either no further treatment or involved-field radiotherapy. Radiotherapy consisted of 24 Gy to all initially involved nodal areas and 16 to 24 Gy to all initially involved extranodal sites. Patients in partial remission were treated with 30 Gy to nodal areas and 18 to 24 Gy to extranodal sites.
RESULTS: Of 739 patients, 421 had a complete remission; 161 of these patients were assigned to no further treatment, and 172 to involved-field radiotherapy. The median follow-up was 79 months. The five-year event-free survival rate was 84 percent in the group that did not receive radiotherapy and 79 percent in the group that received involved-field radiotherapy (P=0.35). The five-year overall survival rates were 91 and 85 percent, respectively (P=0.07). Among the 250 patients in partial remission after chemotherapy, the five-year event-free and overall survival rates were 79 and 87 percent, respectively.
CONCLUSIONS: Involved-field radiotherapy did not improve the outcome in patients with advanced-stage Hodgkin's lymphoma who had a complete remission after MOPP-ABV chemotherapy. Radiotherapy may benefit patients with a partial response after chemotherapy.

Copyright 2003 Massachusetts Medical Society
PMID 12802025
Berthe M P Aleman, John M M Raemaekers, Radka Tomiŝiĉ, Margreet H A Baaijens, Roberto Bortolus, Marnix L M Lybeert, Richard W M van der Maazen, Théodore Girinsky, Geertrui Demeestere, Pieternella Lugtenburg, Yolande Lievens, Daphne de Jong, Antonella Pinna, Michel Henry-Amar, European Organization for Research and Treatment of Cancer (EORTC) Lymphoma Group
Involved-field radiotherapy for patients in partial remission after chemotherapy for advanced Hodgkin's lymphoma.
Int J Radiat Oncol Biol Phys. 2007 Jan 1;67(1):19-30. doi: 10.1016/j.ijrobp.2006.08.041. Epub 2006 Nov 9.
Abstract/Text PURPOSE: The use of radiotherapy in patients with advanced Hodgkin's lymphoma (HL) is controversial. The purpose of this study was to describe the role of radiotherapy in patients with advanced HL who were in partial remission (PR) after chemotherapy.
METHODS: In a prospective randomized trial, patients <70 years old with previously untreated Stage III-IV HL were treated with six to eight cycles of mechlorethamine, vincristine, procarbazine, prednisone/doxorubicin, bleomycine, vinblastine hybrid chemotherapy. Patients in complete remission (CR) after chemotherapy were randomized between no further treatment and involved-field radiotherapy (IF-RT). Those in PR after six cycles received IF-RT (30 Gy to originally involved nodal areas and 18-24 Gy to extranodal sites with or without a boost).
RESULTS: Of 739 enrolled patients, 57% were in CR and 33% in PR after chemotherapy. The median follow-up was 7.8 years. Patients in PR had bulky mediastinal involvement significantly more often than did those in CR after chemotherapy. The 8-year event-free survival and overall survival rate for the 227 patients in PR who received IF-RT was 76% and 84%, respectively. These rates were not significantly different from those for CR patients who received IF-RT (73% and 78%) or for those in CR who did not receive IF-RT (77% and 85%). The incidence of second malignancies in patients in PR who were treated with IF-RT was similar to that in nonirradiated patients.
CONCLUSION: Patients in PR after six cycles of mechlorethamine, vincristine, procarbazine, prednisone/doxorubicine, bleomycine, vinblastine treated with IF-RT had 8-year event-free survival and overall survival rates similar to those of patients in CR, suggesting a definite role for RT in these patients.

PMID 17097834
C J Fabian, C M Mansfield, S Dahlberg, S E Jones, T P Miller, E Van Slyck, P N Grozea, F S Morrison, C A Coltman, R I Fisher
Low-dose involved field radiation after chemotherapy in advanced Hodgkin disease. A Southwest Oncology Group randomized study.
Ann Intern Med. 1994 Jun 1;120(11):903-12.
Abstract/Text OBJECTIVE: To determine if low-dose involved field radiation after complete remission induction with chemotherapy is effective in preventing relapse and improving survival in patients with stage III or IV Hodgkin disease.
DESIGN: A randomized controlled trial with a median follow-up time of 8.1 years.
SETTING: A Southwest Oncology Group multi-institutional study. Patients were entered from university- and community-based practices.
PATIENTS: 278 adults with clinical or pathologic stage III or IV Hodgkin disease, who achieved complete responses after 6 cycles of MOP-BAP (nitrogen mustard, vincristine, prednisone, bleomycin, doxorubicin, and procarbazine) and who agreed to be randomly assigned to either radiation or no further treatment.
INTERVENTION: Patients were assigned to either no further treatment or low-dose radiation to all initially involved sites (radiation dose, 2000 cGy to lymph node areas and 1000 to 1500 cGy to other involved organ sites).
MEASUREMENTS: Differences in remission duration, relapse-free survival, and survival.
RESULTS: Remission duration, relapse-free survival, and overall survival were similar for the two groups (P = 0.09, P > 0.2, and P = 0.14, respectively). Factors that predicted shorter remission duration in a multivariate analysis were nodular sclerosis histology, bulky disease, and receipt of less than 85% of planned chemotherapy. Low-dose radiation improved remission duration in the subgroups of patients with nodular sclerosis and bulky disease. For the 169 patients with nodular sclerosis, the 5-year remission-duration estimate was 82% for the low-dose radiation group and 60% for the no further treatment group (P = 0.002). For all patients with bulky disease, the 5-year remission-duration estimate was 75% for the low-dose radiation group and 57% for the no further treatment group (P = 0.05). No difference in overall survival was noted between low-dose radiation and no further treatment in all patients or major subgroups. The 5-year survival was 86% for all patients who had a complete response as well as for patients in the nodular sclerosis subgroup.
CONCLUSIONS: Low-dose involved field radiation after MOP-BAP chemotherapy in patients with stage III or IV Hodgkin disease did not prolong remission duration or overall survival in randomized patients. However, remission duration was prolonged in several subgroups of patients, most prominently in those with nodular sclerosis histology.

PMID 8172436
Andreas Engert, Heinz Haverkamp, Carsten Kobe, Jana Markova, Christoph Renner, Antony Ho, Josée Zijlstra, Zdenek Král, Michael Fuchs, Michael Hallek, Lothar Kanz, Hartmut Döhner, Bernd Dörken, Nicole Engel, Max Topp, Susanne Klutmann, Holger Amthauer, Andreas Bockisch, Regine Kluge, Clemens Kratochwil, Otmar Schober, Richard Greil, Reinhard Andreesen, Michael Kneba, Michael Pfreundschuh, Harald Stein, Hans Theodor Eich, Rolf-Peter Müller, Markus Dietlein, Peter Borchmann, Volker Diehl, German Hodgkin Study Group, Swiss Group for Clinical Cancer Research, Arbeitsgemeinschaft Medikamentöse Tumortherapie
Reduced-intensity chemotherapy and PET-guided radiotherapy in patients with advanced stage Hodgkin's lymphoma (HD15 trial): a randomised, open-label, phase 3 non-inferiority trial.
Lancet. 2012 May 12;379(9828):1791-9. doi: 10.1016/S0140-6736(11)61940-5. Epub 2012 Apr 4.
Abstract/Text BACKGROUND: The intensity of chemotherapy and need for additional radiotherapy in patients with advanced stage Hodgkin's lymphoma has been unclear. We did a prospective randomised clinical trial comparing two reduced-intensity chemotherapy variants with our previous standard regimen. Chemotherapy was followed by PET-guided radiotherapy.
METHODS: In this parallel group, open-label, multicentre, non-inferiority trial (HD15), 2182 patients with newly diagnosed advanced stage Hodgkin's lymphoma aged 18-60 years were randomly assigned to receive either eight cycles of BEACOPP(escalated) (8×B(esc) group), six cycles of BEACOPP(escalated) (6×B(esc) group), or eight cycles of BEACOPP(14) (8×B(14) group). Randomisation (1:1:1) was done centrally by stratified minimisation. Non-inferiority of the primary endpoint, freedom from treatment failure, was assessed using repeated CIs for the hazard ratio (HR) according to the intention-to-treat principle. Patients with a persistent mass after chemotherapy measuring 2·5 cm or larger and positive on PET scan received additional radiotherapy with 30 Gy; the negative predictive value for tumour recurrence of PET at 12 months was an independent endpoint. This trial is registered with Current Controlled Trials, number ISRCTN32443041.
FINDINGS: Of the 2182 patients enrolled in the study, 2126 patients were included in the intention-to-treat analysis set, 705 in the 8×B(esc) group, 711 in the 6×B(esc) group, and 710 in the 8×B(14) group. Freedom from treatment failure was sequentially non-inferior for the 6×B(esc) and 8×B(14) groups as compared with 8×B(esc). 5-year freedom from treatment failure rates were 84·4% (97·5% CI 81·0-87·7) for the 8×B(esc) group, 89·3% (86·5-92·1) for 6×B(esc) group, and 85·4% (82·1-88·7) for the 8×B(14) group (97·5% CI for difference between 6×B(esc) and 8×B(esc) was 0·5-9·3). Overall survival in the three groups was 91·9%, 95·3%, and 94·5% respectively, and was significantly better with 6×B(esc) than with 8×B(esc) (97·5% CI 0·2-6·5). The 8×B(esc) group showed a higher mortality (7·5%) than the 6×B(esc) (4·6%) and 8×B(14) (5·2%) groups, mainly due to differences in treatment-related events (2·1%, 0·8%, and 0·8%, respectively) and secondary malignancies (1·8%, 0·7%, and 1·1%, respectively). The negative predictive value for PET at 12 months was 94·1% (95% CI 92·1-96·1); and 225 (11%) of 2126 patients received additional radiotherapy.
INTERPRETATION: Treatment with six cycles of BEACOPP(escalated) followed by PET-guided radiotherapy was more effective in terms of freedom from treatment failure and less toxic than eight cycles of the same chemotherapy regimen. Thus, six cycles of BEACOPP(escalated) should be the treatment of choice for advanced stage Hodgkin's lymphoma. PET done after chemotherapy can guide the need for additional radiotherapy in this setting.
FUNDING: Deutsche Krebshilfe and the Swiss Federal Government.

Copyright © 2012 Elsevier Ltd. All rights reserved.
PMID 22480758
Peter Borchmann, Heinz Haverkamp, Volker Diehl, Thomas Cerny, Jana Markova, Anthony D Ho, Hans-Theodor Eich, Hans Konrad Mueller-Hermelink, Lothar Kanz, Richard Greil, Andreas Rank, Ursula Paulus, Lenka Smardova, Christoph Huber, Bernd Dörken, Christoph Nerl, Stefan W Krause, Rolf-Peter Mueller, Michael Fuchs, Andreas Engert
Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage hodgkin's lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group.
J Clin Oncol. 2011 Nov 10;29(32):4234-42. doi: 10.1200/JCO.2010.33.9549. Epub 2011 Oct 11.
Abstract/Text PURPOSE: Eight cycles of BEACOPP(escalated) (escalated dose of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) followed by radiotherapy (RT) to initial bulk or residual tumor mass is the German Hodgkin Study Group standard of care for advanced-stage Hodgkin's lymphoma (HL). However, treatment-related toxicity is a concern, and the role of RT in this setting is unclear. The HD12 study thus aimed to reduce toxicity while maintaining efficacy.
PATIENTS AND METHODS: In this prospectively randomized multicenter trial, eight cycles of BEACOPP(escalated) was compared with four cycles of BEACOPP(escalated) followed by four cycles of the baseline dose of BEACOPP (BEACOPP(baseline); 4 + 4), and RT with no RT in the case of initial bulk or residual disease. The study was designed to exclude a difference in 5-year freedom from treatment failure (FFTF) rate of 6%.
RESULTS: Between January 1999 and January 2003, 1,670 patients age 16 to 65 years were enrolled onto the HD12 study. At 5 years, FFTF was 86.4% in the BEACOPP(escalated) arm and 84.8% in the 4 + 4 arm (difference, -1.6%; 95% CI, -5.2% to 1.9%), and overall survival was 92% versus 90.3% (difference, -1.7%; 95% CI, -4.6% to 1.1%). Deaths related to acute toxicity of chemotherapy were observed in 2.9% of patients (BEACOPP(escalated), n = 19; 4 + 4, n = 27). FFTF was inferior without RT (90.4% v 87%; difference, -3.4%; 95% CI, -6.6% to -0.1%), particularly in patients who had residual disease after chemotherapy (difference, -5.8%; 95% CI, -10.7% to -1.0%), but not in patients with bulk in complete response after chemotherapy (difference, -1.1%; 95% CI, -6.2% to 4%).
CONCLUSION: The reduction of BEACOPP to the 4 + 4 regimen did not substantially reduce severe toxicity but might decrease efficacy. Our results do not support the omission of consolidation RT for patients with residual disease. Alternative strategies for improving the risk-to-benefit ratio for patients with advanced HL are needed.

PMID 21990399
Norbert Schmitz, Beate Pfistner, Michael Sextro, Markus Sieber, Angelo M Carella, Matthias Haenel, Friederike Boissevain, Reinhart Zschaber, Peter Müller, Hartmut Kirchner, Andreas Lohri, Susanne Decker, Bettina Koch, Dirk Hasenclever, Anthony H Goldstone, Volker Diehl, German Hodgkin's Lymphoma Study Group, Lymphoma Working Party of the European Group for Blood and Marrow Transplantation
Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial.
Lancet. 2002 Jun 15;359(9323):2065-71. doi: 10.1016/S0140-6736(02)08938-9.
Abstract/Text BACKGROUND: High-dose chemotherapy followed by transplantation of autologous haemopoietic stem cells (BEAM-HSCT) is frequently used to treat patients with relapsed Hodgkin's disease. We aimed to compare this treatment with conventional aggressive chemotherapy without stem-cell transplantation (Dexa-BEAM).
METHODS: 161 patients between 16 and 60 years of age with relapsed Hodgkin's disease were randomly assigned two cycles of Dexa-BEAM (dexamethasone and carmustine, etoposide, cytarabine, and melphalan) and either two further courses of Dexa-BEAM or high-dose BEAM and transplantation of haemopoietic stem cells. Only patients with chemosensitive disease (complete or partial remission after two courses of Dexa-BEAM) proceeded to further treatment. The primary endpoint was freedom from treatment failure for patients with chemosensitive disease. Analysis was per protocol.
FINDINGS: 17 patients were excluded from the study after randomisation (ten given Dexa-BEAM and seven given BEAM-HSCT). Median follow-up was 39 months (IQR 3-78). Freedom from treatment failure at 3 years was significantly better for patients given BEAM-HSCT (55%) than for those on Dexa-BEAM (34%; difference -21%, 95% CI -39.87 to -2.13; p=0.019). Overall survival of patients given either treatment did not differ significantly.
INTERPRETATION: High-dose BEAM and transplantation of haemopoietic stem cells improves freedom from treatment failure in patients with chemosensitive first relapse of Hodgkin's disease irrespective of length of initial remission.

PMID 12086759
A R Yuen, S A Rosenberg, R T Hoppe, J D Halpern, S J Horning
Comparison between conventional salvage therapy and high-dose therapy with autografting for recurrent or refractory Hodgkin's disease.
Blood. 1997 Feb 1;89(3):814-22.
Abstract/Text Sixty patients with Hodgkin's disease, refractory to or at first recurrence after chemotherapy, received cytoreductive therapy followed by high-dose etoposide, cyclophosphamide and either total body irradiation or carmustine and autografting (median follow-up, 3.6 years; range, 1.1 to 7.5 years). A matched conventional salvage group of 103 patients was selected from patients treated at Stanford University Medical Center between January 1976 and January 1989 (median follow-up, 10.3 years; range, 3.0 to 15.7 years). Overall survival (OS), event-free survival (EFS), and freedom from progression (FFP) at 4 years follow-up favored patients who received high-dose therapy compared with conventional salvage treatment (OS: 54% v 47%, P = .25; EFS: 53% v 27%, P < .01; FFP: 62% v 32%, P < .01). In Cox regression analysis, response to cytoreductive or salvage therapy and B symptoms at relapse were the most important predictors of OS. The use of high-dose therapy at relapse, a longer duration of remission, and favorable response to cytoreductive or salvage therapy were most predictive of superior FFP and EFS. These data from a single institution comparing conventional and high-dose therapy in matched patients demonstrate an advantage for high-dose therapy and autografting in the sustained control of Hodgkin's disease. As with primary therapy, it is difficult to demonstrate a statistically significant survival advantage, despite an apparently superior cure rate. However, patients failing induction therapy or relapsing within 1 year benefited significantly from high-dose therapy by all outcome measures (OS, EFS, FFP). As the transplant-related mortality rates decline in Hodgkin's disease, it is predicted that cure rates and late effects will become ultimate determinants of the success of high-dose therapy and autografting.

PMID 9028312
V Diehl, M Sextro, J Franklin, M L Hansmann, N Harris, E Jaffe, S Poppema, M Harris, K Franssila, J van Krieken, T Marafioti, I Anagnostopoulos, H Stein
Clinical presentation, course, and prognostic factors in lymphocyte-predominant Hodgkin's disease and lymphocyte-rich classical Hodgkin's disease: report from the European Task Force on Lymphoma Project on Lymphocyte-Predominant Hodgkin's Disease.
J Clin Oncol. 1999 Mar;17(3):776-83.
Abstract/Text PURPOSE: Recent studies have suggested that lymphocyte-predominant Hodgkin's disease (LPHD) is both clinically and pathologically distinct from other forms of Hodgkin's disease, including classical Hodgkin's disease (CHD). However, large-scale clinical studies were lacking. This multicenter, retrospective study investigated the clinical characteristics and course of LPHD patients and lymphocyte-rich classical Hodgkin's disease (LRCHD) patients classified according to morphologic and immunophenotypic criteria.
MATERIALS AND METHODS: Clinical data and biopsy material of all available cases initially submitted as LPHD were collected from 17 European and American centers, stained, and reclassified by expert pathologists.
RESULTS: The 426 assessable cases were reclassified as LPHD (51%), LRCHD (27%), CHD (5%), non-Hodgkin's lymphoma (3%), and reactive lesion (3%); 11% of cases were not assessable. Patients with LPHD and LRCHD were predominantly male, with early-stage disease and few risk factors. Patients with LRCHD were significantly older. Survival and failure-free survival rates with adequate therapy were similar for patients with LPHD and LRCHD, and were stage-dependent and not significantly better than stage-comparable results for CHD (German trial data). Twenty-seven percent of relapsing LPHD patients had multiple relapses, which is significantly more than the 5% of relapsing LRCHD patients who had multiple relapses. Lymphocyte-predominant Hodgkin's disease patients had significantly superior survival after relapse compared with LRCHD or CHD patients; however, this was partly due to the younger average age of LPHD patients.
CONCLUSION: The two subgroups of LPHD and LRCHD bore a close clinical resemblance that was distinct from CHD; the course was similar to that of comparable nodular sclerosis and mixed cellularity patients. Thorough staging is necessary to detect advanced disease in LPHD and LRCHD patients. The question of how to treat such patients, either by reducing treatment intensity or following a "watch and wait" approach, remains unanswered.

PMID 10071266
Mubarak Al-Mansour, Joseph M Connors, Randy D Gascoyne, Brian Skinnider, Kerry J Savage
Transformation to aggressive lymphoma in nodular lymphocyte-predominant Hodgkin's lymphoma.
J Clin Oncol. 2010 Feb 10;28(5):793-9. doi: 10.1200/JCO.2009.24.9516. Epub 2010 Jan 4.
Abstract/Text PURPOSE Prior observations suggest a higher risk of transformation of nodular lymphocyte-predominant Hodgkin's lymphoma (NLPHL) to aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), than in classical Hodgkin's lymphoma. We evaluated the frequency of transformation in all patients diagnosed with NLPHL at the British Columbia Cancer Agency with long-term follow-up. PATIENTS AND METHODS The Lymphoid Cancer Database of the British Columbia Cancer Agency was searched to identify all patients diagnosed with NLPHL between 1965 and 2006. After pathologic review, 95 patients with NLPHL were confirmed. Results Patients with NLPHL had the following characteristics at diagnosis: median age of 37 years, 73% male, and 68% stage I or II disease. With a median follow-up time for living patients of 6.5 years (range, 2.5 to 33 years), 13 patients (14%) experienced transformation to aggressive lymphoma (median time to transformation, 8.1 years; range, 0.35 to 20.3 years). The actuarial risk of transformation to aggressive lymphoma was 7% and 30% at 10 and 20 years, respectively. Transformation was more likely in patients with initial splenic involvement (P = .006) at the time of diagnosis of NLPHL. The 10-year progression-free and overall survival rates in patients with transformed lymphoma were 52% and 62%, respectively. CONCLUSION The risk of transformation in patients with NLPHL to DLBCL is substantial and underappreciated. Because transformation can occur years after the primary diagnosis of NLPHL, long-term follow-up of these individuals is necessary to accurately estimate the risk of development of secondary DLBCL.

PMID 20048177
Ronald C Chen, Michael S Chin, Andrea K Ng, Yang Feng, Donna Neuberg, Barbara Silver, Geraldine S Pinkus, Mary Ann Stevenson, Peter M Mauch
Early-stage, lymphocyte-predominant Hodgkin's lymphoma: patient outcomes from a large, single-institution series with long follow-up.
J Clin Oncol. 2010 Jan 1;28(1):136-41. doi: 10.1200/JCO.2009.24.0945. Epub 2009 Nov 23.
Abstract/Text PURPOSE The optimal treatment for early-stage, lymphocyte-predominant Hodgkin's lymphoma (LPHL) is not well defined. Treatment has become less aggressive over time in an attempt to reduce iatrogenic complications, such as cardiac mortality and second cancers, but long-term efficacy is unclear. We present the long-term outcome of patients treated at a single institution. PATIENTS AND METHODS The study population includes 113 patients with stage I or II LPHL treated between 1970 and 2005. Pathologic diagnosis for all patients was confirmed using standard criteria. Ninety-three patients received radiation therapy (RT) alone, 13 received RT with chemotherapy, and seven received chemotherapy alone. Among patients treated with RT, 25 received limited-field, 35 received regional-field, and 46 received extended-field RT. Results Median follow-up was 136 months. Ten-year progression-free survival (PFS) rates were 85% (stage I) and 61% (stage II); overall survival (OS) rates were 94% and 97% for stages I and II, respectively. PFS and OS did not differ among patients who received limited-field, regional-field, or extended-field RT. In contrast, six of seven patients who received chemotherapy alone without RT developed early disease progression and required salvage treatment. Multivariable analysis adjusting for extent of RT, clinical stage, sex, and use of chemotherapy confirmed that the extent of RT was not significantly associated with PFS (P = .67) or OS (P = .99). The addition of chemotherapy to RT did not improve PFS or OS compared with RT alone. CONCLUSION RT alone leads to sustained disease control and high long-term survival rates in patients with early-stage LPHL. This study supports the use of limited-field RT alone to treat this disease.

PMID 19933914
Dennis A Eichenauer, Annette Plütschow, Michael Fuchs, Bastian von Tresckow, Boris Böll, Karolin Behringer, Volker Diehl, Hans Theodor Eich, Peter Borchmann, Andreas Engert
Long-Term Course of Patients With Stage IA Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Report From the German Hodgkin Study Group.
J Clin Oncol. 2015 Sep 10;33(26):2857-62. doi: 10.1200/JCO.2014.60.4363. Epub 2015 Aug 3.
Abstract/Text PURPOSE: The optimal treatment of stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is not well defined. Thus, we performed an analysis using the database of the German Hodgkin Study Group.
PATIENTS AND METHODS: The long-term outcome of 256 patients with stage IA NLPHL was evaluated. Patients had received combined-modality treatment (CMT; n = 72), extended-field radiotherapy (EF-RT; n = 49), involved-field radiotherapy (IF-RT; n = 108), or four weekly standard doses of rituximab (n = 27) within German Hodgkin Study Group clinical trial protocols between 1988 and 2009.
RESULTS: The median age at NLPHL diagnosis was 39 years (range, 16 to 75 years). Most patients were male (76%). The whole patient group had a median follow-up of 91 months (CMT: 95 months; EF-RT: 110 months; IF-RT: 87 months; rituximab: 49 months). At 8 years, progression-free survival and overall survival rates were 88.5% and 98.6% for CMT, 84.3% and 95.7% for EF-RT, and 91.9% and 99.0% for IF-RT, respectively. Patients treated with rituximab had 4-year progression-free and overall survival rates of 81.0% and 100%, respectively. A second malignancy during the course of follow-up was diagnosed in 17 (6.6%) of 256 patients. A total of 12 deaths occurred. However, only one patient died from NLPHL.
CONCLUSION: Tumor control in this analysis was equivalent with CMT, EF-RT, and IF-RT. Therefore, IF-RT, which is associated with the lowest risk for the development of toxic effects, should be considered as standard of care for patients with stage IA NLPHL. Rituximab alone is associated with an increased risk of relapse in this patient population.

© 2015 by American Society of Clinical Oncology.
PMID 26240235
Stephen M Ansell, Alexander M Lesokhin, Ivan Borrello, Ahmad Halwani, Emma C Scott, Martin Gutierrez, Stephen J Schuster, Michael M Millenson, Deepika Cattry, Gordon J Freeman, Scott J Rodig, Bjoern Chapuy, Azra H Ligon, Lili Zhu, Joseph F Grosso, Su Young Kim, John M Timmerman, Margaret A Shipp, Philippe Armand
PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma.
N Engl J Med. 2015 Jan 22;372(4):311-9. doi: 10.1056/NEJMoa1411087. Epub 2014 Dec 6.
Abstract/Text BACKGROUND: Preclinical studies suggest that Reed-Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1-blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma.
METHODS: In this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression.
RESULTS: Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling.
CONCLUSIONS: Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma. (Funded by Bristol-Myers Squibb and others; ClinicalTrials.gov number, NCT01592370.).

PMID 25482239
Anas Younes, Armando Santoro, Margaret Shipp, Pier Luigi Zinzani, John M Timmerman, Stephen Ansell, Philippe Armand, Michelle Fanale, Voravit Ratanatharathorn, John Kuruvilla, Jonathon B Cohen, Graham Collins, Kerry J Savage, Marek Trneny, Kazunobu Kato, Benedetto Farsaci, Susan M Parker, Scott Rodig, Margaretha G M Roemer, Azra H Ligon, Andreas Engert
Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial.
Lancet Oncol. 2016 Sep;17(9):1283-94. doi: 10.1016/S1470-2045(16)30167-X. Epub 2016 Jul 20.
Abstract/Text BACKGROUND: Malignant cells of classical Hodgkin's lymphoma are characterised by genetic alterations at the 9p24.1 locus, leading to overexpression of PD-1 ligands and evasion of immune surveillance. In a phase 1b study, nivolumab, a PD-1-blocking antibody, produced a high response in patients with relapsed and refractory classical Hodgkin's lymphoma, with an acceptable safety profile. We aimed to assess the clinical benefit and safety of nivolumab monotherapy in patients with classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin.
METHODS: In this ongoing, single-arm phase 2 study, adult patients (aged ≥18 years) with recurrent classical Hodgkin's lymphoma who had failed to respond to autologous stem-cell transplantation and had either relapsed after or failed to respond to brentuximab vedotin, and with an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled from 34 hospitals and academic centres across Europe and North America. Patients were given nivolumab intravenously over 60 min at 3 mg/kg every 2 weeks until progression, death, unacceptable toxicity, or withdrawal from study. The primary endpoint was objective response following a prespecified minimum follow-up period of 6 months, assessed by an independent radiological review committee (IRRC). All patients who received at least one dose of nivolumab were included in the primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02181738.
FINDINGS: Among 80 treated patients recruited between Aug 26, 2014, and Feb 20, 2015, the median number of previous therapies was four (IQR 4-7). At a median follow-up of 8·9 months (IQR 7·8-9·9), 53 (66·3%, 95% CI 54·8-76·4) of 80 patients achieved an IRRC-assessed objective response. The most common drug-related adverse events (those that occurred in ≥15% of patients) included fatigue (20 [25%] patients), infusion-related reaction (16 [20%]), and rash (13 [16%]). The most common drug-related grade 3 or 4 adverse events were neutropenia (four [5%] patients) and increased lipase concentrations (four [5%]). The most common serious adverse event (any grade) was pyrexia (three [4%] patients). Three patients died during the study; none of these deaths were judged to be treatment related.
INTERPRETATION: Nivolumab resulted in frequent responses with an acceptable safety profile in patients with classical Hodgkin's lymphoma who progressed after autologous stem-cell transplantation and brentuximab vedotin. Therefore, nivolumab might be a new treatment option for a patient population with a high unmet need. Ongoing follow-up will help to assess the durability of response.
FUNDING: Bristol-Myers Squibb.

Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID 27451390
Wataru Munakata, Ken Ohashi, Nobuhiko Yamauchi, Kensei Tobinai
Fulminant type I diabetes mellitus associated with nivolumab in a patient with relapsed classical Hodgkin lymphoma.
Int J Hematol. 2016 Oct 1;. doi: 10.1007/s12185-016-2101-4. Epub 2016 Oct 1.
Abstract/Text We report the case of a patient with relapsed classical Hodgkin lymphoma who developed fulminant type I diabetes mellitus as a severe adverse event of treatment with the anti-programmed cell death-1 (PD-1) antibody, nivolumab. On the first day of the sixth cycle, the blood glucose level was markedly elevated (375 mg/dL). Although neither ketoacidosis nor ketonuria was detected, the markedly acute onset of the hyperglycemia was consistent with the typical clinical course of fulminant type I diabetes mellitus, and this diagnosis was supported by clinical data. All autoantibodies associated with type I diabetes mellitus were negative. The endogenous insulin secretion ceased completely within 2 weeks. After the blood glucose level was brought under control, nivolumab was resumed and continued without other major adverse events. Human leukocyte antigen (HLA) analysis revealed that the patient carried the HLA-B*4002 haplotype, a susceptibility allele for this type of diabetes mellitus. This case suggests that fulminant type I diabetes mellitus may be triggered by nivolumab in patients with a genetic background associated with the condition, warranting careful future consideration of this particular adverse event.

PMID 27696192
Philippe Armand, Margaret A Shipp, Vincent Ribrag, Jean-Marie Michot, Pier Luigi Zinzani, John Kuruvilla, Ellen S Snyder, Alejandro D Ricart, Arun Balakumaran, Shelonitda Rose, Craig H Moskowitz
Programmed Death-1 Blockade With Pembrolizumab in Patients With Classical Hodgkin Lymphoma After Brentuximab Vedotin Failure.
J Clin Oncol. 2016 Nov 1;34(31):3733-3739. doi: 10.1200/JCO.2016.67.3467.
Abstract/Text Purpose Classical Hodgkin lymphoma (HL) frequently exhibits genetic alterations leading to overexpression of the programmed death-1 (PD-1) ligands, suggesting a possible vulnerability to PD-1 blockade. The phase Ib study KEYNOTE-013 (NCT01953692) tested the safety and efficacy of the anti-PD-1 antibody pembrolizumab in patients with hematologic malignancies. Based on its genetics, HL was included as an independent cohort. Methods We enrolled patients with relapsed or refractory HL whose disease progressed on or after treatment with brentuximab vedotin. Patients received pembrolizumab, 10 mg/kg every 2 weeks, until disease progression occurred. Response to treatment was assessed at week 12 and every 8 weeks thereafter. Principal end points were safety and complete remission (CR) rate. Results Thirty-one patients were enrolled; 55% had more than four lines of prior therapy, and 71% had relapsed after autologous stem cell transplantation. Five patients (16%) experienced grade 3 drug-related adverse events (AEs); there were no grade 4 AEs or deaths related to treatment. The CR rate was 16% (90% CI, 7% to 31%). In addition, 48% of patients achieved a partial remission, for an overall response rate of 65% (90% CI, 48% to 79%). Most of the responses (70%) lasted longer than 24 weeks (range, 0.14+ to 74+ weeks), with a median follow-up of 17 months. The progression-free survival rate was 69% at 24 weeks and 46% at 52 weeks. Biomarker analyses demonstrated a high prevalence of PD-L1 and PD-L2 expression, treatment-induced expansion of T cells and natural killer cells, and activation of interferon-γ, T-cell receptor, and expanded immune-related signaling pathways. Conclusions Pembrolizumab was associated with a favorable safety profile. Pembrolizumab treatment induced favorable responses in a heavily pretreated patient cohort, justifying further studies.

PMID 27354476
Robert Chen, Pier Luigi Zinzani, Michelle A Fanale, Philippe Armand, Nathalie A Johnson, Pauline Brice, John Radford, Vincent Ribrag, Daniel Molin, Theodoros P Vassilakopoulos, Akihiro Tomita, Bastian von Tresckow, Margaret A Shipp, Yinghua Zhang, Alejandro D Ricart, Arun Balakumaran, Craig H Moskowitz, KEYNOTE-087
Phase II Study of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin Lymphoma.
J Clin Oncol. 2017 Jul 1;35(19):2125-2132. doi: 10.1200/JCO.2016.72.1316. Epub 2017 Apr 25.
Abstract/Text Purpose Hodgkin Reed-Sternberg cells harbor alterations in chromosome 9p24.1, leading to overexpression of programmed death-ligand 1 (PD-L1) and PD-L2. Pembrolizumab, a programmed death 1-blocking antibody, demonstrated a high overall response rate (ORR) in patients with relapsed or refractory classic Hodgkin lymphoma (rrHL) in phase I testing. Methods KEYNOTE-087 ( ClinicalTrials.gov identifier, NCT02453594) was a single-arm phase II study of pembrolizumab in three cohorts of patients with rrHL, defined on the basis of lymphoma progression after (1) autologous stem cell transplantation (ASCT) and subsequent brentuximab vedotin (BV); (2) salvage chemotherapy and BV, and thus, ineligible for ASCT because of chemoresistant disease; and (3) ASCT, but without BV after transplantation. Patients received pembrolizumab 200 mg once every 3 weeks. Response was assessed every 12 weeks. The primary end points were ORR by central review and safety. Results A total of 210 patients were enrolled and treated (69 in cohort 1, 81 in cohort 2, and 60 in cohort 3). At the time of analysis, patients received a median of 13 treatment cycles. Per central review, the ORR was 69.0% (95% CI, 62.3% to 75.2%), and the complete response rate was 22.4% (95% CI, 16.9% to 28.6%). By cohort, ORRs were 73.9% for cohort 1, 64.2% for cohort 2, and 70.0% for cohort 3. Thirty-one patients had a response ≥ 6 months. The safety profile was largely consistent with previous pembrolizumab studies. Conclusion Pembrolizumab was associated with high response rates and an acceptable safety profile in patients with rrHL, offering a new treatment paradigm for this disease.

PMID 28441111
Anas Younes, Nancy L Bartlett, John P Leonard, Dana A Kennedy, Carmel M Lynch, Eric L Sievers, Andres Forero-Torres
Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas.
N Engl J Med. 2010 Nov 4;363(19):1812-21. doi: 10.1056/NEJMoa1002965.
Abstract/Text BACKGROUND: Hodgkin's lymphoma and anaplastic large-cell lymphoma are the two most common tumors expressing CD30. Previous attempts to target the CD30 antigen with monoclonal-based therapies have shown minimal activity. To enhance the antitumor activity of CD30-directed therapy, the antitubulin agent monomethyl auristatin E (MMAE) was attached to a CD30-specific monoclonal antibody by an enzyme-cleavable linker, producing the antibody-drug conjugate brentuximab vedotin (SGN-35).
METHODS: In this phase 1, open-label, multicenter dose-escalation study, we administered brentuximab vedotin (at a dose of 0.1 to 3.6 mg per kilogram of body weight) every 3 weeks to 45 patients with relapsed or refractory CD30-positive hematologic cancers, primarily Hodgkin's lymphoma and anaplastic large-cell lymphoma. Patients had received a median of three previous chemotherapy regimens (range, one to seven), and 73% had undergone autologous stem-cell transplantation.
RESULTS: The maximum tolerated dose was 1.8 mg per kilogram, administered every 3 weeks. Objective responses, including 11 complete remissions, were observed in 17 patients. Of 12 patients who received the 1.8-mg-per-kilogram dose, 6 (50%) had an objective response. The median duration of response was at least 9.7 months. Tumor regression was observed in 36 of 42 patients who could be evaluated (86%). The most common adverse events were fatigue, pyrexia, diarrhea, nausea, neutropenia, and peripheral neuropathy.
CONCLUSIONS: Brentuximab vedotin induced durable objective responses and resulted in tumor regression for most patients with relapsed or refractory CD30-positive lymphomas in this phase 1 study. Treatment was associated primarily with grade 1 or 2 (mild-to-moderate) toxic effects. (Funded by Seattle Genetics; ClinicalTrials.gov number, NCT00430846.).

PMID 21047225
Anas Younes, Ajay K Gopal, Scott E Smith, Stephen M Ansell, Joseph D Rosenblatt, Kerry J Savage, Radhakrishnan Ramchandren, Nancy L Bartlett, Bruce D Cheson, Sven de Vos, Andres Forero-Torres, Craig H Moskowitz, Joseph M Connors, Andreas Engert, Emily K Larsen, Dana A Kennedy, Eric L Sievers, Robert Chen
Results of a pivotal phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma.
J Clin Oncol. 2012 Jun 20;30(18):2183-9. doi: 10.1200/JCO.2011.38.0410. Epub 2012 Mar 26.
Abstract/Text PURPOSE: Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E, an antimicrotubule agent, into CD30-expressing cells. In phase I studies, brentuximab vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory CD30-positive lymphomas.
PATIENTS AND METHODS: In this multinational, open-label, phase II study, the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkin's lymphoma (HL) after autologous stem-cell transplantation (auto-SCT). Patients had histologically documented CD30-positive HL by central pathology review. A total of 102 patients were treated with brentuximab vedotin 1.8 mg/kg by intravenous infusion every 3 weeks. In the absence of disease progression or prohibitive toxicity, patients received a maximum of 16 cycles. The primary end point was the overall objective response rate (ORR) determined by an independent radiology review facility.
RESULTS: The ORR was 75% with complete remission (CR) in 34% of patients. The median progression-free survival time for all patients was 5.6 months, and the median duration of response for those in CR was 20.5 months. After a median observation time of more than 1.5 years, 31 patients were alive and free of documented progressive disease. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea.
CONCLUSION: The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75% of patients with relapsed or refractory HL after auto-SCT. Durable CRs approaching 2 years were observed, supporting study in earlier lines of therapy.

PMID 22454421
Robert Chen, Ajay K Gopal, Scott E Smith, Stephen M Ansell, Joseph D Rosenblatt, Kerry J Savage, Joseph M Connors, Andreas Engert, Emily K Larsen, Dirk Huebner, Abraham Fong, Anas Younes
Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma.
Blood. 2016 Sep 22;128(12):1562-6. doi: 10.1182/blood-2016-02-699850. Epub 2016 Jul 18.
Abstract/Text Presented here are the 5-year end-of-study results from the pivotal phase 2 trial of brentuximab vedotin in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) after failed hematopoietic autologous stem cell transplantation. At 5 years, the overall patient population (N = 102) had an estimated overall survival (OS) rate of 41% (95% confidence interval [CI]: 31-51) and progression-free survival (PFS) rate of 22% (95% CI: 13-31). Patients who achieved a complete response (CR) to brentuximab vedotin (N = 34) had estimated OS and PFS rates of 64% (95% CI: 48-80%) and 52% (95% CI: 34-69%), respectively. The median OS and PFS were not reached in CR patients, with 13 patients (38% of all CR patients) remaining in follow-up and in remission at study closure. Of the 13 patients, 4 received consolidative hematopoietic allogeneic stem cell transplant, and 9 (9% of all enrolled patients) remain in sustained CR without receiving any further anticancer therapy after treatment with brentuximab vedotin. Of the patients who experienced treatment-emergent peripheral neuropathy, 88% experienced either resolution (73%) or improvement (14%) in symptoms. These 5-year follow-up data demonstrate that a subset of patients with R/R HL who obtained CR with single-agent brentuximab vedotin achieved long-term disease control and may potentially be cured. The trial was registered at www.clinicaltrials.gov as #NCT00848926.

© 2016 by The American Society of Hematology.
PMID 27432875
Anas Younes, Joseph M Connors, Steven I Park, Michelle Fanale, Megan M O'Meara, Naomi N Hunder, Dirk Huebner, Stephen M Ansell
Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study.
Lancet Oncol. 2013 Dec;14(13):1348-56. doi: 10.1016/S1470-2045(13)70501-1. Epub 2013 Nov 15.
Abstract/Text BACKGROUND: Roughly 70-80% of patients with advanced stage Hodgkin's lymphoma are cured with various first-line and second-line treatments, including ABVD, BEACOPP, and stem-cell transplantation. Brentuximab vedotin has shown significant clinical activity, with a manageable safety profile, in patients with relapsed or refractory Hodgkin's lymphoma. We aimed to assess the safety and early clinical efficacy of this drug as first-line treatment in combination with standard or modified-standard treatment in patients with previously untreated Hodgkin's lymphoma.
METHODS: We did a phase 1, open-label, dose-escalation safety study comparing brentuximab vedotin in combination with standard (ABVD) or a modified-standard (AVD) treatment. Patients were enrolled into the groups sequentially. Main entry criteria were newly diagnosed, treatment-naive, CD30-positive patients with Hodgkin's lymphoma who had histologically confirmed stage IIA bulky disease or stage IIB-IV disease and an Eastern Cooperative Oncology Group performance status of two or less. Patients received doses of 0·6, 0·9, or 1·2 mg/kg brentuximab vedotin by intravenous infusion every 2 weeks with either ABVD (25 mg/m(2) doxorubicin, 10 units/m(2) bleomycin, 6 mg/m(2) vinblastine, and 375 mg/m(2) dacarbazine) or AVD (ABVD modified regimen without the inclusion of bleomycin) for up to six cycles. Our primary objectives were to assess the safety profile and establish the maximum tolerated dose (MTD) of brentuximab vedotin in combination with ABVD and AVD. The safety profile and MTD was assessed for the safety population. The study has completed and the final analysis is presented. This study was registered with ClinicalTrials.gov, number NCT01060904.
FINDINGS: Between Jan 29, 2010, and Sept 17, 2012, 51 patients were enrolled and received at least one dose of brentuximab vedotin. The maximum tolerated dose of brentuximab vedotin when combined with ABVD or AVD was not exceeded at 1·2 mg/kg. 21 (95%) of 22 patients given brentuximab vedotin and ABVD achieved complete remission, as did 24 (96%) of 25 patients given brentuximab vedotin and AVD. Adverse events were generally grade 1 or 2; however, an unacceptable number of patients in the brentuximab vedotin and ABVD groups had pulmonary toxic effects (11 [44%] of 25), which exceeded the historical incidence for ABVD alone. No patients experienced pulmonary toxic effects when treated with brentuximab vedotin plus AVD. The most common grade 3 or worse events were neutropenia (20 [80%] of 25 patients in the brentuximab vedotin and ABVD group vs 20 [77%] of 26 patients in the brentuximab vedotin and AVD group), anaemia (five [20%] vs three [12%]), febrile neutropenia (five [20%] vs two [8%]), pulmonary toxic effects (six [24%] vs 0), syncope (three [12%] vs two [8%]), dyspnoea (three [12%] vs one [4%]), pulmonary embolism (three [12%] vs 0), fatigue (one [4%] each), and leucopenia (one [4%] each). Serious events occured in 41% of all patients (14 [56%] in the brentuximab vedotin and ABVD group and seven [27%] in the brentuximab vedotin and AVD group). Serious events occurring in 10% of patients or more overall were febrile neutropenia (four [16%] in the brentuximab vedotin and ABVD group vs two [8%] in the brentuximab vedotin and AVD group), and, in the brentuximab vedotin and ABVD group only, pulmonary toxic effects (six [24%]).
INTERPRETATION: Brentuximab vedotin should not be given with bleomycin in general or specifically as first-line therapy for patients with treatment naive, advanced stage Hodgkin's lymphoma. 1·2 mg/kg brentuximab vedotin combined with AVD given every 2 weeks was generally well tolerated by patients. At present, a phase 3 trial comparing brentuximab vedotin plus AVD to ABVD alone is ongoing (ClinicalTrials.gov, number NCT01712490) and will formally assess whether brentuximab vedotin plus AVD might redefine therapy in treatment-naive patients with Hodgkin's lymphoma.
FUNDING: Seattle Genetics Inc and Takeda Pharmaceuticals International Co.

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 24239220
Craig H Moskowitz, Auayporn Nademanee, Tamas Masszi, Edward Agura, Jerzy Holowiecki, Muneer H Abidi, Andy I Chen, Patrick Stiff, Alessandro M Gianni, Angelo Carella, Dzhelil Osmanov, Veronika Bachanova, John Sweetenham, Anna Sureda, Dirk Huebner, Eric L Sievers, Andy Chi, Emily K Larsen, Naomi N Hunder, Jan Walewski, AETHERA Study Group
Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin's lymphoma at risk of relapse or progression (AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet. 2015 May 9;385(9980):1853-62. doi: 10.1016/S0140-6736(15)60165-9. Epub 2015 Mar 19.
Abstract/Text BACKGROUND: High-dose therapy followed by autologous stem-cell transplantation is standard of care for patients with relapsed or primary refractory Hodgkin's lymphoma. Roughly 50% of patients might be cured after autologous stem-cell transplantation; however, most patients with unfavourable risk factors progress after transplantation. We aimed to assess whether brentuximab vedotin improves progression-free survival when given as early consolidation after autologous stem-cell transplantation.
METHODS: We did this randomised, double-blind, placebo-controlled, phase 3 trial at 78 sites in North America and Europe. Patients with unfavourable-risk relapsed or primary refractory classic Hodgkin's lymphoma who had undergone autologous stem-cell transplantation were randomly assigned, by fixed-block randomisation with a computer-generated random number sequence, to receive 16 cycles of 1·8 mg/kg brentuximab vedotin or placebo intravenously every 3 weeks, starting 30-45 days after transplantation. Randomisation was stratified by best clinical response after completion of salvage chemotherapy (complete response vs partial response vs stable disease) and primary refractory Hodgkin's lymphoma versus relapsed disease less than 12 months after completion of frontline therapy versus relapse 12 months or more after treatment completion. Patients and study investigators were masked to treatment assignment. The primary endpoint was progression-free survival by independent review, defined as the time from randomisation to the first documentation of tumour progression or death. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01100502.
FINDINGS: Between April 6, 2010, and Sept 21, 2012, we randomly assigned 329 patients to the brentuximab vedotin group (n=165) or the placebo group (n=164). Progression-free survival by independent review was significantly improved in patients in the brentuximab vedotin group compared with those in the placebo group (hazard ratio [HR] 0·57, 95% CI 0·40-0·81; p=0·0013). Median progression-free survival by independent review was 42·9 months (95% CI 30·4-42·9) for patients in the brentuximab vedotin group compared with 24·1 months (11·5-not estimable) for those in the placebo group. We recorded consistent benefit (HR <1) of brentuximab vedotin consolidation across subgroups. The most frequent adverse events in the brentuximab vedotin group were peripheral sensory neuropathy (94 [56%] of 167 patients vs 25 [16%] of 160 patients in the placebo group) and neutropenia (58 [35%] vs 19 [12%] patients). At time of analysis, 28 (17%) of 167 patients had died in the brentuximab vedotin group compared with 25 (16%) of 160 patients in the placebo group.
INTERPRETATION: Early consolidation with brentuximab vedotin after autologous stem-cell transplantation improved progression-free survival in patients with Hodgkin's lymphoma with risk factors for relapse or progression after transplantation. This treatment provides an important therapeutic option for patients undergoing autologous stem-cell transplantation.
FUNDING: Seattle Genetics and Takeda Pharmaceuticals International.

Copyright © 2015 Elsevier Ltd. All rights reserved.
PMID 25796459

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