Diffuse large B-cell lymphoma - null regimens

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The purpose of this page is to provide references to "null therapy" such as placebo and observation. These references provide further insight into the historical development of the treatment landscape. See the main DLBCL page for regimens that include active anticancer treatment.
=Consolidation after upfront therapy=
==Observation==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Horning et al. 2004 (ECOG E1484) 	1984-1992 	Phase 3 (C) 	IFRT 	Seems to have shorter DFS
Bonnet et al. 2007 	1993-2002 	Phase 3 (E-de-esc)	IFRT 	Did not meet primary endpoint of EFS
Habermann et al. 2006 (ECOG E4494) 	1998-2001 	Phase 3 (C) 	Rituximab 	Did not meet primary endpoint of FFS
Haioun et al. 2009 (LNH 98-3) 	1999-2004 	Phase 3 (C) 	Rituximab 	Might have shorter EFS
Witzens-Harig et al. 2015 (HD2002) 	2002-2011 	Phase 3 (C) 	Rituximab 	Shorter OS in males
Jaeger et al. 2015 (NHL13) 	2004-2010 	Phase 3 (C) 	Rituximab 	Did not meet primary endpoint of EFS
Lamy et al. 2017 (LYSA/GOELAMS 02-03)	2005-2014 	Phase 3 (C) 	IFRT 	Non-inferior EFS
No further treatment, also variously termed "observation" and "watchful waiting". Note: in ECOG E4494, a statistically signficant disadvantage to observation was seen in the group receiving CHOP induction, which is no longer standard of care.
====Preceding treatment====
*ECOG E1484: Induction CHOP x 8, with CR
*ECOG E4494: R-CHOP versus CHOP induction
*Bonnet et al. 2007: Induction CHOP x 4
*LNH 98-3: CBVM, then auto HSCT consolidation
*HD2002: "Standard treatment"
*LYSA/GOELAMS 02-03: Induction R-CHOP-14 x 4 to 6
===References===
#ECOG E1484: Horning SJ, Weller E, Kim K, Earle JD, O'Connell MJ, Habermann TM, Glick JH. Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin's lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol. 2004 Aug 1;22(15):3032-8. Epub 2004 Jun 21. link to original article EuroPMC
#ECOG E4494: Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA, Cohn JB, Dakhil SR, Woda B, Fisher RI, Peterson BA, Horning SJ. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006 Jul 1;24(19):3121-7. Epub 2006 Jun 5. link to original article EuroPMC NCT00003150
#Bonnet C, Fillet G, Mounier N, Ganem G, Molina TJ, Thiéblemont C, Fermé C, Quesnel B, Martin C, Gisselbrecht C, Tilly H, Reyes F; Groupe d'Etude des Lymphomes de l'Adulte. CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 2007 Mar 1;25(7):787-92. Epub 2007 Jan 16. link to original article EuroPMC
#LNH 98-3: Haioun C, Mounier N, Emile JF, Ranta D, Coiffier B, Tilly H, Récher C, Fermé C, Gabarre J, Herbrecht R, Morchhauser F, Gisselbrecht C. Rituximab versus observation after high-dose consolidative first-line chemotherapy with autologous stem-cell transplantation in patients with poor-risk diffuse large B-cell lymphoma. Ann Oncol. 2009 Dec;20(12):1985-92. Epub 2009 Jun 30. link to original article EuroPMC NCT00169169
#NHL13: Jaeger U, Trneny M, Melzer H, Praxmarer M, Nawarawong W, Ben Yehuda D, Goldstein D, Mihaljevic B, Ilhan O, Ballova V, Hedenus M, Hsiao LT, Au WY, Burgstaller S, Weidinger G, Keil F, Dittrich C, Skrabs C, Klingler A, Chott A, Fridrik MA, Greil R. Rituximab maintenance for patients with aggressive B-cell lymphoma in first remission: results of the randomized NHL13 trial. Haematologica. 2015 Jul;100(7):955-63. Epub 2015 Apr 24. link to original article link to PMC article EuroPMC NCT00400478
#HD2002: Witzens-Harig M, Benner A, McClanahan F, Klemmer J, Brandt J, Brants E, Rieger M, Meissner J, Hensel M, Neben K, Dreger P, Lengfelder E, Schmidt-Wolf I, Krämer A, Ho AD. Rituximab maintenance improves survival in male patients with diffuse large B-cell lymphoma: results of the HD2002 prospective multicentre randomized phase III trial. Br J Haematol. 2015 Dec;171(5):710-9. Epub 2015 Oct 9. link to original article EuroPMC NCT01933711
#LYSA/GOELAMS 02-03: Lamy T, Damaj G, Soubeyran P, Gyan E, Cartron G, Bouabdallah K, Gressin R, Cornillon J, Banos A, Le Du K, Benchalal M, Moles MP, Le Gouill S, Fleury J, Godmer P, Maisonneuve H, Deconinck E, Houot R, Laribi K, Marolleau JP, Tournilhac O, Branger B, Devillers A, Vuillez JP, Fest T, Colombat P, Costes V, Szablewski V, Béné MC, Delwail V; LYSA; GOELAMS. R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma. Blood. 2018 Jan 11;131(2):174-181. Epub 2017 Oct 23. link to original article link to PMC article EuroPMC NCT00841945
==Placebo==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Crump et al. 2016 (PRELUDE) 	Not reported 	Phase 3 (C)	Enzastaurin 	Did not meet primary endpoint of DFS
Witzig et al. 2018 (PILLAR-2) 	2009-2013 	Phase 3 (C)	Everolimus 	Did not meet primary endpoint of DFSDFS24: 77% vs 77.8%(HR 1.09, 95% CI 0.82-1.45)
Thieblemont et al. 2017 (REMARC)	2009-2014 	Phase 3 (C)	Lenalidomide	Shorter PFSMedian PFS: 58.9 vs NYR mo(HR 1.41, 95% CI 1.08-1.85)
No further antineoplastic treatment.
====Preceding treatment====
*PRELUDE: R-CHOP induction
*REMARC: R-CHOP21 or R-CHOP-14 induction
===References===
#PRELUDE: Crump M, Leppä S, Fayad L, Lee JJ, Di Rocco A, Ogura M, Hagberg H, Schnell F, Rifkin R, Mackensen A, Offner F, Pinter-Brown L, Smith S, Tobinai K, Yeh SP, Hsi ED, Nguyen T, Shi P, Hahka-Kemppinen M, Thornton D, Lin B, Kahl B, Schmitz N, Savage KJ, Habermann T. Randomized, double-blind, phase III trial of enzastaurin versus placebo in patients achieving remission after first-line therapy for high-risk diffuse large B-cell lymphoma. J Clin Oncol. 2016 Jul 20;34(21):2484-92. Epub 2016 May 23. link to original article EuroPMC NCT00332202
#REMARC: Thieblemont C, Tilly H, Gomes da Silva M, Casasnovas RO, Fruchart C, Morschhauser F, Haioun C, Lazarovici J, Grosicka A, Perrot A, Trotman J, Sebban C, Caballero D, Greil R, van Eygen K, Cohen AM, Gonzalez H, Bouabdallah R, Oberic L, Corront B, Choufi B, Lopez-Guillermo A, Catalano J, Van Hoof A, Briere J, Cabeçadas J, Salles G, Gaulard P, Bosly A, Coiffier B. Lenalidomide maintenance compared with placebo in responding elderly patients with diffuse large B-cell lymphoma treated with first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2017 Aug 1;35(22):2473-2481. Epub 2017 Apr 20. link to original article EuroPMC NCT01122472
#PILLAR-2: Witzig TE, Tobinai K, Rigacci L, Ikeda T, Vanazzi A, Hino M, Shi Y, Mayer J, Costa LJ, Bermudez Silva CD, Zhu J, Belada D, Bouabdallah K, Kattan JG, Kuruvilla J, Kim WS, Larouche JF, Ogura M, Ozcan M, Fayad L, Wu C, Fan J, Louveau AL, Voi M, Cavalli F. Adjuvant everolimus in high-risk diffuse large B-cell lymphoma: final results from the PILLAR-2 randomized phase III trial. Ann Oncol. 2018 Mar 1;29(3):707-714. link to original article EuroPMC NCT00790036
=Maintenance after salvage therapy=
==Observation==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Furman et al. 2011 (CALGB 9254) 	1993-1997 	Phase 3 (C)	Anti-B4-bR	Did not meet primary endpoint of EFS
Thompson et al. 2008 (SWOG 9438)	1995-2004 	Phase 3 (C)	IL-2 	Did not meet co-primary endpoints of PFS/OS
Gisselbrecht et al. 2010 (CORAL)	2003-2007 	Phase 3 (C)	Rituximab 	Did not meet secondary endpoint of EFS1
1Reported efficacy for CORAL is based on the 2012 update.
No further treatment.
====Preceding treatment====
*SWOG 9438: Cyclophosphamide, Etoposide, TBI with autologous hematopoietic stem cell transplant consolidation
*CORAL: BEAM with autologous hematopoietic stem cell transplant consolidation
===References===
#SWOG 9438: Thompson JA, Fisher RI, Leblanc M, Forman SJ, Press OW, Unger JM, Nademanee AP, Stiff PJ, Petersdorf SH, Fefer A. Total body irradiation, etoposide, cyclophosphamide, and autologous peripheral blood stem-cell transplantation followed by randomization to therapy with interleukin-2 versus observation for patients with non-Hodgkin lymphoma: results of a phase 3 randomized trial by the Southwest Oncology Group (SWOG 9438). Blood. 2008 Apr 15;111(8):4048-54. Epub 2008 Feb 6. link to original article link to PMC article EuroPMC NCT00002649
#CALGB 9254: Furman RR, Grossbard ML, Johnson JL, Pecora AL, Cassileth PA, Jung SH, Peterson BA, Nadler LM, Freedman A, Bayer RL, Bartlett NL, Hurd DD, Cheson BD; Cancer and Leukemia Group B; ECOG. A phase III study of anti-B4-blocked ricin as adjuvant therapy post-autologous bone marrow transplant: CALGB 9254. Leuk Lymphoma. 2011 Apr;52(4):587-96. Epub 2011 Jan 28. link to original article link to PMC article EuroPMC
#CORAL: Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Brière J, Moskowitz CH, Schmitz N. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010 Sep 20;28(27):4184-90. Epub 2010 Jul 26. Erratum in: J Clin Oncol. 2012 May 20;30(15):1896. link to original article link to PMC article EuroPMC NCT00137995
##Update: Gisselbrecht C, Schmitz N, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Milpied NJ, Radford J, Ketterer N, Shpilberg O, Dührsen U, Hagberg H, Ma DD, Viardot A, Lowenthal R, Brière J, Salles G, Moskowitz CH, Glass B. Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapsed aggressive lymphoma. J Clin Oncol. 2012 Dec 20;30(36):4462-9. Epub 2012 Oct 22. link to original article link to PMC article EuroPMC
==Placebo==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Awaiting publication (Alliance A051301)	2016-2023 	Phase 3 (C)	Ibrutinib 	TBD if different primary endpoint of PFS24
No further active antineoplastic treatment.
===References===
*Alliance A051301: NCT02443077
Category:Diffuse large B-cell lymphoma regimens
Category:Null regimens
Category:Disease-specific pages
Category:Aggressive non-Hodgkin lymphomas
Category:B-cell lymphomas