Chronic lymphocytic leukemia - 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 CLL page for regimens that include active anticancer treatment.
=Consolidation and/or maintenance after first-line therapy=
==Observation==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Wendtner et al. 2004 (GCLLSG CLL4B)	Not reported 	Phase 3 (C) 	Alemtuzumab 	Shorter PFS1
Michallet et al. 2010 	2001-2007 	Phase 3 (C) 	1. Cy/TBI, then auto HSCT2. BEAM, then auto HSCT	Shorter EFS
Sutton et al. 2011 (Auto-LLC 2001) 	2001-2007 	Phase 3 (C) 	Cy/TBI, then auto HSCT 	Shorter EFS
Foà et al. 2014 (ML21445) 	2008-2013 	Randomized Phase 2 (C)	Rituximab 	Might have shorter PFS
Greil et al. 2016 (AGMT CLL-8a) 	2010-2013 	Phase 3 (C) 	Rituximab 	Shorter PFS
Fink et al. 2017 (GCLLSG CLLM1) 	2012-2016 	Phase 3 (C) 	Lenalidomide 	Shorter PFSMedian PFS: 13.3 vs NYR mo(HR 5.88, 95% CI 2.63-14.29)
Dartigeas et al. 2017 (CLL 2007 SA)	2007-2014 	Phase 3 (C) 	Rituximab 	Shorter PFSMedian PFS: 49 vs 59.3 mo(HR 1.82, 95% CI 1.33-2.50)
1Reported efficacy for GCLLSG CLL4B is based on the 2009 update.
No further treatment; used as a comparator arm. GCLLSG CLL4B closed early due to high rates of infections in the experimental arm
====Preceding treatment====
*GCLLSG CLL4B: First-line F x 6 versus FC x 6
*Auto-LLC 2001: First-line miniCHOP-F
*ML21445: First-line Clb-R 
*AGMT CLL-8a: First-line rituximab-containing chemoimmunotherapy
*GCLLSG CLLM1: First-line chemoimmunotherapy
*CLL 2007 SA: First-line FCR x 4
===References===
# GCLLSG CLL4B: Wendtner CM, Ritgen M, Schweighofer CD, Fingerle-Rowson G, Campe H, Jäger G, Eichhorst B, Busch R, Diem H, Engert A, Stilgenbauer S, Döhner H, Kneba M, Emmerich B, Hallek M; German CLL Study Group. Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission--experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia. 2004 Jun;18(6):1093-101. link to original article EuroPMC
## Update: Schweighofer CD, Ritgen M, Eichhorst BF, Busch R, Abenhardt W, Kneba M, Hallek M, Wendtner CM. Consolidation with alemtuzumab improves progression-free survival in patients with chronic lymphocytic leukaemia (CLL) in first remission: long-term follow-up of a randomized phase III trial of the German CLL Study Group (GCLLSG). Br J Haematol. 2009 Jan;144(1):95-8. Epub 2008 Oct 30. link to original article EuroPMC
# Michallet M, Dreger P, Sutton L, Brand R, Richards S, van Os M, Sobh M, Choquet S, Corront B, Dearden C, Gratwohl A, Herr W, Catovsky D, Hallek M, de Witte T, Niederwieser D, Leporrier M, Milligan D; EBMT Chronic Leukemia Working Party. Autologous hematopoietic stem cell transplantation in chronic lymphocytic leukemia: results of European intergroup randomized trial comparing autografting versus observation. Blood. 2011 Feb 3;117(5):1516-21. Epub 2010 Nov 24. link to original article EuroPMC
# Auto-LLC 2001: Sutton L, Chevret S, Tournilhac O, Diviné M, Leblond V, Corront B, Leprêtre S, Eghbali H, Van Den Neste E, Michallet M, Maloisel F, Bouabdallah K, Decaudin D, Berthou C, Brice P, Gonzalez H, Chapiro E, Radford-Weiss I, Leporrier N, Maloum K, Nguyen-Khac F, Davi F, Lejeune J, Merle-Béral H, Leporrier M; Société Française de Greffe de Moelle et de Thérapie Cellulaire; Groupe Français d'étude de la Leucémie Lymphoïde Chronique. Autologous stem cell transplantation as a first-line treatment strategy for chronic lymphocytic leukemia: a multicenter, randomized, controlled trial from the SFGM-TC and GFLLC. Blood. 2011 Jun 9;117(23):6109-19. Epub 2011 Mar 15. link to original article EuroPMC NCT00931645
# ML21445: Foà R, Del Giudice I, Cuneo A, Del Poeta G, Ciolli S, Di Raimondo F, Lauria F, Cencini E, Rigolin GM, Cortelezzi A, Nobile F, Callea V, Brugiatelli M, Massaia M, Molica S, Trentin L, Rizzi R, Specchia G, Di Serio F, Orsucci L, Ambrosetti A, Montillo M, Zinzani PL, Ferrara F, Morabito F, Mura MA, Soriani S, Peragine N, Tavolaro S, Bonina S, Marinelli M, De Propris MS, Starza ID, Piciocchi A, Alietti A, Runggaldier EJ, Gamba E, Mauro FR, Chiaretti S, Guarini A. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients. Am J Hematol. 2014 May;89(5):480-6. Epub 2014 Feb 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC EudraCT 2008-001612-20
# AGMT CLL-8a: Greil R, Obrtlíková P, Smolej L, Kozák T, Steurer M, Andel J, Burgstaller S, Mikušková E, Gercheva L, Nösslinger T, Papajík T, Ladická M, Girschikofsky M, Hrubiško M, Jäger U, Fridrik M, Pecherstorfer M, Králiková E, Burcoveanu C, Spasov E, Petzer A, Mihaylov G, Raynov J, Oexle H, Zabernigg A, Flochová E, Palášthy S, Stehlíková O, Doubek M, Altenhofer P, Pleyer L, Melchardt T, Klingler A, Mayer J, Egle A. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016 Jul;3(7):e317-29. Epub 2016 Jun 16. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT01118234
# GCLLSG CLLM1: Fink AM, Bahlo J, Robrecht S, Al-Sawaf O, Aldaoud A, Hebart H, Jentsch-Ullrich K, Dörfel S, Fischer K, Wendtner CM, Nösslinger T, Ghia P, Bosch F, Kater AP, Döhner H, Kneba M, Kreuzer KA, Tausch E, Stilgenbauer S, Ritgen M, Böttcher S, Eichhorst B, Hallek M. Lenalidomide maintenance after first-line therapy for high-risk chronic lymphocytic leukaemia (CLLM1): final results from a randomised, double-blind, phase 3 study. Lancet Haematol. 2017 Oct;4(10):e475-e486. Epub 2017 Sep 12. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT01556776
# CLL 2007 SA: Dartigeas C, Van Den Neste E, Léger J, Maisonneuve H, Berthou C, Dilhuydy MS, De Guibert S, Leprêtre S, Béné MC, Nguyen-Khac F, Letestu R, Cymbalista F, Rodon P, Aurran-Schleinitz T, Vilque JP, Tournilhac O, Mahé B, Laribi K, Michallet AS, Delmer A, Feugier P, Lévy V, Delépine R, Colombat P, Leblond V; CLL 2007 SA investigators; FILO. Rituximab maintenance versus observation following abbreviated induction with chemoimmunotherapy in elderly patients with previously untreated chronic lymphocytic leukaemia (CLL 2007 SA): an open-label, randomised phase 3 study. Lancet Haematol. 2018 Feb;5(2):e82-e94. Epub 2017 Dec 20. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00645606
=Consolidation and/or maintenance after subsequent lines of therapy=
==Observation==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Greil et al. 2016 (AGMT CLL-8a)	2010-2013 	Phase 3 (C)	Rituximab 	Shorter PFS
van Oers et al. 2015 (PROLONG) 	2010-2014 	Phase 3 (C)	Ofatumumab	Shorter PFSMedian PFS: 15.2 vs 29.4 mo(HR 2.00, 95% CI 1.52-2.63)
No further treatment offered to patients in their second or third CR or PR; prior treatment was not specified in PROLONG. 
====Preceding treatment====
*AGMT CLL-8a: Second-line rituximab-containing chemoimmunotherapy
===References===
# PROLONG: van Oers MH, Kuliczkowski K, Smolej L, Petrini M, Offner F, Grosicki S, Levin MD, Gupta I, Phillips J, Williams V, Manson S, Lisby S, Geisler C; PROLONG study investigators. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol. 2015 Oct;16(13):1370-9. Epub 2015 Sep 13. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00802737
## Update: van Oers M, Smolej L, Petrini M, Offner F, Grosicki S, Levin MD, Davis J, Banerjee H, Stefanelli T, Hoever P, Geisler C. Ofatumumab maintenance prolongs progression-free survival in relapsed chronic lymphocytic leukemia: final analysis of the PROLONG study. Blood Cancer J. 2019 Dec 4;9(12):98. link to original article link to PMC article EuroPMC
# AGMT CLL-8a: Greil R, Obrtlíková P, Smolej L, Kozák T, Steurer M, Andel J, Burgstaller S, Mikušková E, Gercheva L, Nösslinger T, Papajík T, Ladická M, Girschikofsky M, Hrubiško M, Jäger U, Fridrik M, Pecherstorfer M, Králiková E, Burcoveanu C, Spasov E, Petzer A, Mihaylov G, Raynov J, Oexle H, Zabernigg A, Flochová E, Palášthy S, Stehlíková O, Doubek M, Altenhofer P, Pleyer L, Melchardt T, Klingler A, Mayer J, Egle A. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial. Lancet Haematol. 2016 Jul;3(7):e317-29. Epub 2016 Jun 16. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT01118234
==Placebo==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Chanan-Khan et al. 2017 (CONTINUUM)	2009-2015 	Phase 3 (C)	Lenalidomide	Did not meet primary endpoint of OS
No active antineoplastic treatment offered to patients with at least partial response to second-line therapy. 
===References===
# CONTINUUM: Chanan-Khan AA, Zaritskey A, Egyed M, Vokurka S, Semochkin S, Schuh A, Kassis J, Simpson D, Zhang J, Purse B, Foà R. Lenalidomide maintenance therapy in previously treated chronic lymphocytic leukaemia (CONTINUUM): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Haematol. 2017 Nov;4(11):e534-e543. Epub 2017 Sep 25. link to original article EuroPMC NCT00774345
Category:Chronic lymphocytic leukemia regimens
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Category:Indolent lymphomas
Category:Null regimens