Diffuse large B-cell lymphoma

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Are you looking for a regimen, such as CHOP, but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
*For CNS regimens (primary and secondary), please visit this page. If CNS therapy is described as part of a comprehensive protocol, it will also be available here.''
*For pediatric regimens, please visit the pediatric NHL page.
*We have moved How I Treat articles to a dedicated page.
Last updated on 2024-12-02:113 regimens on this page
177 variants on this page
 
=Guidelines=
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
==ASTCT==
* 2023: Epperla et al. ASTCT Clinical Practice Recommendations for Transplantation and Cellular Therapies in Diffuse Large B Cell Lymphoma EuroPMC
==BSH==
*2024: Fox et al. The management of newly diagnosed large B-cell lymphoma: A British Society for Haematology Guideline EuroPMC
*2020: McKay et al. The prevention of central nervous system relapse in diffuse large B-cell lymphoma: a British Society for Haematology good practice paper EuroPMC
==ESMO==
*2016: Vitolo et al. Extranodal diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
*2015: Tilly et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2012: Tilly et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2010: Tilly & Dreyling. Diffuse large B-cell non-Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2009: Tilly & Dreyling. Diffuse large B-cell non-Hodgkin's lymphoma: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
*2013: Ghielmini et al. ESMO Guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) link to PMC article EuroPMC
*2007: Jost. Newly diagnosed large B-cell non-Hodgkin's lymphoma: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2005: Jost et al. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of newly diagnosed large cell non-Hodgkin's lymphoma EuroPMC
**2001: ESMO minimum clinical recommendations for diagnosis, treatment and follow-up of newly diagnosed large cell non-Hodgkin's lymphoma EuroPMC
*2007: Jost. Relapsed large B-cell non-Hodgkin's lymphoma: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2005: Jost & Stahel. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of relapsed large cell non-Hodgkin's lymphoma EuroPMC
**2001: ESMO minimum clinical recommendations for diagnosis, treatment and follow-up of relapsed large cell non-Hodgkin's lymphoma EuroPMC
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - B-cell Lymphomas.
**2016: Zelenetz et al. Diffuse Large B-Cell Lymphoma Version 1.2016 EuroPMC
==SEOM-GOTEL==
*2023: Gumà et al. SEOM-GOTEL clinical guidelines on diffuse large B cell lymphoma (2022) EuroPMC
==SITC==
*2020: Neelapu et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of lymphoma link to PMC article EuroPMC
=Untreated, pre-phase=
==Vincristine & Prednisone==
===Regimen variant #1, PO vincristine===
Study 	Dates of enrollment	Evidence
Peyrade et al. 2016 (LYSA LNH09-7B)	2010-2011 	Phase 2
====Chemotherapy====
*Vincristine (Oncovin) 1 mg PO once on day -7
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg PO once per day on days -7 to -4
7-day course
====Subsequent treatment====
*O-miniCHOP induction
===Regimen variant #2, IV vincristine===
Study 	Dates of enrollment	Evidence
Pfreundschuh et al. 2004 (NHL-B1) 	1993-2000 	Non-randomized part of phase 3 RCT
Pfreundschuh et al. 2004 (NHL-B2) 	1993-2000 	Non-randomized part of phase 3 RCT
Pfreundschuh et al. 2008 (RICOVER-60) 	2000-2005 	Non-randomized part of phase 3 RCT
Pfreundschuh et al. 2014 (SMARTE-R-CHOP-14)	2007-2009 	Phase 2
Note: This was recommended in NHL-B1 and NHL-B2 "to improve the performance status of patients and to ameliorate side-effects of the first chemotherapy cycle." Mandated in RICOVER-60 and SMARTE-R-CHOP-14. NHL-B1 gave the option of a 5 to 7 day course of prednisone.
====Chemotherapy====
*Vincristine (Oncovin) 1 mg IV once (day not specified)
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 7
7-day course
====Subsequent treatment====
*NHL-B1 and NHL-B2: CHOP versus CHOP-14 versus CHOEP-14 versus CHOEP-21 induction
*RICOVER-60: CHOP-14 versus R-CHOP-14 induction
*SMARTE-R-CHOP-14: R-CHOP-14 induction
===References===
#NHL-B1: Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rudolph C, Reiser M, Hossfeld DK, Metzner B, Hasenclever D, Schmitz N, Glass B, Rübe C, Loeffler M; German High-Grade Non-Hodgkin's Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood. 2004 Aug 1;104(3):626-33. Epub 2004 Feb 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#NHL-B2: Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rübe C, Rudolph C, Reiser M, Hossfeld DK, Eimermacher H, Hasenclever D, Schmitz N, Loeffler M; German High-Grade Non-Hodgkin's Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood. 2004 Aug 1;104(3):634-41. Epub 2004 Mar 11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#RICOVER-60: Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trümper L, Balleisen L, Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M; German High-Grade Non-Hodgkin Lymphoma Study Group. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008 Feb;9(2):105-16. Epub 2008 Jan 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00052936
#SMARTE-R-CHOP-14: Pfreundschuh M, Poeschel V, Zeynalova S, Hänel M, Held G, Schmitz N, Viardot A, Dreyling MH, Hallek M, Mueller C, Wiesen MH, Witzens-Harig M, Truemper L, Keller U, Rixecker T, Zwick C, Murawski N; German High-Grade Non-Hodgkin Lymphoma Study Group. Optimization of rituximab for the treatment of diffuse large B-cell lymphoma (II): extended rituximab exposure time in the SMARTE-R-CHOP-14 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group. J Clin Oncol. 2014 Dec 20;32(36):4127-33. Epub 2014 Nov 17. Erratum in: J Clin Oncol. 2015 Jun 10;33(17):1991. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00052936
#LYSA LNH09-7B: Peyrade F, Bologna S, Delwail V, Emile JF, Pascal L, Fermé C, Schiano JM, Coiffier B, Corront B, Farhat H, Fruchart C, Ghesquieres H, Macro M, Tilly H, Choufi B, Delarue R, Fitoussi O, Gabarre J, Haioun C, Jardin F. Combination of ofatumumab and reduced-dose CHOP for diffuse large B-cell lymphomas in patients aged 80 years or older: an open-label, multicentre, single-arm, phase 2 trial from the LYSA group. Lancet Haematol. 2017 Jan;4(1):e46-e55. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01195714
=Untreated, randomized data=
==Hi-CHOP==
Hi-CHOP: Hi (?), Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Li et al. 2024	2018-10 to 2020-09 	Phase 3 (E-switch-ic)	R-CHOP 	Non-inferior ORR at C6D50 (primary endpoint)
====Targeted therapy====
*Zuberitamab (Anruixi) 375 mg/m2 IV once on day 0
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg IV or PO once per day on days 1 to 5
21-day cycle for 6 cycles
===References===
#Li Z, Jiang W, Zhou H, Cen H, Zhang M, Lv F, Zhang Q, Sun X, Liu L, Huang Y, Yang H, Gao S, He C, Yang W, Li W, Yu D, Yang Y, Cheng Y, Qian Z, Xiang Y, Guo Q, Xu B, Song Y, Zhang L, Lin L, Shen J, Yan F, Liu H, Zhang D, Wang J, Zhou M, Zhu X, Zhang W, Zhao W, Feng R, Zhang X, Jin J, Zhong M, Zhang M, Wang J, Jing H, Wang Z, Zhao H, Zhu J. Comparison of zuberitamab plus CHOP versus rituximab plus CHOP for the treatment of drug-naïve patients diagnosed with CD20-positive diffuse large B-cell lymphoma: a phase 3 trial. J Immunother Cancer. 2024 Oct 24;12(10):e008895. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC ChiCTR2000040602
==Pola-R-CHP==
Pola-R-CHP: Polatuzumab, Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Tilly et al. 2021 (POLARIX)	2017-2019 	Phase 3 (E-RT-switch-ooc)	R-CHOP 	Longer PFS (primary endpoint)PFS24: 76.7% vs 70.2%(HR 0.73, 95% CI 0.57-0.95)
====Antibody-drug conjugate therapy====
*Polatuzumab vedotin (Polivy) as follows:
**Cycles 1 to 6: 1.8 mg/kg IV once on day 1
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 1 to 6: 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) as follows:
**Cycles 1 to 6: 50 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) as follows:
**Cycles 1 to 6: 100 mg PO once per day on days 1 to 5
21-day cycle for 8 cycles
===References===
#POLARIX: Tilly H, Morschhauser F, Sehn LH, Friedberg JW, Trněný M, Sharman JP, Herbaux C, Burke JM, Matasar M, Rai S, Izutsu K, Mehta-Shah N, Oberic L, Chauchet A, Jurczak W, Song Y, Greil R, Mykhalska L, Bergua-Burgués JM, Cheung MC, Pinto A, Shin HJ, Hapgood G, Munhoz E, Abrisqueta P, Gau JP, Hirata J, Jiang Y, Yan M, Lee C, Flowers CR, Salles G. Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. N Engl J Med. 2022 Jan 27;386(4):351-363. Epub 2021 Dec 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03274492
==R-ACVBP==
R-ACVBP: Rituximab, Adriamycin (Doxorubicin), Cyclophosphamide, Vindesine, Bleomycin, Prednisone
ACVBP-R: Adriamycin (Doxorubicin), Cyclophosphamide, Vindesine, Bleomycin, Prednisone, Rituximab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Récher et al. 2011 (LNH03-2B) 	2003-2008 	Phase 3 (E-esc)	R-CHOP 	Longer EFS (primary endpoint)EFS36: 81% vs 67%(HR 0.56, 95% CI 0.38-0.83)Longer OS (secondary endpoint)OS36: 92% vs 84%(HR 0.44, 95% CI 0.28-0.81)	Increased toxicity
Ketterer et al. 2013 (LNH03-1B)	2003-2008 	Phase 3 (E-esc)	ACVBP 	Longer PFS (secondary endpoint)PFS36: 95% vs 83%(HR 0.37, 95% CI 0.15-0.89) 	Similar toxicity
Le Gouill et al. 2021 (GAINED) 	2012-2015 	Phase 3 (C) 	G-ACVBP 	Did not meet primary endpoint of EFS24EFS24: 57% vs 60%(HR 1.14, 95% CI 0.91-1.43) 	
Note: Treatment in GAINED was PET-adapted; see paper for details.
====Chemotherapy====
*Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 1200 mg/m2 IV once on day 1
*Vindesine (Eldisine) 2 mg/m2 IV once per day on days 1 & 5
*Bleomycin (Blenoxane) 10 units IV once per day on days 1 & 5
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 5
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 15 mg IT on day 1
====Supportive therapy====
*Filgrastim (Neupogen) 300 mcg (for patients less than 75 kg) or 480 mcg (for patients greater than or equal to 75 kg) SC once per day on days 6 to 13
14-day cycle for 4 cycles 
====Subsequent treatment====
*Methotrexate consolidation, in 4 weeks
===References===
#LNH03-2B: Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, Thiéblemont C, Bosly A, Laurent G, Morschhauser F, Ghesquières H, Jardin F, Bologna S, Fruchart C, Corront B, Gabarre J, Bonnet C, Janvier M, Canioni D, Jais JP, Salles G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26;378(9806):1858-67. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00140595
##Subgroup analysis: Molina TJ, Canioni D, Copie-Bergman C, Recher C, Brière J, Haioun C, Berger F, Fermé C, Copin MC, Casasnovas O, Thieblemont C, Petrella T, Leroy K, Salles G, Fabiani B, Morschauser F, Mounier N, Coiffier B, Jardin F, Gaulard P, Jais JP, Tilly H. Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d'Etudes des Lymphomes de l'Adulte/lymphoma study association phase III trial LNH 03-2B. J Clin Oncol. 2014 Dec 10;32(35):3996-4003. Epub 2014 Nov 10. link to original article EuroPMC
#LNH03-1B: Ketterer N, Coiffier B, Thieblemont C, Fermé C, Brière J, Casasnovas O, Bologna S, Christian B, Connerotte T, Récher C, Bordessoule D, Fruchart C, Delarue R, Bonnet C, Morschhauser F, Anglaret B, Soussain C, Fabiani B, Tilly H, Haioun C. Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol. 2013 Apr;24(4):1032-7. Epub 2012 Dec 12. link to original article EuroPMC NCT00140595
#GAINED: Le Gouill S, Ghesquières H, Oberic L, Morschhauser F, Tilly H, Ribrag V, Lamy T, Thieblemont C, Maisonneuve H, Gressin R, Bouhabdallah K, Haioun C, Damaj G, Fornecker L, Bouhabdallah R, Feugier P, Sibon D, Cartron G, Bonnet C, André M, Chartier L, Ruminy P, Kraeber-Bodéré F, Bodet-Milin C, Berriolo-Riedinger A, Brière J, Jais JP, Molina TJ, Itti E, Casasnovas RO. Obinutuzumab vs rituximab for advanced DLBCL: a PET-guided and randomized phase 3 study by LYSA. Blood. 2021 Apr 29;137(17):2307-2320. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT01659099
==R-CEOP70==
R-CEOP70: Rituximab, Cyclophosphamide, Epirubicin (70 mg/m2 dosing), Oncovin (Vincristine), Prednisolone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2019 (NHL-001)	2013-2016 	Phase 3 (E-switch-ic)	1. R-CEOP90	Lower PFS24 (primary endpoint)
Xu et al. 2019 (NHL-001)	2013-2016 	Phase 3 (E-switch-ic)	2. R-CHOP 	Non-inferior PFS24 (primary endpoint)PFS24: 72.4% vs 72.5%(HR 1.00, 95% CI 0.72-1.37)
Note: this arm was available to patients of all ages. 
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 0
====Chemotherapy====
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 1 to 6: 750 mg/m2 IV once on day 1
*Epirubicin (Ellence) as follows:
**Cycles 1 to 6: 70 mg/m2 IV once on day 1
*Vincristine (Oncovin) as follows:
**Cycles 1 to 6: 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisolone (Millipred) as follows:
**Cycles 1 to 6: 60 mg/m2/day (maximum dose of 100 mg) PO on days 1 to 5
21-day cycle for 8 cycles
====Subsequent treatment====
*NHL-001, patients with bulky disease at diagnosis or residual masses at end of treatment: IFRT consolidation
===References===
#NHL-001: Xu PP, Fu D, Li JY, Hu JD, Wang X, Zhou JF, Yu H, Zhao X, Huang YH, Jiang L, Liu F, Su LP, Chen ZW, Zeng QS, Chen JP, Fang MY, Ma J, Liu T, Song YP, Yu K, Li Y, Qiu LG, Chen XQ, Gu J, Yan JS, Hou M, Huang HY, Wang L, Cheng S, Shen Y, Xiong H, Chen SJ, Zhao WL. Anthracycline dose optimisation in patients with diffuse large B-cell lymphoma: a multicentre, phase 3, randomised, controlled trial. Lancet Haematol. 2019 Jun;6(6):e328-e337. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01852435
==R-CEOP90==
R-CEOP90: Rituximab, Cyclophosphamide, Epirubicin (90 mg/m2 dosing), Oncovin (Vincristine), Prednisolone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Xu et al. 2019 (NHL-001)	2013-2016 	Phase 3 (E-esc)	1. R-CEOP70	Higher PFS24 (primary endpoint)PFS24: 89% vs 77%(HR 0.49, 95% CI 0.27-0.86)
Xu et al. 2019 (NHL-001)	2013-2016 	Phase 3 (E-esc)	2. R-CHOP 	Higher PFS24 (primary endpoint)PFS24: 89% vs 76%(HR 0.44, 95% CI 0.25-0.76)
Note: this arm was only available to patients aged 16-60 years. 
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 0
====Chemotherapy====
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 1 to 6: 750 mg/m2 IV once on day 1
*Epirubicin (Ellence) as follows:
**Cycles 1 to 6: 90 mg/m2 IV once on day 1
*Vincristine (Oncovin) as follows:
**Cycles 1 to 6: 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisolone (Millipred) as follows:
**Cycles 1 to 6: 60 mg/m2/day (maximum dose of 100 mg) PO on days 1 to 5
21-day cycle for 8 cycles
====Subsequent treatment====
*NHL-001, patients with bulky disease at diagnosis or residual masses at end of treatment: IFRT consolidation
===References===
#NHL-001: Xu PP, Fu D, Li JY, Hu JD, Wang X, Zhou JF, Yu H, Zhao X, Huang YH, Jiang L, Liu F, Su LP, Chen ZW, Zeng QS, Chen JP, Fang MY, Ma J, Liu T, Song YP, Yu K, Li Y, Qiu LG, Chen XQ, Gu J, Yan JS, Hou M, Huang HY, Wang L, Cheng S, Shen Y, Xiong H, Chen SJ, Zhao WL. Anthracycline dose optimisation in patients with diffuse large B-cell lymphoma: a multicentre, phase 3, randomised, controlled trial. Lancet Haematol. 2019 Jun;6(6):e328-e337. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01852435
==R-CHOEP-14==
R-CHOEP-14: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Etoposide, Prednisone, 14-day cycles
===Regimen variant #1, flat-dose vincristine===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Adde et al. 2006 	2001-2003 	Phase 2 	 	 	
Schmitz et al. 2012 (DSHNHL 2002-1)	2003-2009 	Phase 3 (C)	R-MegaCHOEP	Did not meet primary endpoint of EFS	Decreased toxicity
Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycles 1 to 4, 6, 8: 375 mg/m2 IV once on day 0
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 2 mg IV once on day 1
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
14-day cycle for 8 cycles
====Subsequent treatment====
*DSHNHL 2002-1, patients with bulky disease (any mass greater than 7.5cm in diameter, or extranodal involvement): "Mandatory" RT x 3600 cGy consolidation
===Regimen variant #2, capped vincristine, with CNS prophylaxis===
Study 	Dates of enrollment	Evidence
Holte et al. 2012 (NLG LBC-04)	2004-2008 	Phase 2
Note: Consolidative radiotherapy "given at the discretion of the individual centers (3600 to 4500 cGy). Indications for giving radiotherapy after the completion of chemotherapy included bulky disease (greater than or equal to 10 cm) at diagnosis, localized PET-positive residual lesions, and residual disease, not eligible for biopsy at a localized site, and potentially curable by radiotherapy."
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
====Supportive therapy====
*ONE of the following:
**Filgrastim (Neupogen) 5 mcg/kg SC once per day from day 4
**Pegfilgrastim (Neulasta) 6 mg SC once on day 4
14-day cycle for 8 cycles
====Subsequent treatment====
*HiDAC consolidation, then HD-MTX for CNS prophylaxis
===References===
#Adde M, Enblad G, Hagberg H, Sundström C, Laurell A. Outcome for young high-risk aggressive B-cell lymphoma patients treated with CHOEP-14 and rituximab (R-CHOEP-14). Med Oncol. 2006;23(2):283-93. link to original article EuroPMC
#DSHNHL 2002-1: Schmitz N, Nickelsen M, Ziepert M, Haenel M, Borchmann P, Schmidt C, Viardot A, Bentz M, Peter N, Ehninger G, Doelken G, Ruebe C, Truemper L, Rosenwald A, Pfreundschuh M, Loeffler M, Glass B; German High-Grade Lymphoma Study Group. Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1). Lancet Oncol. 2012 Dec;13(12):1250-1259. Epub 2012 Nov 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00129090
##Update: Frontzek F, Ziepert M, Nickelsen M, Altmann B, Glass B, Haenel M, Truemper L, Held G, Bentz M, Borchmann P, Dreyling M, Viardot A, Kroschinsky FP, Metzner B, Staiger AM, Horn H, Ott G, Rosenwald A, Loeffler M, Lenz G, Schmitz N. Rituximab plus high-dose chemotherapy (MegaCHOEP) or conventional chemotherapy (CHOEP-14) in young, high-risk patients with aggressive B-cell lymphoma: 10-year follow-up of a randomised, open-label, phase 3 trial. Lancet Haematol. 2021 Apr;8(4):e267-e277. Epub 2021 Mar 2. link to original article EuroPMC
#NLG LBC-04: Holte H, Leppä S, Björkholm M, Fluge O, Jyrkkiö S, Delabie J, Sundström C, Karjalainen-Lindsberg ML, Erlanson M, Kolstad A, Fosså A, Ostenstad B, Löfvenberg E, Nordström M, Janes R, Pedersen LM, Anderson H, Jerkeman M, Eriksson M. Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study. Ann Oncol. 2013 May;24(5):1385-92. Epub 2012 Dec 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01502982
==R-CHOP==
R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone
R-CHOP-21: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone given every 21 days
CHOP-R: Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone, Rituximab
RCHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone
CHOPR: Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone, Rituximab
===Example orders===
*Example orders for R-CHOP in lymphoma
Note: most of the variation between regimen variants is in the dose of prednisone.
===Regimen variant #1, prednisone 40 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Coiffier et al. 2002 (LNH 98-5) 	1998-2000 	Phase 3 (E-RT-esc)	CHOP 	Longer OS (secondary endpoint)OS24: 70% vs 57%(HR 0.64, 95% CI 0.45-0.89)Longer EFS (primary endpoint)
Delarue et al. 2013 (LNH03-6B) 	2003-2008 	Phase 3 (C) 	R-CHOP-14 	Did not meet primary endpoint of EFS
Bartlett et al. 2019 (CALGB 50303)	2005-2013 	Phase 3 (C) 	DA-R-EPOCH	Did not meet primary endpoint of PFSPFS24: 75.5% vs 79%(HR 1.08, 95% CI 0.79-1.47)
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
====Supportive therapy====
*Filgrastim (Neupogen) used for later cycles if patients developed grade 4 neutropenia or febrile neutropenia
21-day cycle for varying durations: 6 cycles (CALGB 50303); 8 cycles (LNH 98-5, LNH03-6B)
====CNS therapy, prophylaxis====
As described in Delarue et al. 2013 (LNH03-6B):
*Methotrexate (MTX) 15 mg IT once on day 1
21-day cycle for 4 cycles
===Regimen variant #2, prednisone 60 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Récher et al. 2011 (LNH03-2B)	2003-2008 	Phase 3 (C)	R-ACVBP 	Shorter EFS (primary endpoint)EFS36: 67% vs 81%(HR 1.79, 95% CI 1.20-2.63)Shorter OS (secondary endpoint)OS36: 84% vs 92%(HR 2.27, 95% CI 1.23-3.57)	Decreased toxicity
Seymour et al. 2014 (MAIN) 	2007-2010 	Phase 3 (C)	1a. RA-CHOP-211b. RA-CHOP-14	Did not meet secondary endpoint of PFS 	Better cardiac safety
Li et al. 2018 (CSWOG0001) 	2008-2014 	Phase 3 (C)	R-CHOP-14 	Did not meet primary endpoint of DFS 	Similar toxicities
Note: Seymour et al. 2014 does not contain dosing details, but did specify a total of 8 cycles.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 5
21-day cycle for 8 cycles
===Regimen variant #3, prednisone 100 mg, capped vincristine, 4+2 cycles===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Poeschel et al. 2019 (FLYER)	2005-2016 	Phase 3 (E-de-esc)	R-CHOP x 6	Non-inferior PFS36 (primary endpoint)PFS36: 96% vs 93%	Less toxic
====Eligibility criteria====
*Age 18 to 60 and no risk factors according to age-adjusted IPI
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 1 to 4: 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) as follows:
**Cycles 1 to 4: 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) as follows:
**Cycles 1 to 4: 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) as follows:
**Cycles 1 to 4: 100 mg PO once per day on days 1 to 5
21-day cycle for 6 cycles
===Regimen variant #4, prednisone 100 mg, capped vincristine, 6 cycles===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Vose et al. 2001 	Not reported 	Phase 2 	 	 	
Merli et al. 2012 (ANZINTER3) 	2003-2006 	Phase 3 (C) 	R-miniCEOP 	Did not meet primary endpoint of EFS 	
Herbrecht et al. 2013 (PIX203) 	2005-2008 	Randomized Phase 2 (C)	CPOP-R 	Inconclusive whether non-inferior CR/CRu rate1 (composite primary endpoint) 	
Poeschel et al. 2019 (FLYER) 	2005-2016 	Phase 3 (C) 	R-CHOP x 4 	Non-inferior PFS36 	More toxic
Oki et al. 2013 (MDACC 2005-0054)	2005 to not reported	Randomized Phase 2 (C)	R-Hyper-CVAD/R-MA	Seems to have lower CR rate 	
Leonard et al. 2017 (C05013) 	2009-2013 	Randomized Phase 2 (C)	VR-CHOP 	Did not meet primary endpoint of PFS 	
Younes et al. 2019 (PHOENIX) 	2013-2015 	Phase 3 (C) 	IR-CHOP 	Did not meet primary endpoint of EFS 	
Nowakowski et al. 2021 (ROBUST) 	2015-2017 	Phase 3 (C) 	R2-CHOP 	Did not meet primary endpoint of PFSMedian PFS: NYR vs NYR(HR 1.18, 95% CI 0.88-1.59)	
Li et al. 2024 	2018-10 to 2020-09 	Phase 3 (C) 	Hi-CHOP 	Non-inferior ORR at C6D50 	
1While the primary endpoint in PIX203 was inconclusive (non-inferiority by CR/CRu rate), this arm seemed to have longer OS.
Note: Patients in PIX203 received a total of 6 cycles if they were in CR after cycle 4. Patients in ROBUST could receive two additional cycles of rituximab (8 total), per local practices.
====Eligibility criteria====
*FLYER: Age 18 to 60 and no risk factors according to age-adjusted IPI
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 0 or 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg IV or PO once per day on days 1 to 5
====Supportive therapy====
*Varies per protocol
*Prophylactic G-CSF used for persisting grade 4 neutropenia or febrile neutropenia.
*Cotrimoxazole (dose/schedule not specified) prophylaxis.
*Erythropoietin use was allowed for hemoglobin less than 11 g/dL.
21-day cycle for 6 cycles
===Regimen variant #5, prednisone 100 mg, capped vincristine, 6+2 cycles===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Vitolo et al. 2017 (GOYA) 	2011-2014 	Phase 3 (C)	G-CHOP 	Did not meet primary endpoint of PFS
Lugtenburg et al. 2017 (MabEase)	2012 to not reported	Phase 3 (C)	1a. R-CHOP (SC Rituximab)1b. R-CHOP-14 (SC Rituximab)	Might have lower CR/CRu rate (composite primary endpoint)
Nowakowski et al. 2021 (ROBUST) 	2015-2017 	Phase 3 (C)	R2-CHOP 	Did not meet primary endpoint of PFSMedian PFS: NYR vs NYR(HR 1.18, 95% CI 0.88-1.59)
Tilly et al. 2021 (POLARIX) 	2017-2019 	Phase 3 (C)	Pola-R-CHP 	Shorter PFS (primary endpoint)PFS24: 70.2% vs 76.7%(HR 1.37, 95% CI 1.05-1.75)
Note: Patients in GOYA received 8 doses of rituximab, regardless of the number of chemotherapy cycles given.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 1 to 6: 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) as follows:
**Cycles 1 to 6: 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) as follows:
**Cycles 1 to 6: 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) as follows:
**Cycles 1 to 6: 100 mg PO once per day on days 1 to 5
21-day cycle for 8 cycles
===Regimen variant #6, prednisone 100 mg, flat-dose vincristine===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Pfreundschuh et al. 2006 (NCIC-CTG LY.9)	2000-2003 	Phase 3 (E-RT-esc)	1a. CHOP1b. CHOEP-211c. MACOP-B1d. PMitCEBO	Longer EFS1 (primary endpoint)EFS72: 74.3% vs 55.8%(HR 0.48, 95% CI 0.36-0.64)	Similar toxicity
1Reported efficacy is based on the 2011 update.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 2 mg IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
====Supportive therapy====
*G-CSF with one of the following:
**Filgrastim (Neupogen) used at physician discretion for neutropenia
**Lenograstim (Granocyte) used at physician discretion for neutropenia
21-day cycle for 6 cycles
====Subsequent treatment====
*Radiation therapy 3000 to 4000 cGy consolidation given to sites of primary bulky disease; 3000 to 4000 cGy to primary extranodal disease at physician discretion
===Regimen variant #7, prednisone 100 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Offner et al. 2015 (LYM-2034)	2010-2011 	Randomized Phase 2 (C)	VR-CAP 	Did not meet primary endpoint of CR rate
====Biomarker eligibility criteria====
*Non-germinal center B-cell (non-GCB) DLBCL
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg/m2 PO once per day on days 1 to 5
21-day cycle for 6 cycles
===Regimen variant #8, rituximab lead-in===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Habermann et al. 2006 (ECOG E4494)	1998-2001 	Phase 3 (E-RT-esc)	CHOP 	Seems to have longer FFS (primary endpoint)
Note: an advantage for maintenance was only seen in the group receiving CHOP upfront, which is no longer standard of care.
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days -7 & -3
**Cycles 2 to 6 up to 8: 375 mg/m2 IV once on day -2
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg/m2 PO once per day on days 1 to 5
====Supportive therapy====
*Recommended: Filgrastim (Neupogen) "according to guidelines"
21-day cycle for 6 to 8 cycles
====Subsequent treatment====
*Rituximab maintenance versus observation
===Regimen variant #9, short-course for early stage DLBCL===
Study 	Dates of enrollment	Evidence
Persky et al. 2008 (SWOG S0014)	2000-2002 	Phase 2
Yoon et al. 2017 (CISL 12-09) 	2010-2013 	Phase 2
Note: CISL 12-09 does not have dosing details.
====Preceding treatment====
*CISL 12-09: Surgical resection
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Pre-phase: 375 mg/m2 IV once on day -7
**Cycles 1 to 3: 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
21-day cycle for 3 cycles
====Subsequent treatment====
*SWOG S0014: IFRT consolidation, to begin 3 weeks after last cycle of R-CHOP
===Regimen variant #10, primary testicular DLBCL===
Study 	Dates of enrollment	Evidence
Vitolo et al. 2011 (IELSG-10)	2001-2006 	Phase 2
Note: This regimen is a component of a sequential treatment protocol.
====Eligibility criteria====
*Primary testicular lymphoma
====Preceding treatment====
*Diagnostic orchiectomy prior to starting chemotherapy
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 0 or 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
21-day cycle for 6 cycles (up to 8 cycles for stage II patients)
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 12 mg IT once per day on days 1, 8, 15, 22
4-week course
====Subsequent treatment====
*RT consolidation
===Regimen variant #11, 2 cycles with response adaptation===
Study 	Dates of enrollment	Evidence
Witzig et al. 2015 (ECOG E3402)	2004-2008 	Phase 2
====Eligibility criteria====
*Stage I-II DLBCL based on CT (not PET-CT) imaging
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg/m2 PO once per day on days 1 to 5
21-day cycle for 2 cycles
====Subsequent treatment====
*ECOG E3402, CR based on CT scan: R-CHOP continuation x 2 (4 cycles total), then ibritumomab tiuxetan consolidation
*ECOG E3402, CRu or PR based on CT scan: R-CHOP continuation x 4 (6 cycles total), then ibritumomab tiuxetan consolidation
===References===
#Vose JM, Link BK, Grossbard ML, Czuczman M, Grillo-Lopez A, Gilman P, Lowe A, Kunkel LA, Fisher RI. Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. J Clin Oncol. 2001 Jan 15;19(2):389-97. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#LNH 98-5: Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C; Groupe d'Etude des Lymphomes de l'Adulte. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jan 24;346(4):235-42. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Fermé C, Christian B, Lepage E, Tilly H, Morschhauser F, Gaulard P, Salles G, Bosly A, Gisselbrecht C, Reyes F, Coiffier B. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 2005 Jun 20;23(18):4117-26. Epub 2005 May 2. link to original article EuroPMC
##Update: Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, Lefort S, Marit G, Macro M, Sebban C, Belhadj K, Bordessoule D, Fermé C, Tilly H. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood. 2010 Sep 23;116(12):2040-5. Epub 2010 Jun 14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC content property of HemOnc.org
##Update: Mounier N, Heutte N, Thieblemont C, Briere J, Gaulard P, Feugier P, Ghesquieres H, Van Den Neste E, Robu D, Tilly H, Bouabdallah R, Safar V, Coiffier B; Groupe d'Etude des Lymphomes de l'Adulte (GELA). Ten-year relative survival and causes of death in elderly patients treated with R-CHOP or CHOP in the GELA LNH-985 trial. Clin Lymphoma Myeloma Leuk. 2012 Jun;12(3):151-4. Epub 2012 Feb 1. link to original article EuroPMC
#NCIC-CTG LY.9: Pfreundschuh M, Trümper L, Osterborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, Walewski J, Zinzani PL, Stahel R, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, López-Guillermo A, Corrado C, Scheliga A, Milpied N, Mendila M, Rashford M, Kuhnt E, Loeffler M; MabThera International Trial Group. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006 May;7(5):379-91. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00064116
##Update: Pfreundschuh M, Kuhnt E, Trümper L, Osterborg A, Trneny M, Shepherd L, Gill DS, Walewski J, Pettengell R, Jaeger U, Zinzani PL, Shpilberg O, Kvaloy S, de Nully Brown P, Stahel R, Milpied N, López-Guillermo A, Poeschel V, Grass S, Loeffler M, Murawski N; MabThera International Trial (MInT) Group. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol. 2011 Oct;12(11):1013-22. Epub 2011 Sep 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003150
#SWOG S0014: Persky DO, Unger JM, Spier CM, Stea B, LeBlanc M, McCarty MJ, Rimsza LM, Fisher RI, Miller TP; SWOG. Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014. J Clin Oncol. 2008 May 10;26(14):2258-63. Epub 2008 Apr 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#IELSG-10: Vitolo U, Chiappella A, Ferreri AJ, Martelli M, Baldi I, Balzarotti M, Bottelli C, Conconi A, Gomez H, Lopez-Guillermo A, Martinelli G, Merli F, Novero D, Orsucci L, Pavone V, Ricardi U, Storti S, Gospodarowicz MK, Cavalli F, Sarris AH, Zucca E. First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximab-CHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international phase II trial. J Clin Oncol. 2011 Jul 10;29(20):2766-72. Epub 2011 Jun 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00210379
#ANZINTER3: Merli F, Luminari S, Rossi G, Mammi C, Marcheselli L, Tucci A, Ilariucci F, Chiappella A, Musso M, Di Rocco A, Stelitano C, Alvarez I, Baldini L, Mazza P, Salvi F, Arcari A, Fragasso A, Gobbi PG, Liberati AM, Federico M. Cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab versus epirubicin, cyclophosphamide, vinblastine, prednisone and rituximab for the initial treatment of elderly "fit" patients with diffuse large B-cell lymphoma: results from the ANZINTER3 trial of the Intergruppo Italiano Linfomi. Leuk Lymphoma. 2012 Apr;53(4):581-8. Epub 2011 Nov 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01148446
#LNH03-2B: Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, Thiéblemont C, Bosly A, Laurent G, Morschhauser F, Ghesquières H, Jardin F, Bologna S, Fruchart C, Corront B, Gabarre J, Bonnet C, Janvier M, Canioni D, Jais JP, Salles G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26;378(9806):1858-67. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00140595
##Subgroup analysis: Molina TJ, Canioni D, Copie-Bergman C, Recher C, Brière J, Haioun C, Berger F, Fermé C, Copin MC, Casasnovas O, Thieblemont C, Petrella T, Leroy K, Salles G, Fabiani B, Morschauser F, Mounier N, Coiffier B, Jardin F, Gaulard P, Jais JP, Tilly H. Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d'Etudes des Lymphomes de l'Adulte/lymphoma study association phase III trial LNH 03-2B. J Clin Oncol. 2014 Dec 10;32(35):3996-4003. Epub 2014 Nov 10. link to original article EuroPMC
#LNH03-6B: Delarue R, Tilly H, Mounier N, Petrella T, Salles G, Thieblemont C, Bologna S, Ghesquières H, Hacini M, Fruchart C, Ysebaert L, Fermé C, Casasnovas O, Van Hoof A, Thyss A, Delmer A, Fitoussi O, Molina TJ, Haioun C, Bosly A. Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol. 2013 May;14(6):525-33. Epub 2013 Apr 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00144755
##Update: Camus V, Belot A, Oberic L, Sibon D, Ghesquières H, Thieblemont C, Fruchart C, Casasnovas O, Michot JM, Molina TJ, Bosly A, Joubert C, Haioun C, Nicolas-Virelizier E, Feugier P, Fitoussi O, Delarue R, Tilly H. Outcomes of older patients with diffuse large B-cell lymphoma treated with R-CHOP: 10-year follow-up of the LNH03-6B trial. Blood Adv. 2022 Dec 27;6(24):6169-6179. link to original article link to PMC article EuroPMC
#PIX203: Herbrecht R, Cernohous P, Engert A, Le Gouill S, Macdonald D, Machida C, Myint H, Saleh A, Singer J, Wilhelm M, van der Jagt R. Comparison of pixantrone-based regimen (CPOP-R) with doxorubicin-based therapy (CHOP-R) for treatment of diffuse large B-cell lymphoma. Ann Oncol. 2013 Oct;24(10):2618-23. Epub 2013 Aug 14. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT00268853
#MDACC 2005-0054: Oki Y, Westin JR, Vega F, Chuang H, Fowler N, Neelapu S, Hagemeister FB, McLaughlin P, Kwak LW, Romaguera JE, Fanale M, Younes A, Rodriguez MA, Orlowski RZ, Wang M, Ouzounian ST, Samaniego F, Fayad L. Prospective phase II study of rituximab with alternating cycles of hyper-CVAD and high-dose methotrexate with cytarabine for young patients with high-risk diffuse large B-cell lymphoma. Br J Haematol. 2013 Dec;163(5):611-20. Epub 2013 Oct 1. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00290498
#SWOG S9704: Stiff PJ, Unger JM, Cook JR, Constine LS, Couban S, Stewart DA, Shea TC, Porcu P, Winter JN, Kahl BS, Miller TP, Tubbs RR, Marcellus D, Friedberg JW, Barton KP, Mills GM, LeBlanc M, Rimsza LM, Forman SJ, Fisher RI. Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med. 2013 Oct 31;369(18):1681-90. link to original article link to PMC article does not contain dosing details EuroPMC NCT00004031
##Subgroup analysis: Puvvada SD, Stiff PJ, Leblanc M, Cook JR, Couban S, Leonard JP, Kahl B, Marcellus D, Shea TC, Winter JN, Li H, Rimsza LM, Friedberg JW, Smith SM. Outcomes of MYC-associated lymphomas after R-CHOP with and without consolidative autologous stem cell transplant: subset analysis of randomized trial intergroup SWOG S9704. Br J Haematol. 2016 Sep;174(5):686-91. Epub 2016 Apr 13. link to original article link to PMC article EuroPMC
#MAIN: Seymour JF, Pfreundschuh M, Trnený M, Sehn LH, Catalano J, Csinady E, Moore N, Coiffier B; MAIN Study Investigators. R-CHOP with or without bevacizumab in patients with previously untreated diffuse large B-cell lymphoma: final MAIN study outcomes. Haematologica. 2014 Aug;99(8):1343-9. Epub 2014 Jun 3. link to original article link to PMC article does not contain dosing details EuroPMC NCT00486759
#Retrospective: Howlett C, Snedecor SJ, Landsburg DJ, Svoboda J, Chong EA, Schuster SJ, Nasta SD, Feldman T, Rago A, Walsh KM, Weber S, Goy A, Mato A. Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis. Br J Haematol. 2015 Aug;170(4):504-14. Epub 2015 Apr 24. link to original article EuroPMC
#ECOG E3402: Witzig TE, Hong F, Micallef IN, Gascoyne RD, Dogan A, Wagner H Jr, Kahl BS, Advani RH, Horning SJ. A phase II trial of RCHOP followed by radioimmunotherapy for early stage (stages I/II) diffuse large B-cell non-Hodgkin lymphoma: ECOG3402. Br J Haematol. 2015 Sep;170(5):679-86. Epub 2015 May 14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00088881
#LYM-2034: Offner F, Samoilova O, Osmanov E, Eom HS, Topp MS, Raposo J, Pavlov V, Ricci D, Chaturvedi S, Zhu E, van de Velde H, Enny C, Rizo A, Ferhanoglu B. Frontline rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VR-CAP) or vincristine (R-CHOP) for non-GCB DLBCL. Blood. 2015 Oct 15;126(16):1893-901. Epub 2015 Jul 31. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01040871
#CISL 12-09: Yoon DH, Sohn BS, Oh SY, Lee WS, Lee SM, Yang DH, Huh J, Suh C. Feasibility of abbreviated cycles of immunochemotherapy for completely resected limited-stage CD20+ diffuse large B-cell lymphoma (CISL 12-09). Oncotarget. 2017 Feb 21;8(8):13367-13374. link to original article link to PMC article does not contain dosing details EuroPMC NCT01279902
#GOYA: Vitolo U, Trněný M, Belada D, Burke JM, Carella AM, Chua N, Abrisqueta P, Demeter J, Flinn I, Hong X, Kim WS, Pinto A, Shi YK, Tatsumi Y, Oestergaard MZ, Wenger M, Fingerle-Rowson G, Catalani O, Nielsen T, Martelli M, Sehn LH. Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma. J Clin Oncol. 2017 Nov 1;35(31):3529-3537. Epub 2017 Aug 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01287741
##Update: Sehn LH, Martelli M, Trněný M, Liu W, Bolen CR, Knapp A, Sahin D, Sellam G, Vitolo U. A randomized, open-label, Phase III study of obinutuzumab or rituximab plus CHOP in patients with previously untreated diffuse large B-Cell lymphoma: final analysis of GOYA. J Hematol Oncol. 2020 Jun 6;13(1):71. link to original article link to PMC article EuroPMC
#C05013: Leonard JP, Kolibaba KS, Reeves JA, Tulpule A, Flinn IW, Kolevska T, Robles R, Flowers CR, Collins R, DiBella NJ, Papish SW, Venugopal P, Horodner A, Tabatabai A, Hajdenberg J, Park J, Neuwirth R, Mulligan G, Suryanarayan K, Esseltine DL, de Vos S. Randomized phase II study of R-CHOP with or without bortezomib in previously untreated patients with non-germinal center B-cell-like diffuse large B-cell lymphoma. J Clin Oncol. 2017 Nov 1;35(31):3538-3546. Epub 2017 Sep 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00931918
#MabEase: Lugtenburg P, Avivi I, Berenschot H, Ilhan O, Marolleau JP, Nagler A, Rueda A, Tani M, Turgut M, Osborne S, Smith R, Pfreundschuh M. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica. 2017 Nov;102(11):1913-1922. Epub 2017 Sep 21. link to original article contains partial protocol link to PMC article EuroPMC NCT01649856
#CSWOG0001: Li X, Huang H, Xu B, Guo H, Lin Y, Ye S, Yi J, Li W, Wu X, Wang W, Zhan H, Xie D, Peng J, Cao Y, Pu X, Guo C, Hong H, Wang Z, Fang X, Zhou Y, Lin S, Liu Q, Lin T. Dose-Dense Rituximab-CHOP versus Standard Rituximab-CHOP in Newly Diagnosed Chinese Patients with Diffuse Large B-Cell Lymphoma: A Randomized, Multicenter, Open-Label Phase 3 Trial. Cancer Res Treat. 2019 Jul;51(3):919-932. Epub 2018 Oct 2. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01793844
#PHOENIX: Younes A, Sehn LH, Johnson P, Zinzani PL, Hong X, Zhu J, Patti C, Belada D, Samoilova O, Suh C, Leppä S, Rai S, Turgut M, Jurczak W, Cheung MC, Gurion R, Yeh SP, Lopez-Hernandez A, Dührsen U, Thieblemont C, Chiattone CS, Balasubramanian S, Carey J, Liu G, Shreeve SM, Sun S, Zhuang SH, Vermeulen J, Staudt LM, Wilson W; PHOENIX investigators. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019 May 20;37(15):1285-1295. Epub 2019 Mar 22. link to original article link to PMC article EuroPMC NCT01855750
#CALGB 50303: Bartlett NL, Wilson WH, Jung SH, Hsi ED, Maurer MJ, Pederson LD, Polley MC, Pitcher BN, Cheson BD, Kahl BS, Friedberg JW, Staudt LM, Wagner-Johnston ND, Blum KA, Abramson JS, Reddy NM, Winter JN, Chang JE, Gopal AK, Chadburn A, Mathew S, Fisher RI, Richards KL, Schöder H, Zelenetz AD, Leonard JP. Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303. J Clin Oncol. 2019 Jul 20;37(21):1790-1799. Epub 2019 Apr 2. link to original article link to PMC article dosing details in supplement have been reviewed by our editors EuroPMC NCT00118209
#FLYER: Poeschel V, Held G, Ziepert M, Witzens-Harig M, Holte H, Thurner L, Borchmann P, Viardot A, Soekler M, Keller U, Schmidt C, Truemper L, Mahlberg R, Marks R, Hoeffkes HG, Metzner B, Dierlamm J, Frickhofen N, Haenel M, Neubauer A, Kneba M, Merli F, Tucci A, de Nully Brown P, Federico M, Lengfelder E, di Rocco A, Trappe R, Rosenwald A, Berdel C, Maisenhoelder M, Shpilberg O, Amam J, Christofyllakis K, Hartmann F, Murawski N, Stilgenbauer S, Nickelsen M, Wulf G, Glass B, Schmitz N, Altmann B, Loeffler M, Pfreundschuh M; FLYER Trial Investigators; German Lymphoma Alliance. Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial. Lancet. 2019 Dec 21;394(10216):2271-2281. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00278421
#ROBUST: Nowakowski GS, Chiappella A, Gascoyne RD, Scott DW, Zhang Q, Jurczak W, Özcan M, Hong X, Zhu J, Jin J, Belada D, Bergua JM, Piazza F, Mócikova H, Molinari AL, Yoon DH, Cavallo F, Tani M, Yamamoto K, Izutsu K, Kato K, Czuczman M, Hersey S, Kilcoyne A, Russo J, Hudak K, Zhang J, Wade S, Witzig TE, Vitolo U. ROBUST: A Phase III Study of Lenalidomide Plus R-CHOP Versus Placebo Plus R-CHOP in Previously Untreated Patients With ABC-Type Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2021 Apr 20;39(12):1317-1328. Epub 2021 Feb 23. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02285062
#POLARIX: Tilly H, Morschhauser F, Sehn LH, Friedberg JW, Trněný M, Sharman JP, Herbaux C, Burke JM, Matasar M, Rai S, Izutsu K, Mehta-Shah N, Oberic L, Chauchet A, Jurczak W, Song Y, Greil R, Mykhalska L, Bergua-Burgués JM, Cheung MC, Pinto A, Shin HJ, Hapgood G, Munhoz E, Abrisqueta P, Gau JP, Hirata J, Jiang Y, Yan M, Lee C, Flowers CR, Salles G. Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma. N Engl J Med. 2022 Jan 27;386(4):351-363. Epub 2021 Dec 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03274492
#Shi Y, Zhang Q, Hong X, Wang Z, Gao Y, Zou L, Cen H, Gui L, Li Y, Feng J, Wang Z, Zhang M, Jin C, Zhang W, Hu J, Zheng C, Zheng Z, Zhang L, Chen S, Huang Y, Tang Y, Gao Y, Hao M, Li X, Chang C, Yang H, Wu H, Shen L, Ke X, Zhang L, Xi Y, Yang L, Xie L, Gai W, Ji Y. Comparison of efficacy and safety of ripertamab (SCT400) versus rituximab (Mabthera® ) in combination with CHOP in patients with previously untreated CD20-positive diffuse large B-cell lymphoma: A randomized, single-blind, phase III clinical trial. Hematol Oncol. 2022 Dec;40(5):930-940. Epub 2022 Aug 12. link to original article EuroPMC
#Li Z, Jiang W, Zhou H, Cen H, Zhang M, Lv F, Zhang Q, Sun X, Liu L, Huang Y, Yang H, Gao S, He C, Yang W, Li W, Yu D, Yang Y, Cheng Y, Qian Z, Xiang Y, Guo Q, Xu B, Song Y, Zhang L, Lin L, Shen J, Yan F, Liu H, Zhang D, Wang J, Zhou M, Zhu X, Zhang W, Zhao W, Feng R, Zhang X, Jin J, Zhong M, Zhang M, Wang J, Jing H, Wang Z, Zhao H, Zhu J. Comparison of zuberitamab plus CHOP versus rituximab plus CHOP for the treatment of drug-naïve patients diagnosed with CD20-positive diffuse large B-cell lymphoma: a phase 3 trial. J Immunother Cancer. 2024 Oct 24;12(10):e008895. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC ChiCTR2000040602
#frontMIND: NCT04824092
==R-CHOP (Prednisolone)==
R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisolone
===Example orders===
*Example orders for R-CHOP in lymphoma
===Regimen variant #1, prednisolone 40 mg/m2, 8 cycles===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Cunningham et al. 2013 (UK NCRI R-CHOP14v21)	2005-2008 	Phase 3 (C)	R-CHOP-14 	Did not meet primary endpoint of OS 	
Fridrik et al. 2016 (AGMT NHL-14) 	2007-2010 	Phase 3 (C)	R-COMP 	Did not meet secondary efficacy endpoints	Did not meet primary endpoint of reduced cardiotoxicity
Note: Cunningham et al. 2013 states that the regimen was based on LNH 98-5, but notably it uses prednisolone instead of prednisone. AGMT NHL-14 states that R-CHOP was "given in standard doses" per LNH 98-5, but this regimen uses prednisone, whereas the title and text of Fridrik et al. 2016 imply that prednisolone was used. The authors have confirmed that prednisolone was used, due to prednisone not being available in Austria.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisolone (Millipred) 40 mg/m2 PO once per day on days 1 to 5
====CNS therapy, prophylaxis====
Per investigator discretion, but Cunningham et al. 2013 recommended that patients who had involvement of the "bone marrow, peripheral blood, nasal or paranasal sinuses, orbit, and testis" (they probably intended to say "or testis") receive:
*Methotrexate (MTX) 12.5 mg IT "for the first three cycles of treatment, administered as per local guidelines." No other details given.
====Supportive therapy====
*Described in Cunningham et al. 2013
*Lenograstim (Granocyte) (dose/route not specified) given on days 4 to 12 at physician discretion
*Allopurinol (Zyloprim) 300 mg PO once per day during cycle 1
*Co-trimoxazole 80/400 mg PO twice per day on 3 days per week, taken throughout therapy, ending 2 weeks after chemotherapy is completed
21-day cycle for 8 cycles
===Regimen variant #2, prednisolone 60 mg/m2, 6 + 2 cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ohmachi et al. 2021 (JCOG0601)	2007-2014 	Phase 3 (C)	R-CHOP; weekly rituximab	Did not meet primary endpoint of PFS
Note: This regimen was intended for stage I nonbulky patients who were at least 65 years old.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 1 to 6: 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) as follows:
**Cycles 1 to 6: 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) as follows:
**Cycles 1 to 6: 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisolone (Millipred) as follows:
**Cycles 1 to 6: 60 mg/m2 PO once per day on days 1 to 5
21-day cycle for 8 cycles
===Regimen variant #3, prednisolone 60 mg/m2, 8 cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ohmachi et al. 2021 (JCOG0601)	2007-2014 	Phase 3 (C)	R-CHOP; weekly rituximab	Did not meet primary endpoint of PFS
Note: This regimen was intended for stage I bulky and stage II to IV patients who were at least 65 years old.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisolone (Millipred) 60 mg/m2 PO once per day on days 1 to 5
21-day cycle for 8 cycles
===Regimen variant #4, prednisolone 100 mg, 4 + 2 cycles===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Poeschel et al. 2019 (FLYER)	2005-2016 	Phase 3 (E-de-esc)	R-CHOP x 6	Non-inferior PFS36 (primary endpoint)PFS36: 96% vs 93%	Less toxic
====Eligibility criteria====
*Age 18 to 60 and no risk factors according to age-adjusted IPI
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 1 to 4: 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) as follows:
**Cycles 1 to 4: 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) as follows:
**Cycles 1 to 4: 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisolone (Millipred) as follows:
**Cycles 1 to 4: 100 mg IV or PO once per day on days 1 to 5
21-day cycle for 6 cycles
===Regimen variant #5, prednisolone 100 mg, 6 cycles===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Poeschel et al. 2019 (FLYER) 	2005-2016 	Phase 3 (C)	R-CHOP x 4	Non-inferior PFS36 	More toxic
Payandeh et al. 2016 	2011-2014 	Phase 3 (C)	R-CHOP-14 	Might have shorter OSOS60: 67.5% vs 89%(aHR 1.73, 95% CI 0.98-3.07)	
Davies et al. 2019 (REMoDL-B)	2011-2015 	Phase 3 (C)	RB-CHOP 	Did not meet primary endpoint of PFS30 	
Note: this was the lower bound of cycles specified by Payandeh et al. 2016.
====Eligibility criteria====
*FLYER: Age 18 to 60 and no risk factors according to age-adjusted IPI
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisolone (Millipred) 100 mg PO once per day on days 1 to 5
21-day cycle for 6 cycles
===Regimen variant #6, prednisolone 100 mg, 6 + 2 cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ohmachi et al. 2021 (JCOG0601)	2007-2014 	Phase 3 (C)	R-CHOP; weekly rituximab	Did not meet primary endpoint of PFS
Note: This regimen was intended for stage I nonbulky patients who were younger than 65 years old.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 1 to 6: 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) as follows:
**Cycles 1 to 6: 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) as follows:
**Cycles 1 to 6: 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisolone (Millipred) as follows:
**Cycles 1 to 6: 100 mg PO once per day on days 1 to 5
21-day cycle for 8 cycles
===Regimen variant #7, prednisolone 100 mg, 8 cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ohmachi et al. 2021 (JCOG0601)	2007-2014 	Phase 3 (C)	R-CHOP; weekly rituximab	Did not meet primary endpoint of PFS
Payandeh et al. 2016 	2011-2014 	Phase 3 (C)	R-CHOP-14 	Might have shorter OSOS60: 67.5% vs 89%(aHR 1.73, 95% CI 0.98-3.07)
Note: This was the upper bound of cycles specified by Payandeh et al. 2016. In JCOG0601, this regimen was intended for stage I bulky and stage II to IV patients who were younger than 65 years old.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisolone (Millipred) 100 mg/m2 PO once per day on days 1 to 5
21-day cycle for 8 cycles
===References===
#UK NCRI R-CHOP14v21: Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, Pocock C, Ardeshna KM, Radford JA, McMillan A, Davies J, Turner D, Kruger A, Johnson P, Gambell J, Linch D. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet. 2013 May 25;381(9880):1817-26. Epub 2013 Apr 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN16017947
#AGMT NHL-14: Fridrik MA, Jaeger U, Petzer A, Willenbacher W, Keil F, Lang A, Andel J, Burgstaller S, Krieger O, Oberaigner W, Sihorsch K, Greil R; Arbeitsgemeinschaft Medikamentöse Tumortherapie. Cardiotoxicity with rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone compared to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in frontline treatment of patients with diffuse large B-cell lymphoma: a randomised phase-III study from the Austrian Cancer Drug Therapy Working Group (NHL-14). Eur J Cancer. 2016 May;58:112-21. Epub 2016 Mar 15. link to original article does not contain dosing details EuroPMC NCT00575406
#Payandeh M, Najafi S, Shojaiyan FZ, Sadeghi M. Phase III of study of R-CHOP-21 vs R-CHOP-14 for untreated stage III and IV B-cell non-Hodgkin's lymphoma: a report from Iran. Asian Pac J Cancer Prev. 2016;17(3):1513-7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#REMoDL-B: Davies A, Cummin TE, Barrans S, Maishman T, Mamot C, Novak U, Caddy J, Stanton L, Kazmi-Stokes S, McMillan A, Fields P, Pocock C, Collins GP, Stephens R, Cucco F, Clipson A, Sha C, Tooze R, Care MA, Griffiths G, Du MQ, Westhead DR, Burton C, Johnson PWM. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol. 2019 May;20(5):649-662. Epub 2019 Apr 1. link to original article link to PMC article EuroPMC NCT01324596
#FLYER: Poeschel V, Held G, Ziepert M, Witzens-Harig M, Holte H, Thurner L, Borchmann P, Viardot A, Soekler M, Keller U, Schmidt C, Truemper L, Mahlberg R, Marks R, Hoeffkes HG, Metzner B, Dierlamm J, Frickhofen N, Haenel M, Neubauer A, Kneba M, Merli F, Tucci A, de Nully Brown P, Federico M, Lengfelder E, di Rocco A, Trappe R, Rosenwald A, Berdel C, Maisenhoelder M, Shpilberg O, Amam J, Christofyllakis K, Hartmann F, Murawski N, Stilgenbauer S, Nickelsen M, Wulf G, Glass B, Schmitz N, Altmann B, Loeffler M, Pfreundschuh M; FLYER Trial Investigators; German Lymphoma Alliance. Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial. Lancet. 2019 Dec 21;394(10216):2271-2281. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00278421
#JCOG0601: Ohmachi K, Kinoshita T, Tobinai K, Ogawa G, Mizutani T, Yamauchi N, Fukuhara N, Uchida T, Yamamoto K, Miyazaki K, Tsukamoto N, Iida S, Utsumi T, Yoshida I, Imaizumi Y, Tokunaga T, Yoshida S, Masaki Y, Murayama T, Yakushijin Y, Suehiro Y, Nosaka K, Dobashi N, Kuroda J, Takamatsu Y, Maruyama D, Ando K, Ishizawa K, Ogura M, Yoshino T, Hotta T, Tsukasaki K, Nagai H; Japan Clinical Oncology Group. A randomized phase 2/3 study of R-CHOP vs CHOP combined with dose-dense rituximab for DLBCL: the JCOG0601 trial. Blood Adv. 2021 Feb 23;5(4):984-993. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC jRCTs031180139
==R-CHOP (SC Rituximab)==
R-CHOP: Rituximab and hyaluronidase, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisolone
===Example orders===
*Example orders for R-CHOP in lymphoma
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Lugtenburg et al. 2017 (MabEase)	2012 to not reported	Phase 3 (E-RT-switch-ic)	1a. R-CHOP1b. R-CHOP-14	Might have higher CR/CRu rate (composite primary endpoint)
Note: the details for CHOP were not available in the manuscript or supplement; we have reproduced common CHOP dosing, here. For patients achieving CR after cycle 4, the CHOP could be omitted after cycle 6.
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once on day 1
*Rituximab and hyaluronidase human (Rituxan Hycela) as follows:
**Cycles 2 to 8: 1400 mg SC once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg/m2 PO once per day on days 1 to 5
21-day cycle for 6 to 8 cycles
===References===
#MabEase: Lugtenburg P, Avivi I, Berenschot H, Ilhan O, Marolleau JP, Nagler A, Rueda A, Tani M, Turgut M, Osborne S, Smith R, Pfreundschuh M. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica. 2017 Nov;102(11):1913-1922. Epub 2017 Sep 21. link to original article contains partial protocol link to PMC article EuroPMC NCT01649856
==R-CHOP-14==
R-CHOP-14: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone every 14 days
===Synopsis===
To be completed. Note that most of the variation below is in the steroid dose.
===Regimen variant #1, prednisone 40 mg/m2, 4 to 6 cycles===
Study 	Dates of enrollment	Evidence
Lamy et al. 2017 (LYSA/GOELAMS 02-03)	2005-2014 	Non-randomized part of phase 3 RCT
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
14-day cycle for 4 to 6 cycles
====Subsequent treatment====
*Observation versus IFRT x 4000 cGy consolidation
===Regimen variant #2, prednisone 40 mg/m2, 8 cycles===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Delarue et al. 2013 (LNH03-6B)	2003-2008 	Phase 3 (E-esc)	R-CHOP21 	Did not meet primary endpoint of EFS
Le Gouill et al. 2021 (GAINED)	2012-2015 	Phase 3 (C) 	G-CHOP 	Did not meet primary endpoint of EFS24
Note: treatment in GAINED was PET-adapted; see paper for details.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
====Supportive therapy====
*ONE of the following, "according to the treating doctor's decision, fulfilling existing guidelines and product labelling at that time."
**Granulocyte colony-stimulating factor
**Pegylated G-CSF
====CNS therapy, prophylaxis====
*Methotrexate (MTX) as follows:
**Cycles 1 to 4: 15 mg IT once on day 1
14-day cycle for 8 cycles
===Regimen variant #3, prednisone 100 mg, BSA-based vincristine, standard-dose IV rituximab===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Cortelazzo et al. 2016 	2005-2011 	Phase 3 (C)	R-HDS 	Did not meet primary endpoint of EFS36 	
Chiappella et al. 2017 (DLCL04) 	2006-2010 	Phase 3 (C)	1. R-MegaCHOP-14 	Not reported 	
Chiappella et al. 2017 (DLCL04) 	2006-2010 	Phase 3 (C)	2. R-CHOP-14, then R-MAD, then BEAM, then auto HSCT 3. R-MegaCHOP-14, then R-MAD, then BEAM, then auto HSCT	Did not meet primary endpoint of FFS24 	
Seymour et al. 2014 (MAIN) 	2007-2010 	Phase 3 (C)	1a. RA-CHOP-211b. RA-CHOP-14 	Did not meet secondary endpoint of PFS 	Better cardiac safety
Lugtenburg et al. 2020 (HOVON-84)	2007-2012 	Phase 3 (C)	RR-CHOP-14 	Did not meet primary endpoint of CR rate	Less neutropenia and infections
Note: in MAIN, CHOP-14 was given for 6 cycles and rituximab for 8 cycles. In Cortelazzo et al. 2016, there was no cap on the vincristine dose, and there was also a discrepancy between the prednisone dose in the body of the manuscript and that in the appendix Figure A1; these discrepancies were clarified by the corresponding author in January 2017. In the abstract of DLCL04, there was no cap on vincristine.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
====Supportive therapy====
*DLCL04: Lenograstim (Granocyte) 263 mcg SC once per day, started on day 3 and continued for 6 to 8 days
*Others: ONE of the following:
**Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 7 to 11
**Pegfilgrastim (Neulasta)
14-day cycle for 6 to 8 cycles (see note)
===Regimen variant #4, prednisone 100 mg, flat dose vincristine, 2 cycles, with response adaptation===
Study 	Dates of enrollment	Evidence
Dührsen et al. 2018 (PETAL)	2007-2012 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*Vincristine & prednisone pre-phase
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 2
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 2
*Vincristine (Oncovin) 2 mg IV once on day 2
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 2 to 6
14-day cycle for 2 cycles
====Subsequent treatment====
*PETAL, PET-negative: R-CHOP continuation x 4 (6 cycles total) versus R-CHOP continuation x 4 followed by rituximab de-intensification x 2
*PETAL, PET-positive: R-CHOP continuation x 6 (8 cycles total) versus intensive Burkitt lymphoma protocol salvage
===Regimen variant #5, prednisone 100 mg, flat dose vincristine, 6 cycles, extended rituximab exposure===
Study 	Dates of enrollment	Evidence
Pfreundschuh et al. 2014 (SMARTE-R-CHOP-14)	2007-2009 	Phase 2
====Preceding treatment====
*Vincristine & prednisone pre-phase
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days -4, 0, 10, 29, 57, 99, 155, 239 (independent of CHOP cycles)
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 2 mg IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
====Supportive therapy====
*ONE of the following starting on day 4, to continue until count recovery:
**Filgrastim (Neupogen)
**Lenograstim (Granocyte)
14-day cycle for 6 cycles
====Subsequent treatment====
*SMARTE-R-CHOP-14, patients with initial bulky disease ("lymphoma masses or conglomerates with a diameter greater than or equal to 7.5 cm) or extranodal involvement"): RT x 3600 cGy consolidation
===Regimen variant #6, prednisone 100 mg, flat dose vincristine, 6-8 cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Pfreundschuh et al. 2008 (RICOVER-60)	2000-2005 	Phase 3 (E-esc) 	1. CHOP-14 x 6 	Longer OS (secondary endpoint)
Pfreundschuh et al. 2008 (RICOVER-60)	2000-2005 	Phase 3 (E-esc) 	2. CHOP-14 x 8 	Not reported
Pfreundschuh et al. 2008 (RICOVER-60)	2000-2005 	Phase 3 (E-esc) 	3. R-CHOP-14 x 8	Not reported
Held et al. 2014 (RICOVER-noRTh) 	2005-2007 	Non-randomized part of RCT	 	
====Preceding treatment====
*RICOVER-60: Vincristine & prednisone pre-phase
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 2 mg IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
====Supportive therapy====
*ONE of the following starting on day 4, to continue until count recovery:
**Filgrastim (Neupogen)
**Lenograstim (Granocyte)
14-day cycle for 6 to 8 cycles (8 doses of rituximab regardless of total number of cycles)
====Subsequent treatment====
*RICOVER-60: Patients with initial bulky disease ("lymphoma masses or conglomerates with a diameter greater than or equal to 7.5 cm) or extranodal involvement"): RT x 3600 cGy consolidation
*RICOVER-noRTh: RT x 3600 cGy consolidation versus observation
===References===
#RICOVER-60: Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trümper L, Balleisen L, Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M; German High-Grade Non-Hodgkin Lymphoma Study Group. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008 Feb;9(2):105-16. Epub 2008 Jan 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00052936
#Abstract: S. Le Gouill, N. J. Milpied, T. Lamy, V. Delwail, R. Gressin, D. Guyotat, G. L. Damaj, C. Foussard, G. Cartron, H. Maisonneuve, E. Deconinck, F. Dreyfus, E. Gyan, L. Sutton, N. Morineau, M. Alexis, F. Perry, M. Sauvezie. First-line rituximab (R) high-dose therapy (R-HDT) versus R-CHOP14 for young adults with diffuse large B-cell lymphoma: Preliminary results of the GOELAMS 075 prospective multicenter randomized trial. Journal of Clinical Oncology 29, no. 15_suppl (May 2011) 8003-8003. link to abstract
#LNH03-6B: Delarue R, Tilly H, Mounier N, Petrella T, Salles G, Thieblemont C, Bologna S, Ghesquières H, Hacini M, Fruchart C, Ysebaert L, Fermé C, Casasnovas O, Van Hoof A, Thyss A, Delmer A, Fitoussi O, Molina TJ, Haioun C, Bosly A. Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol. 2013 May;14(6):525-33. Epub 2013 Apr 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00144755
##Update: Camus V, Belot A, Oberic L, Sibon D, Ghesquières H, Thieblemont C, Fruchart C, Casasnovas O, Michot JM, Molina TJ, Bosly A, Joubert C, Haioun C, Nicolas-Virelizier E, Feugier P, Fitoussi O, Delarue R, Tilly H. Outcomes of older patients with diffuse large B-cell lymphoma treated with R-CHOP: 10-year follow-up of the LNH03-6B trial. Blood Adv. 2022 Dec 27;6(24):6169-6179. link to original article link to PMC article EuroPMC
#RICOVER-noRTh: Held G, Murawski N, Ziepert M, Fleckenstein J, Pöschel V, Zwick C, Bittenbring J, Hänel M, Wilhelm S, Schubert J, Schmitz N, Löffler M, Rübe C, Pfreundschuh M. Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol. 2014 Apr 10;32(11):1112-8. Epub 2014 Feb 3. link to original article EuroPMC NCT00052936
#MAIN: Seymour JF, Pfreundschuh M, Trnený M, Sehn LH, Catalano J, Csinady E, Moore N, Coiffier B; MAIN Study Investigators. R-CHOP with or without bevacizumab in patients with previously untreated diffuse large B-cell lymphoma: final MAIN study outcomes. Haematologica. 2014 Aug;99(8):1343-9. Epub 2014 Jun 3. link to original article link to PMC article does not contain dosing details EuroPMC NCT00486759
#SMARTE-R-CHOP-14: Pfreundschuh M, Poeschel V, Zeynalova S, Hänel M, Held G, Schmitz N, Viardot A, Dreyling MH, Hallek M, Mueller C, Wiesen MH, Witzens-Harig M, Truemper L, Keller U, Rixecker T, Zwick C, Murawski N; German High-Grade Non-Hodgkin Lymphoma Study Group. Optimization of rituximab for the treatment of diffuse large B-cell lymphoma (II): extended rituximab exposure time in the SMARTE-R-CHOP-14 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group. J Clin Oncol. 2014 Dec 20;32(36):4127-33. Epub 2014 Nov 17. Erratum in: J Clin Oncol. 2015 Jun 10;33(17):1991. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00052936
#Cortelazzo S, Tarella C, Gianni AM, Ladetto M, Barbui AM, Rossi A, Gritti G, Corradini P, Di Nicola M, Patti C, Mulé A, Zanni M, Zoli V, Billio A, Piccin A, Negri G, Castellino C, Di Raimondo F, Ferreri AJ, Benedetti F, La Nasa G, Gini G, Trentin L, Frezzato M, Flenghi L, Falorio S, Chilosi M, Bruna R, Tabanelli V, Pileri S, Masciulli A, Delaini F, Boschini C, Rambaldi A. Randomized trial comparing R-CHOP versus high-dose sequential chemotherapy in high-risk patients with diffuse large B-cell lymphomas. J Clin Oncol. 2016 Nov 20;34(33):4015-4022. Epub 2016 Oct 31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00355199
#DLCL04: Chiappella A, Martelli M, Angelucci E, Brusamolino E, Evangelista A, Carella AM, Stelitano C, Rossi G, Balzarotti M, Merli F, Gaidano G, Pavone V, Rigacci L, Zaja F, D'Arco A, Cascavilla N, Russo E, Castellino A, Gotti M, Congiu AG, Cabras MG, Tucci A, Agostinelli C, Ciccone G, Pileri SA, Vitolo U. Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study. Lancet Oncol. 2017 Aug;18(8):1076-1088. Epub 2017 Jun 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00499018
#MabEase: Lugtenburg P, Avivi I, Berenschot H, Ilhan O, Marolleau JP, Nagler A, Rueda A, Tani M, Turgut M, Osborne S, Smith R, Pfreundschuh M. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica. 2017 Nov;102(11):1913-1922. Epub 2017 Sep 21. link to original article contains partial protocol link to PMC article EuroPMC NCT01649856
#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. 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00841945
#PETAL: Dührsen U, Müller S, Hertenstein B, Thomssen H, Kotzerke J, Mesters R, Berdel WE, Franzius C, Kroschinsky F, Weckesser M, Kofahl-Krause D, Bengel FM, Dürig J, Matschke J, Schmitz C, Pöppel T, Ose C, Brinkmann M, La Rosée P, Freesmeyer M, Hertel A, Höffkes HG, Behringer D, Prange-Krex G, Wilop S, Krohn T, Holzinger J, Griesshammer M, Giagounidis A, Raghavachar A, Maschmeyer G, Brink I, Bernhard H, Haberkorn U, Gaska T, Kurch L, van Assema DME, Klapper W, Hoelzer D, Geworski L, Jöckel KH, Scherag A, Bockisch A, Rekowski J, Hüttmann A; PETAL Trial Investigators. Positron emission tomography-guided therapy of aggressive non-Hodgkin lymphomas (PETAL): a multicenter, randomized phase III trial. J Clin Oncol. 2018 Jul 10;36(20):2024-2034. Epub 2018 May 11. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT00554164
#HOVON-84: Lugtenburg PJ, de Nully Brown P, van der Holt B, D'Amore FA, Koene HR, de Jongh E, Fijnheer R, van Esser JW, Böhmer LH, Pruijt JF, Verhoef GE, Hoogendoorn M, Bilgin MY, Nijland M, van der Burg-de Graauw NC, Oosterveld M, Jie KG, Larsen TS, van der Poel MW, Leijs MB, Silbermann MH, van Marwijk Kooy M, Beeker A, Kersten MJ, Doorduijn JK, Tick LW, Brouwer RE, Lam KH, Burggraaff CN, de Keizer B, Arens AI, de Jong D, Hoekstra OS, Zijlstra-Baalbergen JM. Rituximab-CHOP With Early Rituximab Intensification for Diffuse Large B-Cell Lymphoma: A Randomized Phase III Trial of the HOVON and the Nordic Lymphoma Group (HOVON-84). J Clin Oncol. 2020 Oct 10;38(29):3377-3387. Epub 2020 Jul 30. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC EudraCT 2006-005174-42
#GAINED: Le Gouill S, Ghesquières H, Oberic L, Morschhauser F, Tilly H, Ribrag V, Lamy T, Thieblemont C, Maisonneuve H, Gressin R, Bouhabdallah K, Haioun C, Damaj G, Fornecker L, Bouhabdallah R, Feugier P, Sibon D, Cartron G, Bonnet C, André M, Chartier L, Ruminy P, Kraeber-Bodéré F, Bodet-Milin C, Berriolo-Riedinger A, Brière J, Jais JP, Molina TJ, Itti E, Casasnovas RO. Obinutuzumab vs rituximab for advanced DLBCL: a PET-guided and randomized phase 3 study by LYSA. Blood. 2021 Apr 29;137(17):2307-2320. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT01659099
#SEXIE-R-CHOP-14: NCT00290667
==R-CHOP-14 (Prednisolone)==
R-CHOP-14: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisolone every 14 days
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Hara et al. 2018	2006-2013 	Phase 3 (C)	R-THP-COP 	Non-inferior CR rate
Note: large portions of the protocol, including the total number of cycles, are in Japanese.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 3
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 3
*Vincristine (Oncovin) 1.4 mg/m2 IV once on day 3
====Glucocorticoid therapy====
*Prednisolone (Millipred) 100 mg PO once per day on days 3 to 7
====Supportive therapy====
*Filgrastim (Neupogen) 50 mcg/kg SC once per day on days 9 to 14
14-day cycle for 6 cycles (see note)
===Regimen variant #2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Cunningham et al. 2013 (UK NCRI R-CHOP14v21)	2005-2008 	Phase 3 (E-esc)	R-CHOP-21 	Did not meet primary endpoint of OSOS24: 83% vs 81%(HR 0.90, 95% CI 0.70-1.15)
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 1 to 6: 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) as follows:
**Cycles 1 to 6: 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) as follows:
**Cycles 1 to 6: 2 mg IV once on day 1
====Glucocorticoid therapy====
*Prednisolone (Millipred) as follows:
**Cycles 1 to 6: 100 mg PO once per day on days 1 to 5
====CNS therapy, prophylaxis====
Per investigator discretion, but Cunningham et al. 2013 recommended that patients who had involvement of the "bone marrow, peripheral blood, nasal or paranasal sinuses, orbit, and testis" (they probably intended to say "or testis") receive:
*Methotrexate (MTX) 12.5 mg IT "for the first three cycles of treatment, administered as per local guidelines." No other details given.
====Supportive therapy====
*Lenograstim (Granocyte) (dose/route not specified) given on days 4 to 12
*Allopurinol (Zyloprim) 300 mg PO once per day during cycle 1
*Co-trimoxazole 480 mg (route not specified) twice per day on 3 days per week, taken throughout therapy, ending 2 weeks after treatment is completed
14-day cycle for 8 cycles
===References===
#UK NCRI R-CHOP14v21: Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, Pocock C, Ardeshna KM, Radford JA, McMillan A, Davies J, Turner D, Kruger A, Johnson P, Gambell J, Linch D. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet. 2013 May 25;381(9880):1817-26. Epub 2013 Apr 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN16017947
#Hara T, Yoshikawa T, Goto H, Sawada M, Yamada T, Fukuno K, Kasahara S, Shibata Y, Matsumoto T, Mabuchi R, Nakamura N, Nakamura H, Ninomiya S, Kitagawa J, Kanemura N, Nannya Y, Katsumura N, Takahashi T, Kito Y, Takami T, Miyazaki T, Takeuchi T, Shimizu M, Tsurumi H. R-THP-COP versus R-CHOP in patients younger than 70 years with untreated diffuse large B cell lymphoma: A randomized, open-label, noninferiority phase 3 trial. Hematol Oncol. 2018 Oct;36(4):638-644. Epub 2018 Jun 8. link to original article dosing details in supplement have been reviewed by our editors EuroPMC UMIN000007283
==R-CHOP-14 (SC Rituximab)==
R-CHOP-14: Rituximab and hyaluronidaase, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone every 14 days
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Lugtenburg et al. 2017 (MabEase)	2012 to not reported	Phase 3 (E-RT-switch-ic)	1a. R-CHOP1b. R-CHOP-14	Might have higher CR/CRu rate (composite primary endpoint)
Note: the details for CHOP-14 were not available in the manuscript or supplement; we have reproduced common CHOP-14 dosing, here. For patients achieving CR after cycle 4, the CHOP-14 could be omitted after cycle 6.
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once on day 1
*Rituximab and hyaluronidase human (Rituxan Hycela) as follows:
**Cycles 2 to 8: 1400 mg SC once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
====Supportive therapy====
*ONE of the following:
**Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 7 to 11
**Pegfilgrastim (Neulasta)
14-day cycle for 6 to 8 cycles
===References===
#MabEase: Lugtenburg P, Avivi I, Berenschot H, Ilhan O, Marolleau JP, Nagler A, Rueda A, Tani M, Turgut M, Osborne S, Smith R, Pfreundschuh M. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica. 2017 Nov;102(11):1913-1922. Epub 2017 Sep 21. link to original article contains partial protocol link to PMC article EuroPMC NCT01649856
==R2-CHOP==
R2-CHOP: Rituximab, Revlimid (Lenalidomide), Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone
LR-CHOP-21: Lenalidomide, Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone given every 21 days
===Regimen variant #1, len 15 mg/day for 14 d/cycle, pred 40 mg/m2===
Study 	Dates of enrollment	Evidence	Efficacy
Vitolo et al. 2014 (REAL07)	2008-2009 	Phase 2 	ORR: 92% (95% CI 81–97)
Note: CNS prophylaxis was offered to "at risk" patients.
====Targeted therapy====
*Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 14
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
====CNS therapy, prophylaxis====
*Methotrexate (MTX) as follows:
**Cycles 1 to 4: 12 mg IT once on day 1
====Supportive therapy====
*Granulocyte colony-stimulating factors (dose/duration not specified)
*Low-molecular-weight heparins (dose/duration not specified)
*PCP prophylaxis with one of the following:
**Trimethoprim-Sulfamethoxazole (Bactrim DS) (dose/duration not specified)
**Pentamidine (Nebupent) (dose/duration not specified)
*Carriers of hepatitis B virus: Lamivudine (Epivir) (dose/duration not specified)
21-day cycle for 6 cycles
===Regimen variant #2, len 15 mg/day for 14 d/cycle, pred 100 mg===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Nowakowski et al. 2021 (ROBUST)	2015-2017 	Phase 3 (E-esc)	R-CHOP 	Did not meet primary endpoint of PFSMedian PFS: NYR vs NYR(HR 0.85, 95% CI 0.63-1.14)
Note: patients were allowed to receive to additional doses of rituximab, per local practices.
====Biomarker eligibility criteria====
*ABC subtype, per NanoString Lymphoma Subtyping Test
====Targeted therapy====
*Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 14
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
21-day cycle for 6 cycles
===Regimen variant #3, len 25 mg/day for 10 d/cycle===
Study 	Dates of enrollment	Evidence	Efficacy
Nowakowski et al. 2014 (Mayo Clinic MC078E)	2008-09 to 2013-01 	Phase 2 	ORR: 98%
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 10
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg/m2 PO once per day on days 1 to 5
====Supportive therapy====
*Pegfilgrastim (Neulasta) 6 mg SC once on day 2
*Aspirin 81 mg PO once per day unless on therapeutic dose Warfarin (Coumadin) or low molecular weight heparin
21-day cycle for up to 6 cycles
===References===
#REAL07: Vitolo U, Chiappella A, Franceschetti S, Carella AM, Baldi I, Inghirami G, Spina M, Pavone V, Ladetto M, Liberati AM, Molinari AL, Zinzani P, Salvi F, Fattori PP, Zaccaria A, Dreyling M, Botto B, Castellino A, Congiu A, Gaudiano M, Zanni M, Ciccone G, Gaidano G, Rossi G; Fondazione Italiana Linfomi. Lenalidomide plus R-CHOP21 in elderly patients with untreated diffuse large B-cell lymphoma: results of the REAL07 open-label, multicentre, phase 2 trial. Lancet Oncol. 2014 Jun;15(7):730-7. Epub 2014 May 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00907348
#Mayo Clinic MC078E: Nowakowski GS, LaPlant B, Macon WR, Reeder CB, Foran JM, Nelson GD, Thompson CA, Rivera CE, Inwards DJ, Micallef IN, Johnston PB, Porrata LF, Ansell SM, Gascoyne RD, Habermann TM, Witzig TE. Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-cell lymphoma: a phase II study. J Clin Oncol. 2015 Jan 20;33(3):251-7. Epub 2014 Aug 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00670358
#ROBUST: Nowakowski GS, Chiappella A, Gascoyne RD, Scott DW, Zhang Q, Jurczak W, Özcan M, Hong X, Zhu J, Jin J, Belada D, Bergua JM, Piazza F, Mócikova H, Molinari AL, Yoon DH, Cavallo F, Tani M, Yamamoto K, Izutsu K, Kato K, Czuczman M, Hersey S, Kilcoyne A, Russo J, Hudak K, Zhang J, Wade S, Witzig TE, Vitolo U. ROBUST: A Phase III Study of Lenalidomide Plus R-CHOP Versus Placebo Plus R-CHOP in Previously Untreated Patients With ABC-Type Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2021 Apr 20;39(12):1317-1328. Epub 2021 Feb 23. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02285062
==DA-R-EPOCH==
DA-R-EPOCH: Dose Adjusted Rituximab, Etoposide, Prednisone, Oncovin (Vincristine), Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin)
DA-EPOCH-R
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy 	Comparative Toxicity
Wilson et al. 2008 	Not reported 	Phase 2 	 	 	
Wilson et al. 2011 (CALGB 50103) 	2002-2004 	Phase 2 	 	 	
García-Suárez et al. 2007 	2002-2006 	Phase 2 	 	 	
Purroy et al. 2014 	2002-2008 	Phase 2 	 	CR rate: 80.2%, 95% CI 75.8-84.6 	
Bartlett et al. 2019 (CALGB 50303)	2005-2013 	Phase 3 (E-esc)	R-CHOP 	Did not meet primary endpoint of PFSPFS24: 79% vs 75.5%(HR 0.93, 95% CI 0.68-1.27)	Increased toxicity
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once per cycle on day -1 or 1, given before the start of EPOCH (depending on reference)
====Chemotherapy====
*Etoposide (Vepesid) 50 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 200 mg/m2)
*Vincristine (Oncovin) 0.4 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1.6 mg/m2)
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 15 minutes once on day 5
*Doxorubicin (Adriamycin) 10 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 40 mg/m2)
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2 PO twice per day on days 1 to 5
====Supportive therapy====
*Growth factor support with one of the following:
**Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 6 and continuing until ANC greater than 5000/μL past nadir
**Pegfilgrastim (Neulasta) 6 mg SC once on day 6 (option per Purroy et al. 2014)
*PCP prophylaxis with any one of the following:
**Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day 3 days per week 
***Alternative used only in García-Suárez et al. 2007: cotrimoxazole 480 mg PO twice per day 3 days per week
**Atovaquone (Mepron) 1500 mg PO once per day
**Pentamidine (Nebupent) 300 mg nebulized every 28 days
*Only in García-Suárez et al. 2007: Darbepoetin alfa (Aranesp) 2.25 mcg/kg SC when hemoglobin concentration was less than or equal to 10 g/dL.
21-day cycle for 6 to 8 cycles
====Dose and schedule modifications====
*Start cycle 1 as described above.
*Obtain CBCs twice per week for nadir measurements.
*If nadir ANC greater than 500/μL, increase etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
*If nadir ANC less than 500/μL on 1 or 2 measurements, use same doses as last cycle.
*If nadir ANC less than 500/μL on at least 3 measurements, decrease etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
*And/or if nadir platelet count less than 25 x 109/L on at least 1 measurement, decrease etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
*Dose adjustments below the cycle 1 starting dose only applies to cyclophosphamide. The lowest etoposide and doxorubicin would be dosed at is the original cycle 1 dose.
*Can start new cycle every 21 days if ANC greater than 1000/μL and platelets greater than 100 x 109/L. If counts are below those levels, check daily CBC and continue growth factor support until counts are adequate and next cycle can start.
===References===
#García-Suárez J, Bañas H, Arribas I, De Miguel D, Pascual T, Burgaleta C. Dose-adjusted EPOCH plus rituximab is an effective regimen in patients with poor-prognostic untreated diffuse large B-cell lymphoma: results from a prospective observational study. Br J Haematol. 2007 Jan;136(2):276-85. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Wilson WH, Dunleavy K, Pittaluga S, Hegde U, Grant N, Steinberg SM, Raffeld M, Gutierrez M, Chabner BA, Staudt L, Jaffe ES, Janik JE. Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin Oncol. 2008 Jun 1;26(16):2717-24. Epub 2008 Mar 31. link to original article link to PMC article EuroPMC
#CALGB 50103: Wilson WH, Jung SH, Porcu P, Hurd D, Johnson J, Martin SE, Czuczman M, Lai R, Said J, Chadburn A, Jones D, Dunleavy K, Canellos G, Zelenetz AD, Cheson BD, Hsi ED; Cancer and Leukemia Group B. A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. Haematologica. 2012 May;97(5):758-65. Epub 2011 Dec 1. link to original article link to PMC article EuroPMC NCT00032019
#Purroy N, Bergua J, Gallur L, Prieto J, Lopez LA, Sancho JM, García-Marco JA, Castellví J, Montes-Moreno S, Batlle A, de Villambrosia SG, Carnicero F, Ferrando-Lamana L, Piris MA, Lopez A; PETHEMA. Long-term follow-up of dose-adjusted EPOCH plus rituximab (DA-EPOCH-R) in untreated patients with poor prognosis large B-cell lymphoma: a phase II study conducted by the Spanish PETHEMA group. Br J Haematol. 2015 Apr;169(2):188-98. Epub 2014 Dec 18. link to original article dosing details not present; refers to Wilson et al. 2002 EuroPMC EudraCT 2004-001684-22
#Retrospective: Howlett C, Snedecor SJ, Landsburg DJ, Svoboda J, Chong EA, Schuster SJ, Nasta SD, Feldman T, Rago A, Walsh KM, Weber S, Goy A, Mato A. Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis. Br J Haematol. 2015 Aug;170(4):504-14. Epub 2015 Apr 24. link to original article EuroPMC
#CALGB 50303: Bartlett NL, Wilson WH, Jung SH, Hsi ED, Maurer MJ, Pederson LD, Polley MC, Pitcher BN, Cheson BD, Kahl BS, Friedberg JW, Staudt LM, Wagner-Johnston ND, Blum KA, Abramson JS, Reddy NM, Winter JN, Chang JE, Gopal AK, Chadburn A, Mathew S, Fisher RI, Richards KL, Schöder H, Zelenetz AD, Leonard JP. Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303. J Clin Oncol. 2019 Jul 20;37(21):1790-1799. Epub 2019 Apr 2. link to original article link to PMC article dosing details in supplement have been reviewed by our editors EuroPMC NCT00118209
==R-Hyper-CVAD/R-MA==
R-Hyper-CVAD/R-MA: Rituximab, Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone alternating with Rituximab, Methotrexate, Ara-C (Cytarabine)
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Oki et al. 2013 (MDACC 2005-0054)	2005 to not reported	Randomized Phase 2 (E-esc)	R-CHOP 	Seems to have higher CR rate (primary endpoint)
Note: This regimen was intended for high-risk DLBCL (IPI greater than or equal to 3). The authors report "excellent outcome" in patients 45 years old or younger, however patients older than 45 years old had "unacceptable mortality."
====Targeted therapy, all cycles====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy, Hyper-CVAD portion (cycles 1, 3, 5; "Part A")====
*Cyclophosphamide (Cytoxan) 300 mg/m2 IV every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m2)
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 5 & 12
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 5
====Glucocorticoid therapy, Hyper-CVAD portion (cycles 1, 3, 5; "Part A")====
*Dexamethasone (Decadron) 40 mg IV or PO once per day on days 2 to 5
====Supportive therapy, Hyper-CVAD portion (cycles 1, 3, 5; "Part A")====
*Mesna (Mesnex) 600 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 1800 mg/m2)
*Filgrastim (Neupogen) or Pegfilgrastim (Neulasta) starting 24 to 48 hours after completion of chemotherapy
*Ciprofloxacin (Cipro) 500 mg PO twice per day for 10 days after chemotherapy
*Fluconazole (Diflucan) 100 mg PO once per day for 10 days after chemotherapy
*Valacyclovir (Valtrex) 500 mg PO once per day for 10 days after chemotherapy
====Chemotherapy, MA portion (cycles 2, 4, 6; "Part B")====
*Methotrexate (MTX) 200 mg/m2 IV over 2 hours once on day 1, then 800 mg/m2 IV over 22 hours (total dose per cycle: 1000 mg/m2)
*Cytarabine (Ara-C) 3000 mg/m2 IV over 2 hours every 12 hours on days 3 & 4 (total dose per cycle: 12,000 mg/m2)
====Supportive therapy, MA portion (cycles 2, 4, 6; "Part B")====
*Leucovorin (Folinic acid) (dose/timing not specified) until serum methotrexate level less than 100 nmol/L
*Sodium bicarbonate 1300 mg PO twice per day until methotrexate level less than 100 nmol/L
*Filgrastim (Neupogen) or Pegfilgrastim (Neulasta) starting 24 to 48 hours after completion of chemotherapy
*Ciprofloxacin (Cipro) 500 mg PO twice per day for 10 days after chemotherapy
*Fluconazole (Diflucan) 100 mg PO once per day for 10 days after chemotherapy
*Valacyclovir (Valtrex) 500 mg PO once per day for 10 days after chemotherapy
6 cycles; next cycle to start once ANC is greater than or equal to 1000/μL and platelet count is greater than or equal to 100 x 109/L.
====CNS prophylaxis, both portions====
"Recommended in patients with paraspinal disease, paranasal sinus disease, testicular disease, bone marrow disease, diffuse osseous disease or greater than or equal to 2 sites of extranodal disease. Actual administration of prophylactic intrathecal chemotherapy was at the treating physician's discretion."
====Dose modifications, Hyper-CVAD portion (cycles 1, 3, 5; "Part A")====
*Vincristine (Oncovin) reduced once by 50% for NCI common toxicity criteria Grade 2+ peripheral neuropathy, omitted if Grade 2+ peripheral neuropathy persists
*Doxorubicin (Adriamycin) and Cyclophosphamide (Cytoxan) reduced by 20% in subsequent A cycles if neutropenic fever occurs, grade 3/4 non-hematological toxicity, or ANC less than 750/μL or platelet count less than 75 x 109/L on day 21
Although the protocol does not specify, it is assumed that if these thresholds are not met by day 21, the next cycle will start with the dose reductions as specified.
====Dose modifications, MA portion (cycles 2, 4, 6; "Part B")====
*Methotrexate (MTX) reduced by 25% in subsequent B cycles if neutropenic fever occurs, grade 3/4 non-hematological toxicity, or ANC less than 750/μL or platelet count less than 75 x 109/L on day 21
*Cytarabine (Ara-C) reduced by 33% in subsequent B cycles if neutropenic fever occurs, grade 3/4 non-hematological toxicity, or ANC less than 750/μL or platelet count less than 75 x 109/L on day 21
===References===
#MDACC 2005-0054: Oki Y, Westin JR, Vega F, Chuang H, Fowler N, Neelapu S, Hagemeister FB, McLaughlin P, Kwak LW, Romaguera JE, Fanale M, Younes A, Rodriguez MA, Orlowski RZ, Wang M, Ouzounian ST, Samaniego F, Fayad L. Prospective phase II study of rituximab with alternating cycles of hyper-CVAD and high-dose methotrexate with cytarabine for young patients with high-risk diffuse large B-cell lymphoma. Br J Haematol. 2013 Dec;163(5):611-20. Epub 2013 Oct 1. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00290498
#Retrospective: Howlett C, Snedecor SJ, Landsburg DJ, Svoboda J, Chong EA, Schuster SJ, Nasta SD, Feldman T, Rago A, Walsh KM, Weber S, Goy A, Mato A. Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis. Br J Haematol. 2015 Aug;170(4):504-14. Epub 2015 Apr 24. link to original article EuroPMC
==R-MegaCHOP-14==
R-MegaCHOP-14: Rituximab, "Mega" (high-dose) Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne every 14 days
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Chiappella et al. 2017 (DLCL04)	2006-2010 	Phase 3 (E-esc)	1. R-CHOP-14 	Not reported
Chiappella et al. 2017 (DLCL04)	2006-2010 	Phase 3 (E-esc)	2. R-CHOP-14, then R-MAD, then BEAM, then auto HSCT 3. R-MegaCHOP-14, then R-MAD, then BEAM, then auto HSCT	Did not meet primary endpoint of FFS24
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1200 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 70 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
====Supportive therapy====
*Pegfilgrastim (Neulasta) 6 mg SC once on day 2, given 24 hours after chemotherapy
14-day cycle for 6 cycles
===References===
#Chiappella A, Martelli M, Angelucci E, Brusamolino E, Evangelista A, Carella AM, Stelitano C, Rossi G, Balzarotti M, Merli F, Gaidano G, Pavone V, Rigacci L, Zaja F, D'Arco A, Cascavilla N, Russo E, Castellino A, Gotti M, Congiu AG, Cabras MG, Tucci A, Agostinelli C, Ciccone G, Pileri SA, Vitolo U. Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study. Lancet Oncol. 2017 Aug;18(8):1076-1088. Epub 2017 Jun 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00499018
==R-miniCHOP (SC Rituximab)==
R-miniCHOP: Rituximab and hyaluronidaase, reduced-dose (mini) Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Oberic et al. 2021 (SENIOR)	2014-2017 	Phase 3 (C)	R2-miniCHOP	Did not meet primary endpoint of OSOS24: 66% vs 65.7%
Note: this regimen was intended for patients 80 years old or older.
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once on day 1
*Rituximab and hyaluronidase human (Rituxan Hycela) as follows:
**Cycles 2 to 6: 1400 mg SC once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 400 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 25 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1 mg IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
21-day cycle for 6 cycles
===References===
#SENIOR: Oberic L, Peyrade F, Puyade M, Bonnet C, Dartigues-Cuillères P, Fabiani B, Ruminy P, Maisonneuve H, Abraham J, Thieblemont C, Feugier P, Salles G, Bijou F, Pica GM, Damaj G, Haioun C, Casasnovas RO, Farhat H, Le Calloch R, Waultier-Rascalou A, Malak S, Paget J, Gat E, Tilly H, Jardin F. Subcutaneous Rituximab-MiniCHOP Compared With Subcutaneous Rituximab-MiniCHOP Plus Lenalidomide in Diffuse Large B-Cell Lymphoma for Patients Age 80 Years or Older. J Clin Oncol. 2021 Apr 10;39(11):1203-1213. Epub 2021 Jan 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02128061
==R-miniCEOP==
R-miniCEOP: Rituximab, mini, Cyclophosphamide, Epirubicin, O?? (vinblastine), Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Merli et al. 2012 (ANZINTER3)	2003-2006 	Phase 3 (E-de-esc)	R-CHOP 	Did not meet primary endpoint of EFS
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1
*Vinblastine (Velban) 5 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 50 mg/m2 IV or PO once per day on days 1 to 5
====Supportive therapy====
*Prophylactic G-CSF used for persisting grade 4 neutropenia or febrile neutropenia.
*Cotrimoxazole (dose/route/schedule not specified) prophylaxis.
*Erythropoietin use was allowed for hemoglobin less than 11 g/dL.
21-day cycle for 6 cycles
====Subsequent treatment====
*ANZINTER3, patients with initial bulky disease and/or partially responding sites: RT consolidation
===References===
#ANZINTER3: Merli F, Luminari S, Rossi G, Mammi C, Marcheselli L, Tucci A, Ilariucci F, Chiappella A, Musso M, Di Rocco A, Stelitano C, Alvarez I, Baldini L, Mazza P, Salvi F, Arcari A, Fragasso A, Gobbi PG, Liberati AM, Federico M. Cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab versus epirubicin, cyclophosphamide, vinblastine, prednisone and rituximab for the initial treatment of elderly "fit" patients with diffuse large B-cell lymphoma: results from the ANZINTER3 trial of the Intergruppo Italiano Linfomi. Leuk Lymphoma. 2012 Apr;53(4):581-8. Epub 2011 Nov 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01148446
==R-THP-COP==
R-THP-COP-14: Rituximab, THP (Pirarubicin), Cyclophosphamide, Oncovin (Vincristine), Prednisolone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Hara et al. 2018	2006-2013 	Phase 3 (E-switch-ic)	R-CHOP-14 	Non-inferior CR rate (primary endpoint)
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 3
*Pirarubicin (THP) 50 mg/m2 IV once on day 3
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 3
====Glucocorticoid therapy====
*Prednisolone (Millipred) 100 mg PO once per day on days 3 to 7
14- to 21-day cycle for 6 to 8 cycles
===References===
#Hara T, Yoshikawa T, Goto H, Sawada M, Yamada T, Fukuno K, Kasahara S, Shibata Y, Matsumoto T, Mabuchi R, Nakamura N, Nakamura H, Ninomiya S, Kitagawa J, Kanemura N, Nannya Y, Katsumura N, Takahashi T, Kito Y, Takami T, Miyazaki T, Takeuchi T, Shimizu M, Tsurumi H. R-THP-COP versus R-CHOP in patients younger than 70 years with untreated diffuse large B cell lymphoma: A randomized, open-label, noninferiority phase 3 trial. Hematol Oncol. 2018 Oct;36(4):638-644. Epub 2018 Jun 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC UMIN000007283
=Untreated, non-randomized or retrospective data=
==Bendamustine & Rituximab (BR)==
BR: Bendamustine, Rituximab
===Regimen variant #1, 90 mg/m2===
Study 	Dates of enrollment	Evidence
Park et al. 2016 (LCCC 1011)	2011-2013 	Phase 2
Note: this dosing was intended for patients with ECOG PS = 3 at baseline.
====Chemotherapy====
*Bendamustine 90 mg/m2 IV once per day on days 1 & 2, given first on day 1
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1, given second
21-day cycle for up to 8 cycles
====Dose and schedule modifications====
**Bendamustine dose increased to 120 mg/m2 if ECOG PS improved to less than or equal to 2 after 3 cycles
===Regimen variant #2, 120 mg/m2===
Study 	Dates of enrollment	Evidence
Park et al. 2016 (LCCC 1011)	2011-2013 	Phase 2
====Chemotherapy====
*Bendamustine 120 mg/m2 IV once per day on days 1 & 2, given first on day 1
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1, given second
21-day cycle for up to 8 cycles
===References===
#LCCC 1011: Park SI, Grover NS, Olajide O, Asch AS, Wall JG, Richards KL, Sobol AL, Deal AM, Ivanova A, Foster MC, Muss HB, Shea TC. A phase II trial of bendamustine in combination with rituximab in older patients with previously untreated diffuse large B-cell lymphoma. Br J Haematol. 2016 Oct;175(2):281-289. Epub 2016 Jul 22. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01234467
==Helicobacter pylori eradication therapy==
===Regimen variant #1, before 1996===
Study 	Evidence
Kuo et al. 2012	Retrospective
Note: This regimen was intended for the treatment of gastric DLBCL only; H. pylori eradication would not be an appropriate treatment for systemic DLBCL. While the regimen is described in Kuo et al. 2012, the cohort described in this paper was treated well after 1996.
====Antibiotic therapy====
*Amoxicillin 500 mg PO every 6 hours
*Metronidazole (Flagyl) 250 mg PO every 6 hours
*One of the following:
**Bismuth subcitrate 120 mg PO every 6 hours
**Omeprazole (Prilosec) 20 mg PO twice per day
28-day course
===Regimen variant #2, after 1996===
Study 	Dates of enrollment	Evidence
Kuo et al. 2012	2002-06 to 2009-06 	Retrospective
Note: This regimen was intended for the treatment of gastric DLBCL only; H. pylori eradication would not be an appropriate treatment for systemic DLBCL.
====Antibiotic therapy====
*Amoxicillin 500 mg PO every 6 hours
*Clarithromycin (Biaxin) 500 mg PO twice per day
*Omeprazole (Prilosec) 20 mg PO twice per day
14-day course
===References===
#Retrospective: Kuo SH, Yeh KH, Wu MS, Lin CW, Hsu PN, Wang HP, Chen LT, Cheng AL. Helicobacter pylori eradication therapy is effective in the treatment of early-stage H pylori-positive gastric diffuse large B-cell lymphomas. Blood. 2012 May 24;119(21):4838-44. Epub 2012 Mar 7. link to original article EuroPMC
==O-miniCHOP==
O-miniCHOP: Ofatumumab, reduced-dose (mini) Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne
===Regimen===
Study 	Dates of enrollment	Evidence
Peyrade et al. 2017 (LYSA LNH09-7B)	2010-2011 	Phase 2
====Preceding treatment====
*Vincristine & prednisone pre-phase
====Targeted therapy====
*Ofatumumab (Arzerra) 1000 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 400 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 25 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1 mg IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
====Supportive therapy====
*Acetaminophen (Tylenol) 1000 mg PO once on day 1, prior to ofatumumab
*Diphenhydramine (Benadryl) 50 mg (route not specified) once on day 1, prior to ofatumumab
21-day cycle for 6 cycles
===References===
#LYSA LNH09-7B: Peyrade F, Bologna S, Delwail V, Emile JF, Pascal L, Fermé C, Schiano JM, Coiffier B, Corront B, Farhat H, Fruchart C, Ghesquieres H, Macro M, Tilly H, Choufi B, Delarue R, Fitoussi O, Gabarre J, Haioun C, Jardin F; LYSA. Combination of ofatumumab and reduced-dose CHOP for diffuse large B-cell lymphomas in patients aged 80 years or older: an open-label, multicentre, single-arm, phase 2 trial from the LYSA group. Lancet Haematol. 2017 Jan;4(1):e46-e55. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01195714
==R-BL==
R-BL: Rituximab, Bendamustine, Lenalidomide
===Regimen===
Study 	Dates of enrollment	Evidence 	Efficacy
Hitz et al. 2016 (SAKK 38/08)	Not reported 	Phase 2, fewer than 20 pts in subgroup	ORR: 61% (95% CI 45-76%)
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
*Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
====Chemotherapy====
*Bendamustine 70 mg/m2 IV once per day on days 1 & 2
28-day cycle for 6 cycles
===References===
#SAKK 38/08: Hitz F, Zucca E, Pabst T, Fischer N, Cairoli A, Samaras P, Caspar CB, Mach N, Krasniqi F, Schmidt A, Rothermundt C, Enoiu M, Eckhardt K, Berardi Vilei S, Rondeau S, Mey U. Rituximab, bendamustine and lenalidomide in patients with aggressive B-cell lymphoma not eligible for anthracycline-based therapy or intensive salvage chemotherapy - SAKK 38/08. Br J Haematol. 2016 Jul;174(2):255-63. Epub 2016 Mar 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00987493
==R-CDOP==
R-CDOP: Rituximab, Cyclophosphamide, Doxil (Pegylated liposomal doxorubicin), Oncovin (Vincristine), Prednisone
DRCOP: Doxil (Pegylated liposomal doxorubicin), Rituximab, Cyclophosphamide, Oncovin (Vincristine), Prednisone
===Regimen variant #1===
Study 	Dates of enrollment	Evidence
Oki et al. 2014 (MDACC 2004-0305)	2005-08 to 2009-05 	Phase 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Pegylated liposomal doxorubicin (Doxil) 40 mg/m2 (maximum dose of 90 mg) IV over 60 minutes once on day 1
*Vincristine (Oncovin) 2 mg IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
====Supportive therapy====
*Filgrastim (Neupogen) 5 mcg/kg SC once per day from day 2 until ANC greater than 3000/μl
OR
*Pegfilgrastim (Neulasta) 6 mg SC once on day 2
21-day cycle for 6 to 8 cycles
====Dose and schedule modifications====
*Dose reduction level 1 (see paper for triggers):
**Pegylated liposomal doxorubicin (Doxil) reduced to 35 mg/m2
**Cyclophosphamide (Cytoxan) reduced to 600 mg/m2
*Dose reduction level 2 (see paper for triggers):
**Pegylated liposomal doxorubicin (Doxil) reduced to 30 mg/m2
**Cyclophosphamide (Cytoxan) reduced to 450 mg/m2
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Zaja et al. 2006	2002-12 to 2004-06 	Phase 2
Note: Only the dose of liposomal doxorubicin and number of cycles used were specified in the abstract. The doses of the other medications and schedule are provided based on the standard R-CHOP regimen, whose references can be found on this page. 
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Pegylated liposomal doxorubicin (Doxil) 30 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
21-day cycle for 6 cycles
===References===
#Zaja F, Tomadini V, Zaccaria A, Lenoci M, Battista M, Molinari AL, Fabbri A, Battista R, Cabras MG, Gallamini A, Fanin R. CHOP-rituximab with pegylated liposomal doxorubicin for the treatment of elderly patients with diffuse large B-cell lymphoma. Leuk Lymphoma. 2006 Oct;47(10):2174-80. link to original article EuroPMC
#MDACC 2004-0305: Oki Y, Ewer MS, Lenihan DJ, Fisch MJ, Hagemeister FB, Fanale M, Romaguera J, Pro B, Fowler N, Younes A, Astrow AB, Huang X, Kwak LW, Samaniego F, McLaughlin P, Neelapu SS, Wang M, Fayad LE, Durand JB, Rodriguez MA. Pegylated liposomal doxorubicin replacing conventional doxorubicin in standard R-CHOP chemotherapy for elderly patients with diffuse large B-cell lymphoma: an open label, single arm, phase II trial. Clin Lymphoma Myeloma Leuk. 2015 Mar;15(3):152-8. Epub 2014 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00101010
==R-CEOP90==
R-CEOP90: Rituximab, Cyclophosphamide, Epirubicin (90 mg/m2 dosing), Oncovin (Vincristine), Prednisolone
===Regimen variant #1, 4 cycles===
Study 	Dates of enrollment	Evidence
Cai et al. 2014	2004-11 to 2009-09 	Phase 2
Note: This regimen was intended to reduce cardiotoxicity and was not just for patients with contraindicated doxorubicin. Note that the cycle length was not explicitly defined in the paper but was reported as a median of 21 days (range 21 to 33 days). 
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 2
*Epirubicin (Ellence) 90 mg/m2 IV once on day 2
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 2
====Glucocorticoid therapy====
*Prednisolone (Millipred) 100 mg/day PO on days 2 to 6
21-day cycle for 4 cycles
====Subsequent treatment====
*Cai et al. 2014, patients with stage IA or IIA disease with bulky disease and extranodal and residual masses: IFRT x 3000 to 4500 cGy consolidation
===Regimen variant #2, 6 cycles===
Study 	Dates of enrollment	Evidence
Cai et al. 2014	2004-11 to 2009-09 	Phase 2
Note: This regimen was intended to reduce cardiotoxicity and was not just for patients with contraindicated doxorubicin. Note that the cycle length was not explicitly defined in the paper but was reported as a median of 21 days (range 21 to 33 days). 
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 2
*Epirubicin (Ellence) 90 mg/m2 IV once on day 2
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 2
====Glucocorticoid therapy====
*Prednisolone (Millipred) 100 mg/day PO on days 2 to 6
21-day cycle for 6 cycles (see note)
===References===
#Cai QC, Gao Y, Wang XX, Cai QQ, Lin ZX, Bai B, Guo Y, Huang HQ. Long-term results of the R-CEOP90 in the treatment of young patients with chemotherapy-naïve diffuse large B cell lymphoma: a phase II study. Leuk Lymphoma. 2014 Oct;55(10):2387-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==R-CEOP (Etoposide)==
R-CEOP: Rituximab, Cyclophosphamide, Etoposide, Oncovin (Vincristine), Prednisone
===Regimen===
Study 	Evidence
Moccia et al. 2009	Retrospective
Note: This regimen was intended for patients with a contraindication to anthracyclines. Only the dose of etoposide and number of cycles used were specified in the abstract. The doses of the other medications and schedule are provided based on the standard R-CHOP regimen, whose references can be found on this page. 
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Etoposide (Vepesid) 50 mg/m2 IV once on day 1, then 100 mg/m2 PO once per day on days 2 & 3
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
**Alternate dosing used in the R-CHOP regimens described in Coiffier et al. 2002 & 2010; Feugier et al. 2005; Mounier et al. 2012 - LNH 98-5: 40 mg/m2 PO once per day on days 1 to 5
21-day cycle for 3 to 4 cycles +/- radiation therapy for patients with limited stage disease; 6 cycles for patients with advanced stage disease
===References===
#Retrospective: Abstract: Moccia, Alden A., Schaff, Kimberly, Hoskins, Paul, Klasa, Richard, Savage, Kerry J., Shenkier, Tamara, Gascoyne, Randy D., Connors, Joseph M., Sehn, Laurie H. R-CHOP with Etoposide Substituted for Doxorubicin (R-CEOP): Excellent Outcome in Diffuse Large B Cell Lymphoma for Patients with a Contraindication to Anthracyclines. ASH Annual Meeting Abstracts 2009 114: 408 link to abstract
==R-GCVP==
R-GCVP: Rituximab, Gemcitabine, Cyclophosphamide, Vincristine, Prednisolone
===Regimen===
Study 	Dates of enrollment	Evidence
Fields et al. 2013 (UCL/05/154)	2008-2010 	Phase 2
Note: This regimen was intended for use in patients unlikely to tolerate anthracyclines due to cardiac comorbidity.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Gemcitabine (Gemzar) as follows:
**Cycle 1: 750 mg/m2 IV over 30 minutes once per day on days 1 & 8
**Cycle 2: 875 mg/m2 IV over 30 minutes once per day on days 1 & 8
**Cycles 3 to 6: 1000 mg/m2 IV over 30 minutes once per day on days 1 & 8
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
====Glucocorticoid therapy====
*Prednisolone (Millipred) 100 mg PO once per day on days 1 to 5
====Supportive therapy====
*Acetaminophen (Tylenol) 1000 mg (route not specified) once on day 1, prior to rituximab
*Chlorpheniramine (Chlor-Trimeton) 10 mg IV once on day 1, prior to rituximab
*Pegfilgrastim (Neulasta) 6 mg SC once on day 9
====CNS therapy, prophylaxis====
*Methotrexate (MTX) 12.5 mg IT x 3 cycles (timing not specified) for patients at high risk of CNS relapse
21-day cycle for 6 cycles
===References===
#UCL/05/154: Fields PA, Townsend W, Webb A, Counsell N, Pocock C, Smith P, Jack A, El-Mehidi N, Johnson PW, Radford J, Linch DC, Cunningham D. De novo treatment of diffuse large B-cell lymphoma with rituximab, cyclophosphamide, vincristine, gemcitabine, and prednisolone in patients with cardiac comorbidity: a United kingdom national cancer research institute trial. J Clin Oncol. 2014 Feb 1;32(4):282-7. Epub 2013 Nov 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00971763
==R-MegaCHOP==
R-MegaCHOP: Rituximab, Mega, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne
===Regimen===
Study 	Dates of enrollment	Evidence
Pardal et al. 2014 (GELTAMO-2006)	2007-2009 	Phase 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 1500 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 65 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1.4 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 5
====Supportive therapy====
*Pegfilgrastim (Neulasta) given after each cycle
21-day cycle for 3 cycles
====Subsequent treatment====
*GELTAMO-2006, negative PET-CT after 3 cycles: R-MegaCHOP continuation x 3 for a total of 6 cycles
*GELTAMO-2006, positive PET-CT after 3 cycles: R-IFE salvage
===References===
#GELTAMO-2006: Pardal E, Coronado M, Martín A, Grande C, Marín-Niebla A, Panizo C, Bello JL, Conde E, Hernández MT, Arranz R, Bargay J, González-Barca E, Pérez-Ceballos E, Montes-Moreno S, Caballero MD. Intensification treatment based on early FDG-PET in patients with high-risk diffuse large B-cell lymphoma: a phase II GELTAMO trial. Br J Haematol. 2014 Nov;167(3):327-36. Epub 2014 Jul 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01361191
==R-miniCHOP==
R-miniCHOP: Rituximab, reduced-dose (mini) Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne
===Regimen===
Study 	Dates of enrollment	Evidence
Peyrade et al. 2011 (LNH03-7B)	2006-2009 	Phase 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 400 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 25 mg/m2 IV once on day 1
*Vincristine (Oncovin) 1 mg IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
====Supportive therapy====
*"Prevention of tumour lysis syndrome by alkalinisation or hypouricaemic drugs was done if necessary."
* Serotonin (5-HT3) antagonist given every cycle.
*Prophylactic G-CSF or erythropoietin was left to treating physician's discretion.
21-day cycle for 6 cycles
====Dose and schedule modifications====
*No dose adjustments for hematologic toxicity. If needed, the subsequent R-miniCHOP cycle was postponed until ANC was greater than or equal to 1000/μL and platelet count was greater than or equal to 100 x 109/L, with a maximum of 28 days between cycles. Treatment was stopped if patients' counts were not adequate within 28 days.
*Patients with severe neutropenia or neutropenic fever received G-CSF (dose not specified) SC once per day on days 6 to 13 of the subsequent cycle until ANC was greater than or equal to 1000/μL.
===References===
#LNH03-7B: Peyrade F, Jardin F, Thieblemont C, Thyss A, Emile JF, Castaigne S, Coiffier B, Haioun C, Bologna S, Fitoussi O, Lepeu G, Fruchart C, Bordessoule D, Blanc M, Delarue R, Janvier M, Salles B, André M, Fournier M, Gaulard P, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2011 May;12(5):460-8. Epub 2011 Apr 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01087424
#SWOG S1918: NCT04799275
=Consolidation after upfront therapy=
==CBV, then auto HSCT==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Stiff et al. 2013 (SWOG S9704)	1999-2007 	Phase 3 (E-esc)	R-CHOP x 8	Higher PFS24 (co-primary endpoint)PFS24: 69% vs 55%(HR 0.58, 95% CI 0.40-0.85)Did not meet co-primary endpoint of OS24OS24: 74% vs 71%(HR 1.26, 95% CI 0.82-1.94)
====Preceding treatment====
*Induction R-CHOP x 6
===References===
#SWOG S9704: Stiff PJ, Unger JM, Cook JR, Constine LS, Couban S, Stewart DA, Shea TC, Porcu P, Winter JN, Kahl BS, Miller TP, Tubbs RR, Marcellus D, Friedberg JW, Barton KP, Mills GM, LeBlanc M, Rimsza LM, Forman SJ, Fisher RI. Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med. 2013 Oct 31;369(18):1681-90. link to original article link to PMC article EuroPMC NCT00004031
##Subgroup analysis: Puvvada SD, Stiff PJ, Leblanc M, Cook JR, Couban S, Leonard JP, Kahl B, Marcellus D, Shea TC, Winter JN, Li H, Rimsza LM, Friedberg JW, Smith SM. Outcomes of MYC-associated lymphomas after R-CHOP with and without consolidative autologous stem cell transplant: subset analysis of randomized trial intergroup SWOG S9704. Br J Haematol. 2016 Sep;174(5):686-91. Epub 2016 Apr 13. link to original article link to PMC article EuroPMC
==CBV-Mx, then auto HSCT==
===Regimen===
Study 	Dates of enrollment	Evidence
Haioun et al. 2009 (LNH 98-3)	1999-2004 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*ACE versus ACVBP induction
====Subsequent treatment====
*Observation versus rituximab maintenance
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00169169
==Cytarabine monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Récher et al. 2011 (LNH03-2B) 	2003-2008 	Non-randomized part of phase 3 RCT
Ketterer et al. 2013 (LNH03-1B)	2003-2008 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*REI consolidation x 4
====Chemotherapy====
*Cytarabine (Ara-C) 100 mg/m2 SC once per day on days 1 to 4
14-day cycle for 2 cycles
===References===
#LNH03-2B: Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, Thiéblemont C, Bosly A, Laurent G, Morschhauser F, Ghesquières H, Jardin F, Bologna S, Fruchart C, Corront B, Gabarre J, Bonnet C, Janvier M, Canioni D, Jais JP, Salles G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26;378(9806):1858-67. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00140595
##Subgroup analysis: Molina TJ, Canioni D, Copie-Bergman C, Recher C, Brière J, Haioun C, Berger F, Fermé C, Copin MC, Casasnovas O, Thieblemont C, Petrella T, Leroy K, Salles G, Fabiani B, Morschauser F, Mounier N, Coiffier B, Jardin F, Gaulard P, Jais JP, Tilly H. Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d'Etudes des Lymphomes de l'Adulte/lymphoma study association phase III trial LNH 03-2B. J Clin Oncol. 2014 Dec 10;32(35):3996-4003. Epub 2014 Nov 10. link to original article EuroPMC
#LNH03-1B: Ketterer N, Coiffier B, Thieblemont C, Fermé C, Brière J, Casasnovas O, Bologna S, Christian B, Connerotte T, Récher C, Bordessoule D, Fruchart C, Delarue R, Bonnet C, Morschhauser F, Anglaret B, Soussain C, Fabiani B, Tilly H, Haioun C. Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol. 2013 Apr;24(4):1032-7. Epub 2012 Dec 12. link to original article EuroPMC NCT00140595
==Ibritumomab tiuxetan protocol==
===Regimen variant #1, no cap===
Study 	Dates of enrollment	Evidence
Witzig et al. 2015 (ECOG E3402)	2004-2008 	Phase 2
====Preceding treatment====
*Induction R-CHOP x 4 to 6
====Targeted therapy====
*Rituximab (Rituxan) 250 mg/m2 IV once per day on days 1 & 8
====Radioconjugate therapy====
*Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 14.8 MBq/kg IV once on day 8
8-day course
====Subsequent treatment====
*ECOG E3402, patients with CT or PET positive disease 12 weeks after radioimmunotherapy: IFRT x 3000 cGy consolidation
===Regimen variant #2, capped dose===
Study 	Dates of enrollment	Evidence
Persky et al. 2014 (SWOG S0313)	2004-2008 	Phase 2
====Preceding treatment====
*CHOP induction x 3, then IFRT consolidation
====Targeted therapy====
*Rituximab (Rituxan) 250 mg/m2 IV once per day on days 1 & 8 +/- 1 day, given first on day 7, 8, or 9
====Radioconjugate therapy====
*Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day 8 +/- 1 day, given second, within 4 hours of rituximab
One course
===References===
#SWOG S0313: Persky DO, Miller TP, Unger JM, Spier CM, Puvvada S, Stea BD, Press OW, Constine LS, Barton KP, Friedberg JW, LeBlanc M, Fisher RI. Ibritumomab consolidation after 3 cycles of CHOP plus radiotherapy in high-risk limited-stage aggressive B-cell lymphoma: SWOG S0313. Blood. 2015 Jan 8;125(2):236-41. Epub 2014 Nov 13. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00070018
#ECOG E3402: Witzig TE, Hong F, Micallef IN, Gascoyne RD, Dogan A, Wagner H Jr, Kahl BS, Advani RH, Horning SJ. A phase II trial of RCHOP followed by radioimmunotherapy for early stage (stages I/II) diffuse large B-cell non-Hodgkin lymphoma: ECOG3402. Br J Haematol. 2015 Sep;170(5):679-86. Epub 2015 May 14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00088881
==Methotrexate monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Récher et al. 2011 (LNH03-2B) 	2003-2008 	Non-randomized part of phase 3 RCT
Ketterer et al. 2013 (LNH03-1B)	2003-2008 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*R-ACVBP induction x 4
====Chemotherapy====
*Methotrexate (MTX) 3000 mg/m2 IV once on day 1
====Supportive therapy====
*Calcium folinate - Leucovorin (Folinic acid) rescue
14-day cycle for 2 cycles
====Subsequent treatment====
*REI consolidation, in 2 weeks
===References===
#LNH03-2B: Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, Thiéblemont C, Bosly A, Laurent G, Morschhauser F, Ghesquières H, Jardin F, Bologna S, Fruchart C, Corront B, Gabarre J, Bonnet C, Janvier M, Canioni D, Jais JP, Salles G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26;378(9806):1858-67. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00140595
##Subgroup analysis: Molina TJ, Canioni D, Copie-Bergman C, Recher C, Brière J, Haioun C, Berger F, Fermé C, Copin MC, Casasnovas O, Thieblemont C, Petrella T, Leroy K, Salles G, Fabiani B, Morschauser F, Mounier N, Coiffier B, Jardin F, Gaulard P, Jais JP, Tilly H. Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d'Etudes des Lymphomes de l'Adulte/lymphoma study association phase III trial LNH 03-2B. J Clin Oncol. 2014 Dec 10;32(35):3996-4003. Epub 2014 Nov 10. link to original article EuroPMC
#LNH03-1B: Ketterer N, Coiffier B, Thieblemont C, Fermé C, Brière J, Casasnovas O, Bologna S, Christian B, Connerotte T, Récher C, Bordessoule D, Fruchart C, Delarue R, Bonnet C, Morschhauser F, Anglaret B, Soussain C, Fabiani B, Tilly H, Haioun C. Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol. 2013 Apr;24(4):1032-7. Epub 2012 Dec 12. link to original article EuroPMC NCT00140595
==Radiation therapy==
===Regimen variant #1, testicular irradiation===
Study 	Dates of enrollment	Evidence
Vitolo et al. 2011 (IELSG-10)	2001-2006 	Phase 2
====Preceding treatment====
*Induction R-CHOP x 6 to 8 cycles
====Radiotherapy====
*External beam radiotherapy 2500 to 3000 cGy to the contralateral testis. For patients with stage II disease, involved-field radiation therapy was added; see paper for details.
===Regimen variant #2, IFRT x 3000 cGy===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Horning et al. 2004 (ECOG E1484)	1984-1992 	Phase 3 (E-esc)	Observation	Seems to have longer DFS (primary endpoint)DFS72: 69% vs 53%(HR not reported, p=0.04)
====Preceding treatment====
*ECOG E1484: Induction CHOP x 8, with CR
====Radiotherapy====
*IFRT 3000 cGy
===Regimen variant #3, 3600 cGy===
Study 	Dates of enrollment	Evidence
Pfreundschuh et al. 2004 (NHL-B2) 	1993-2000 	Non-randomized part of phase 3 RCT
Pfreundschuh et al. 2008 (RICOVER-60) 	2000-2005 	Non-randomized part of phase 3 RCT
Schmitz et al. 2012 (DSHNHL 2002-1) 	2003-2009 	Non-randomized part of phase 3 RCT
Pfreundschuh et al. 2014 (SMARTE-R-CHOP-14)	2007-2009 	Phase 2
====Preceding treatment====
*NHL-B2: Induction CHOEP-14 x 6 versus CHOEP-21 x 6 versus CHOP-14 x 6 versus CHOP-21 x 6
*RICOVER-60: Induction CHOP-14 x 6 versus CHOP-14 x 8 versus R-CHOP-14 x 6 versus R-CHOP-14 x 8
*DSHNHL 2002-1: Induction R-CHOEP-14 x 8 versus R-MegaCHOEP
*SMARTE-R-CHOP-14: Induction R-CHOP-14 x 6
====Radiotherapy====
*External beam radiotherapy 3600 cGy in 180 to 200 cGy daily fractions over 4 weeks
===Regimen variant #4, IFRT x 4000 cGy===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Horning et al. 2004 (ECOG E1484) 	1984-1992 	Non-randomized part of phase 3 RCT	 	
Bonnet et al. 2007 	1993-2002 	Phase 3 (C) 	Observation	Did not meet primary endpoint of EFS
Persky et al. 2014 (SWOG S0313) 	2004-2008 	Phase 2 	 	
Lamy et al. 2017 (LYSA/GOELAMS 02-03)	2005-2014 	Phase 3 (E-esc) 	Observation	Non-inferior EFS
====Preceding treatment====
*ECOG E1484: Induction CHOP x 8, with PR
*SWOG S0313: Induction CHOP x 3, with CR
*Bonnet et al. 2007: Induction CHOP x 4
*LYSA/GOELAMS 02-03: Induction R-CHOP-14 x 4 to 6
====Radiotherapy====
*External beam radiotherapy 4000 cGy in daily fractions of 180 to 200 cGy
====Subsequent treatment====
*SWOG S0313: Ibritumomab tiuxetan consolidation
===Regimen variant #5, IFRT x 4000 to 5500 cGy===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Miller et al. 1998 (SWOG S8736) 	1988-1995 	Phase 3 (E-switch-ooc) 	See link 	See link
Persky et al. 2008 (SWOG S0014) 	2000-2002 	Phase 2 	 	
Pfreundschuh et al. 2006 (NCIC-CTG LY.9)	2000-2003 	Non-randomized part of phase 3 RCT	 	
Persky et al. 2014 (SWOG S0313) 	2004-2008 	Phase 2 	 	
Note: these studies did not specify an exact dose; see papers for details.
====Preceding treatment====
*SWOG S8736 and SWOG S0014: Induction CHOP x 3
*NCIC-CTG LY.9: Induction CHOP-like therapy x 6 versus R-CHOP-like therapy x 6
*SWOG S0313: Induction CHOP x 3, with PR
====Radiotherapy====
*External beam radiotherapy 4600 to 5000 cGy in daily fractions of 180 to 200 cGy
====Subsequent treatment====
*SWOG S0313: Ibritumumoab tiuxetan consolidation
===References===
#SWOG S8736: Miller TP, Dahlberg S, Cassady JR, Adelstein DJ, Spier CM, Grogan TM, LeBlanc M, Carlin S, Chase E, Fisher RI. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med. 1998 Jul 2;339(1):21-6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00005089
##Update: Stephens DM, Li H, LeBlanc ML, Puvvada SD, Persky D, Friedberg JW, Smith SM. Continued risk of relapse independent of treatment modality in limited-stage diffuse large B-cell lymphoma: Final and long-term analysis of Southwest Oncology Group study S8736. J Clin Oncol. 2016 Sep 1;34(25):2997-3004. Epub 2016 Jul 5. link to original article link to PMC article EuroPMC
#NHL-B2: Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rübe C, Rudolph C, Reiser M, Hossfeld DK, Eimermacher H, Hasenclever D, Schmitz N, Loeffler M; German High-Grade Non-Hodgkin's Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood. 2004 Aug 1;104(3):634-41. Epub 2004 Mar 11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#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
#LNH 93-01: Reyes F, Lepage E, Ganem G, Molina TJ, Brice P, Coiffier B, Morel P, Ferme C, Bosly A, Lederlin P, Laurent G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med. 2005 Mar 24;352(12):1197-205. link to original article EuroPMC
#NCIC-CTG LY.9: Pfreundschuh M, Trümper L, Osterborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, Walewski J, Zinzani PL, Stahel R, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, López-Guillermo A, Corrado C, Scheliga A, Milpied N, Mendila M, Rashford M, Kuhnt E, Loeffler M; MabThera International Trial Group. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006 May;7(5):379-91. link to original article EuroPMC NCT00064116
##Update: Pfreundschuh M, Kuhnt E, Trümper L, Osterborg A, Trneny M, Shepherd L, Gill DS, Walewski J, Pettengell R, Jaeger U, Zinzani PL, Shpilberg O, Kvaloy S, de Nully Brown P, Stahel R, Milpied N, López-Guillermo A, Poeschel V, Grass S, Loeffler M, Murawski N; MabThera International Trial (MInT) Group. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol. 2011 Oct;12(11):1013-22. Epub 2011 Sep 21. link to original article EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
#RICOVER-60: Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trümper L, Balleisen L, Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M; German High-Grade Non-Hodgkin Lymphoma Study Group. Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008 Feb;9(2):105-16. Epub 2008 Jan 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00052936
#SWOG S0014: Persky DO, Unger JM, Spier CM, Stea B, LeBlanc M, McCarty MJ, Rimsza LM, Fisher RI, Miller TP; SWOG. Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014. J Clin Oncol. 2008 May 10;26(14):2258-63. Epub 2008 Apr 14. link to original article does not contain dosing details EuroPMC
#IELSG-10: Vitolo U, Chiappella A, Ferreri AJ, Martelli M, Baldi I, Balzarotti M, Bottelli C, Conconi A, Gomez H, Lopez-Guillermo A, Martinelli G, Merli F, Novero D, Orsucci L, Pavone V, Ricardi U, Storti S, Gospodarowicz MK, Cavalli F, Sarris AH, Zucca E. First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximab-CHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international phase II trial. J Clin Oncol. 2011 Jul 10;29(20):2766-72. Epub 2011 Jun 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00210379
#DSHNHL 2002-1: Schmitz N, Nickelsen M, Ziepert M, Haenel M, Borchmann P, Schmidt C, Viardot A, Bentz M, Peter N, Ehninger G, Doelken G, Ruebe C, Truemper L, Rosenwald A, Pfreundschuh M, Loeffler M, Glass B; German High-Grade Lymphoma Study Group. Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1). Lancet Oncol. 2012 Dec;13(12):1250-1259. Epub 2012 Nov 16. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00129090
#SWOG S0313: Persky DO, Miller TP, Unger JM, Spier CM, Puvvada S, Stea BD, Press OW, Constine LS, Barton KP, Friedberg JW, LeBlanc M, Fisher RI. Ibritumomab consolidation after 3 cycles of CHOP plus radiotherapy in high-risk limited-stage aggressive B-cell lymphoma: SWOG S0313. Blood. 2015 Jan 8;125(2):236-41. Epub 2014 Nov 13. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00070018
#SMARTE-R-CHOP-14: Pfreundschuh M, Poeschel V, Zeynalova S, Hänel M, Held G, Schmitz N, Viardot A, Dreyling MH, Hallek M, Mueller C, Wiesen MH, Witzens-Harig M, Truemper L, Keller U, Rixecker T, Zwick C, Murawski N; German High-Grade Non-Hodgkin Lymphoma Study Group. Optimization of rituximab for the treatment of diffuse large B-cell lymphoma (II): extended rituximab exposure time in the SMARTE-R-CHOP-14 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group. J Clin Oncol. 2014 Dec 20;32(36):4127-33. Epub 2014 Nov 17. Erratum in: J Clin Oncol. 2015 Jun 10;33(17):1991. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00052936
#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. 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00841945
==R-IFE==
R-IFE: Rituximab, IFosfamide, Etoposide
REI: Rituximab, Etoposide, Ifosfamide
===Regimen===
Study 	Dates of enrollment	Evidence
Récher et al. 2011 (LNH03-2B) 	2003-2008 	Non-randomized part of phase 3 RCT
Ketterer et al. 2013 (LNH03-1B)	2003-2008 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*Methotrexate consolidation x 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Etoposide (Vepesid) 300 mg/m2 IV once on day 1
*Ifosfamide (Ifex) 1500 mg/m2 IV once on day 1
14-day cycle for 4 cycles
====Subsequent treatment====
*Cytarabine consolidation, in 2 weeks
===References===
#LNH03-2B: Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, Thiéblemont C, Bosly A, Laurent G, Morschhauser F, Ghesquières H, Jardin F, Bologna S, Fruchart C, Corront B, Gabarre J, Bonnet C, Janvier M, Canioni D, Jais JP, Salles G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26;378(9806):1858-67. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00140595
##Subgroup analysis: Molina TJ, Canioni D, Copie-Bergman C, Recher C, Brière J, Haioun C, Berger F, Fermé C, Copin MC, Casasnovas O, Thieblemont C, Petrella T, Leroy K, Salles G, Fabiani B, Morschauser F, Mounier N, Coiffier B, Jardin F, Gaulard P, Jais JP, Tilly H. Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d'Etudes des Lymphomes de l'Adulte/lymphoma study association phase III trial LNH 03-2B. J Clin Oncol. 2014 Dec 10;32(35):3996-4003. Epub 2014 Nov 10. link to original article EuroPMC
#LNH03-1B: Ketterer N, Coiffier B, Thieblemont C, Fermé C, Brière J, Casasnovas O, Bologna S, Christian B, Connerotte T, Récher C, Bordessoule D, Fruchart C, Delarue R, Bonnet C, Morschhauser F, Anglaret B, Soussain C, Fabiani B, Tilly H, Haioun C. Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol. 2013 Apr;24(4):1032-7. Epub 2012 Dec 12. link to original article EuroPMC NCT00140595
==TBI, then auto HSCT==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Stiff et al. 2013 (SWOG S9704)	1999-2007 	Phase 3 (E-esc)	R-CHOP x 8	Higher PFS24 (co-primary endpoint)PFS24: 69% vs 55%(HR 0.58, 95% CI 0.40-0.85)Did not meet co-primary endpoint of OS24OS24: 74% vs 71%(HR 1.26, 95% CI 0.82-1.94)
====Preceding treatment====
*Induction R-CHOP x 6
===References===
#SWOG S9704: Stiff PJ, Unger JM, Cook JR, Constine LS, Couban S, Stewart DA, Shea TC, Porcu P, Winter JN, Kahl BS, Miller TP, Tubbs RR, Marcellus D, Friedberg JW, Barton KP, Mills GM, LeBlanc M, Rimsza LM, Forman SJ, Fisher RI. Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med. 2013 Oct 31;369(18):1681-90. link to original article link to PMC article EuroPMC NCT00004031
##Subgroup analysis: Puvvada SD, Stiff PJ, Leblanc M, Cook JR, Couban S, Leonard JP, Kahl B, Marcellus D, Shea TC, Winter JN, Li H, Rimsza LM, Friedberg JW, Smith SM. Outcomes of MYC-associated lymphomas after R-CHOP with and without consolidative autologous stem cell transplant: subset analysis of randomized trial intergroup SWOG S9704. Br J Haematol. 2016 Sep;174(5):686-91. Epub 2016 Apr 13. link to original article link to PMC article EuroPMC
==Z-BEAM, then auto HSCT==
Z-BEAM: Zevalin (Ibritumomab tiuxetan), BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Shimoni et al. 2012 (SHEBA-07-4466-AN-CTIL)	Not reported 	Randomized Phase 2 (E-esc)	BEAM 	Did not meet primary endpoint of PFS24
Briones et al. 2013 (GELTAMO Z-BEAM LDCGB) 	2008-2010 	Phase 2 	 	
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Fruchart et al. 2014 (ZBEAM2)	2007-2008 	Phase 2
====Preceding treatment====
*R-ACVBP or R-CHOP induction
===References===
#Shimoni A, Zwas ST, Oksman Y, Hardan I, Shem-Tov N, Yerushalmi R, Avigdor A, Ben-Bassat I, Nagler A. Yttrium-90-ibritumomab tiuxetan (Zevalin) combined with high-dose BEAM chemotherapy and autologous stem cell transplantation for chemo-refractory aggressive non-Hodgkin's lymphoma. Exp Hematol. 2007 Apr;35(4):534-40. link to original article EuroPMC
#SHEBA-07-4466-AN-CTIL: Shimoni A, Avivi I, Rowe JM, Yeshurun M, Levi I, Or R, Patachenko P, Avigdor A, Zwas T, Nagler A. A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma. Cancer. 2012 Oct 1;118(19):4706-14. Epub 2012 Jan 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00491491
#GELTAMO Z-BEAM LDCGB: Briones J, Novelli S, García-Marco JA, Tomás JF, Bernal T, Grande C, Canales MA, Torres A, Moraleda JM, Panizo C, Jarque I, Palmero F, Hernández M, González-Barca E, López D, Caballero D. Autologous stem cell transplantation after conditioning with Yttrium-90 ibritumomab tiuxetan plus beam in refractory non-Hodgkin diffuse large B-cell lymphoma: results of a prospective, multicenter, phase II clinical trial. Haematologica. 2014 Mar;99(3):505-10. Epub 2013 Oct 25. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC EudraCT 2007-003198-22
#ZBEAM2: Fruchart C, Tilly H, Morschhauser F, Ghesquières H, Bouteloup M, Fermé C, Van Den Neste E, Bordessoule D, Bouabdallah R, Delmer A, Casasnovas RO, Ysebaert L, Ciappuccini R, Briere J, Gisselbrecht C. Upfront consolidation combining yttrium-90 ibritumomab tiuxetan and high-dose therapy with stem cell transplantation in poor-risk patients with diffuse large B cell lymphoma. Biol Blood Marrow Transplant. 2014 Dec;20(12):1905-11. Epub 2014 Jul 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00689169
=Maintenance after upfront therapy=
==Lenalidomide monotherapy==
===Regimen variant #1, 1 year===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Reddy et al. 2016 (VICC HEM 0835)	2008-2013 	Randomized Phase 2 (E-de-esc)	Lenalidomide & Rituximab	Did not meet primary endpoint of RFS12
====Preceding treatment====
*Induction R-CHOP with or without radiation
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycle for 12 cycles
===Regimen variant #2, 2 years===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Thieblemont et al. 2017 (REMARC)	2009-2014 	Phase 3 (E-esc)	Placebo 	Longer PFS (primary endpoint)Median PFS: NYR vs 58.9 mo(HR 0.71, 95% CI 0.54-0.93)
====Preceding treatment====
*R-CHOP-21 or R-CHOP14 induction
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycle for up to 26 cycles (2 years)
===References===
#VICC HEM 0835: Reddy NM, Greer JP, Morgan DS, Chen H, Park SI, Richards KL. A phase II randomized study of lenalidomide or lenalidomide and rituximab as maintenance therapy following standard chemotherapy for patients with high/high-intermediate risk diffuse large B-cell lymphoma. Leukemia. 2017 Jan;31(1):241-244. Epub 2016 Sep 22. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00765245
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01122472
==Rituximab monotherapy==
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Jaeger et al. 2015 (NHL13)	2004-2010 	Phase 3 (E-esc)	Observation	Did not meet primary endpoint of EFS
Patients required to be in CR or CRu prior to enrollment. The protocol was amended after the first 69 patients enrolled to increase length of treatment from 1 to 2 years.
====Preceding treatment====
*Induction R-CHOP-like chemotherapy x 4 to 8 (8 doses of rituximab)
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
2-month cycle for 6 to 12 cycles (1 to 2 years)
===Regimen variant #2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Witzens-Harig et al. 2015 (HD2002)	2002-2011 	Phase 3 (E-esc)	Observation	Longer OS in males (secondary endpoint)
====Preceding treatment====
*"Standard treatment" induction which was not further described in the paper, beyond that a majority of patient received R-CHOP (see Tables)
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
3-month cycle for 8 cycles (2 years)
===Regimen variant #3===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Haioun et al. 2009 (LNH 98-3)	1999-2004 	Phase 3 (E-esc)	Observation	Might have longer EFS (primary endpoint)EFS48: 80% vs 71%(HR not reported, p=0.099)
====Preceding treatment====
*CBVM, then auto HSCT consolidation
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
4-week course
===Regimen variant #4===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Habermann et al. 2006 (ECOG E4494)	1998-2001 	Phase 3 (E-esc)	Observation	Did not meet primary endpoint of FFS
Note: in ECOG E4494, rituximab maintenance had longer FFS in the group receiving CHOP upfront, which is no longer standard of care.
====Preceding treatment====
*R-CHOP versus CHOP induction
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
6-month cycle for 4 cycles (2 years)
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003150
#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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01933711
=Relapsed or refractory, salvage therapy=
==Axicabtagene ciloleucel monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Locke et al. 2021 (ZUMA-7)	2018-01-25 to 2019-10-04	Phase 3 (E-RT-switch-ooc)	1a. R-ICE1b. R-ESHAP1c. R-DHAP1d. R-GDP	Longer EFS (primary endpoint)Median EFS: 8.3 vs 2 mo(HR 0.40, 95% CI 0.31-0.51)Seems to have longer OS1 (secondary endpoint)Median OS: NYR vs 31.1 mo(HR 0.73, 95% CI 0.54-0.98)
1Reported efficacy is based on the 2023 update.
====Prior treatment criteria====
*Failure of first-line chemoimmunotherapy including an anti-CD20 monoclonal antibody and an anthracycline-containing regimen
====Preceding treatment====
*Lymphodepletion with FC
====Immunotherapy====
*Axicabtagene ciloleucel (Yescarta) target dose of 2 x 106 CAR T cells/kg IV once on day 0
One course
===References===
#ZUMA-7: Locke FL, Miklos DB, Jacobson CA, Perales MA, Kersten MJ, Oluwole OO, Ghobadi A, Rapoport AP, McGuirk J, Pagel JM, Muñoz J, Farooq U, van Meerten T, Reagan PM, Sureda A, Flinn IW, Vandenberghe P, Song KW, Dickinson M, Minnema MC, Riedell PA, Leslie LA, Chaganti S, Yang Y, Filosto S, Shah J, Schupp M, To C, Cheng P, Gordon LI, Westin JR; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):640-654. Epub 2021 Dec 11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03391466
##HRQoL analysis: Elsawy M, Chavez JC, Avivi I, Larouche JF, Wannesson L, Cwynarski K, Osman K, Davison K, Rudzki JD, Dahiya S, Dorritie K, Jaglowski S, Radford J, Morschhauser F, Cunningham D, Martin Garcia-Sancho A, Tzachanis D, Ulrickson ML, Karmali R, Kekre N, Thieblemont C, Enblad G, Dreger P, Malladi R, Joshi N, Wang WJ, Solem CT, Snider JT, Cheng P, To C, Kersten MJ. Patient-reported outcomes in ZUMA-7, a phase 3 study of axicabtagene ciloleucel in second-line large B-cell lymphoma. Blood. 2022 Nov 24;140(21):2248-2260. link to original article link to PMC article EuroPMC
##Q-TWiST analysis: Kersten MJ, Qiao Y, Shah R, Solem C, Snider JT, To C, Cheng P, Spooner C, Perales MA. Quality-Adjusted Time without Symptoms or Toxicity: Analysis of Axicabtagene Ciloleucel versus Standard of Care in Patients with Relapsed/Refractory Large B Cell Lymphoma. Transplant Cell Ther. 2023 May;29(5):335.e1-335.e8. Epub 2023 Jan 14. link to original article link to PMC article EuroPMC
##Update: Westin JR, Oluwole OO, Kersten MJ, Miklos DB, Perales MA, Ghobadi A, Rapoport AP, Sureda A, Jacobson CA, Farooq U, van Meerten T, Ulrickson M, Elsawy M, Leslie LA, Chaganti S, Dickinson M, Dorritie K, Reagan PM, McGuirk J, Song KW, Riedell PA, Minnema MC, Yang Y, Vardhanabhuti S, Filosto S, Cheng P, Shahani SA, Schupp M, To C, Locke FL; ZUMA-7 Investigators and Kite Members. Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma. N Engl J Med. 2023 Jul 13;389(2):148-157. Epub 2023 Jun 5. link to original article EuroPMC
==Glofit-GemOx==
Glofit-GemOx: Glofitamab, Gemcitabine, Oxaliplatin
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Abramson et al. 2024 (STARGLO)	2021-02-23 to 2023-03-14	Phase 3 (E-switch-ooc)	R-GemOx 	Longer OS1 (primary endpoint)Median OS: 25.5 vs 12.9 mo(HR 0.62, 95% CI 0.43-0.88)
1Reported efficacy is based on the updated analysis presented along with the primary results in Abramson et al. 2024
====Immunotherapy====
*Glofitamab (Columvi) as follows:
**Cycle 1: 2.5 mg IV once on day 8, then 10 mg IV once on day 15
**Cycles 2 to 12: 30 mg IV once on day 1
====Chemotherapy====
*Gemcitabine (Gemzar) as follows:
**Cycle 1: 1000 mg/m2 IV once on day 2
**Cycles 2 to 8: 1000 mg/m2 IV once on day 1
*Oxaliplatin (Eloxatin) as follows:
**Cycle 1: 100 mg/m2 IV once on day 2
**Cycles 2 to 8: 100 mg/m2 IV once on day 1
====Supportive therapy====
*Dexamethasone (Decadron) 20 mg (route not specified) once, given 60 minutes prior to each glofitamab infusion, until at least cycle 4 without CRS
*Obinutuzumab (Gazyva) as follows:
**Cycle 1: 1000 mg IV once on day 1
21-day cycle for up to 12 cycles
===References===
#STARGLO: Abramson JS, Ku M, Hertzberg M, Huang HQ, Fox CP, Zhang H, Yoon DH, Kim WS, Abdulhaq H, Townsend W, Herbaux C, Zaucha JM, Zhang QY, Chang H, Liu Y, Cheah CY, Ghesquieres H, Simko S, Orellana-Noia V, Ta R, Relf J, Dixon M, Kallemeijn M, Mulvihill E, Huang H, Lundberg L, Gregory GP. Glofitamab plus gemcitabine and oxaliplatin (GemOx) versus rituximab-GemOx for relapsed or refractory diffuse large B-cell lymphoma (STARGLO): a global phase 3, randomised, open-label trial. Lancet. 2024 Nov 16;404(10466):1940-1954. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04408638
==Lisocabtagene maraleucel monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kamdar et al. 2022 (TRANSFORM)	2018-2020 	Phase 3 (E-RT-switch-ooc)	1a. R-ICE1b. R-DHAP1c. R-GDP	Longer EFS1 (primary endpoint)Median EFS: NYR vs 2.4 mo(HR 0.36, 95% CI 0.24-0.52)
1Reported efficacy is based on the 2023 update.
====Preceding treatment====
*FC lymphodepletion
====Immunotherapy====
*Lisocabtagene maraleucel (Breyanzi) target dose of 100 x 106 CAR T cells/kg IV once on day 0
One course
===References===
#TRANSFORM: Kamdar M, Solomon SR, Arnason J, Johnston PB, Glass B, Bachanova V, Ibrahimi S, Mielke S, Mutsaers P, Hernandez-Ilizaliturri F, Izutsu K, Morschhauser F, Lunning M, Maloney DG, Crotta A, Montheard S, Previtali A, Stepan L, Ogasawara K, Mack T, Abramson JS; TRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022 Jun 18;399(10343):2294-2308. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03575351
##Update: Abramson JS, Solomon SR, Arnason J, Johnston PB, Glass B, Bachanova V, Ibrahimi S, Mielke S, Mutsaers P, Hernandez-Ilizaliturri F, Izutsu K, Morschhauser F, Lunning M, Crotta A, Montheard S, Previtali A, Ogasawara K, Kamdar M. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood. 2023 Apr 6;141(14):1675-1684. link to original article link to PMC article EuroPMC
==O-DHAP==
O-DHAP: Ofatumumab, Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Matasar et al. 2013 (GSK 110927) 	2009-2011 	Phase 2 	 	
van Imhoff et al. 2016 (ORCHARRD)	2010-2013 	Phase 3 (E-switch-ic)	R-DHAP 	Did not meet primary endpoint of PFS
====Targeted therapy====
*Ofatumumab (Arzerra) as follows:
**Cycle 1: 1000 mg IV once per day on days 1 & 8
**Cycles 2 & 3: 1000 mg IV once on day 1
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4
====Chemotherapy====
*Cytarabine (Ara-C) 2000 mg/m2 IV every 12 hours on day 2 (total dose per cycle: 4000 mg/m2)
*Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 1
====Supportive therapy====
*GSK 110927 recommended: Filgrastim (Neupogen) or Pegfilgrastim (Neulasta)
21-day cycle for 3 cycles
====Subsequent treatment====
*GSK 110927, responders: Stem-cell mobilization, then autologous hematopoietic stem cell transplant consolidation (regimen not specified)
*ORCHARRD, responders located outside of Japan: BEAM with autologous hematopoietic stem cell transplant consolidation
*ORCHARRD, responders located in Japan: LEED with autologous hematopoietic stem cell transplant consolidation
===References===
#GSK 110927: Matasar MJ, Czuczman MS, Rodriguez MA, Fennessy M, Shea TC, Spitzer G, Lossos IS, Kharfan-Dabaja MA, Joyce R, Fayad L, Henkel K, Liao Q, Edvardsen K, Jewell RC, Fecteau D, Singh RP, Lisby S, Moskowitz CH. Ofatumumab in combination with ICE or DHAP chemotherapy in relapsed or refractory intermediate grade B-cell lymphoma. Blood. 2013 Jul 25;122(4):499-506. Epub 2013 May 21. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00823719
#ORCHARRD: van Imhoff GW, McMillan A, Matasar MJ, Radford J, Ardeshna KM, Kuliczkowski K, Kim W, Hong X, Goerloev JS, Davies A, Barrigón MD, Ogura M, Leppä S, Fennessy M, Liao Q, van der Holt B, Lisby S, Hagenbeek A. Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: The ORCHARRD Study. J Clin Oncol. 2017 Feb 10;35(5):544-51. Epub 2016 Dec 28. link to original article link to data supplement dosing details in supplement have been reviewed by our editors EuroPMC NCT01014208
==O-ICE==
O-ICE: Ofatumumab, Ifosfamide, Carboplatin, Etoposide
===Regimen===
Study 	Dates of enrollment	Evidence
Matasar et al. 2013 (GSK 110927)	2009-2011 	Phase 2
Note: Subsequent consolidation therapy was not specified.
====Targeted therapy====
*Ofatumumab (Arzerra) as follows:
**Cycle 1: 1000 mg IV once per day on days 1 & 8
**Cycles 2 & 3: 1000 mg IV once on day 1
====Chemotherapy====
*Ifosfamide (Ifex) 5000 mg/m2 IV continuous infusion over 24 hours, started on day 2, mixed with mesna
*Carboplatin (Paraplatin) AUC 5 (maximum dose of 800 mg) IV once on either day 1 or 2
**Carboplatin AUC calculated based on a 12-hour creatinine clearance
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
====Supportive therapy====
*Mesna (Mesnex) 5000 mg/m2 IV continuous infusion over 24 hours, started on day 2, mixed with ifosfamide
*Recommended: Filgrastim (Neupogen) or Pegfilgrastim (Neulasta)
21-day cycle for 3 cycles
===References===
#GSK 110927: Matasar MJ, Czuczman MS, Rodriguez MA, Fennessy M, Shea TC, Spitzer G, Lossos IS, Kharfan-Dabaja MA, Joyce R, Fayad L, Henkel K, Liao Q, Edvardsen K, Jewell RC, Fecteau D, Singh RP, Lisby S, Moskowitz CH. Ofatumumab in combination with ICE or DHAP chemotherapy in relapsed or refractory intermediate grade B-cell lymphoma. Blood. 2013 Jul 25;122(4):499-506. Epub 2013 May 21. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00823719
==R-DexaBEAM==
R-DexaBEAM: Rituximab, Dexamethasone, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan
===Regimen===
Study 	Dates of enrollment	Evidence
Kirschey et al. 2014 (Mz-135)	2002-2006 	Phase 2
Note: the dosing in the manuscript was different than below. The below are the correct doses as verified by the authors.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1 & 8
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 8 mg PO three times per day on days 1 to 10
====Chemotherapy====
*Carmustine (BCNU) 60 mg/m2 IV once on day 3
*Etoposide (Vepesid) 75 mg/m2 IV once per day on days 4 to 7
*Cytarabine (Ara-C) 100 mg/m2 IV twice per day on days 4 to 7
*Melphalan (Alkeran) 20 mg/m2 IV once on day 2
3- to 4-week cycle for 2 cycles
====Subsequent treatment====
*R-BEAM with autologous hematopoietic stem cell transplant or R-TBI/Cy with autologous hematopoietic stem cell transplant consolidation
===References===
#Mz-135: Kirschey S, Flohr T, Wolf HH, Frickhofen N, Gramatzki M, Link H, Basara N, Peter N, Meyer RG, Schmitz N, Weidmann E, Banat A, Schulz A, Kolbe K, Derigs G, Theobald M, Hess G. Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: mature results of a phase II multicentre study. Br J Haematol. 2015 Mar;168(6):824-34. Epub 2014 Dec 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02099292
==R-DHAOx==
R-DHAOx: Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Oxaliplatin
ROAD: Rituximab, Oxaliplatin, Ara-C (Cytarabine), Dexamethasone
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Witzig et al. 2017 (MCCRC MC0485)	2006-2008 	Phase 2 	ORR: 71% (95% CI, 56–84)
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15
**Cycle 2: 375 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg IV or PO once per day on days 2 to 5
====Chemotherapy====
*Cytarabine (Ara-C) 2000 mg/m2 IV over 3 hours once per day on days 2 & 3, second dose to be given no sooner than 12 hours and no later than 24 hours after end of first dose
*Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 2
====Supportive therapy====
*Pegfilgrastim (Neulasta) 6 mg SC once on day 4
21-day cycles
====Subsequent treatment====
*Most responders: High-dose chemotherapy with autologous hematopoietic stem cell transplant consolidation after 2 cycles, although this was not mandated in the protocol
===References===
#MCCRC MC0485: Witzig TE, Johnston PB, LaPlant BR, Kurtin PJ, Pederson LD, Moore DF Jr, Nabbout NH, Nikcevich DA, Rowland KM, Grothey A. Long-term follow-up of chemoimmunotherapy with rituximab, oxaliplatin, cytosine arabinoside, dexamethasone (ROAD) in patients with relapsed CD20+ B-cell non-Hodgkin lymphoma: Results of a study of the Mayo Clinic Cancer Center Research Consortium (MCCRC) MC0485 now known as academic and community cancer research united (ACCRU). Am J Hematol. 2017 Oct;92(10):1004-1010. Epub 2017 Aug 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00166439
==R-DHAP==
R-DHAP: Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin)
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Gisselbrecht et al. 2010 (CORAL) 	2003-2007 	Phase 3 (E-switch-ic)	R-ICE 	Did not meet primary endpoint of mobilization-adjusted response rate after 3 cycles
van Imhoff et al. 2016 (ORCHARRD)	2010-2013 	Phase 3 (C) 	O-DHAP 	Did not meet primary endpoint of PFS
Note: CORAL made reference to Velasquez et al. 1988 to describe this regimen, although this reference is for DHAP, not R-DHAP. The paper also contains the following regimen information:
====Targeted therapy====
*Rituximab (Rituxan) as follows, given first:
**Cycle 1: 375 mg/m2 IV once per day on days -1 & 1 (CORAL) or days 1 & 8 (ORCHARRD)
**Cycle 2: 375 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
====Chemotherapy====
*Cytarabine (Ara-C) 2000 mg/m2 IV over 3 hours every 12 hours on day 2 (total dose per cycle: 4000 mg/m2)
*Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 1
====Supportive therapy====
*CORAL: G-CSF "depending on site policy, with R-DHAP, but always after the third cycle until the end of leukaphereses"
21-day cycle for 3 cycles
====Subsequent treatment====
*CORAL, responders: BEAM with autologous hematopoietic stem cell transplant consolidation
*ORCHARRD, responders located outside of Japan: BEAM with autologous hematopoietic stem cell transplant consolidation
*ORCHARRD, responders located in Japan: LEED with autologous hematopoietic stem cell transplant consolidation
===Regimen variant #2===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Crump et al. 2014 (NCIC-CTG LY.12)	2003-2011 	Phase 3 (C)	R-GDP 	Non-inferior RR after 2 cycles
Locke et al. 2021 (ZUMA-7) 	2018-01-25 to 2019-10-04	Phase 3 (C)	Axi-cel 	Shorter EFSMedian EFS: 2 vs 8.3 mo(HR 2.50, 95% CI 1.96-3.23)Seems to have shorter OS1Median OS: 31.1 vs NYR mo(HR 1.37, 95% CI 1.02-1.85)
Kamdar et al. 2022 (TRANSFORM) 	2018-2020 	Phase 3 (C)	Liso-cel 	Shorter EFS2Median EFS: 2.4 vs NYR mo(HR 2.78, 95% CI 1.92-4.17)
Bishop et al. 2021 (BELINDA) 	2019-2021 	Phase 3 (C)	Tisagenlecleucel	Did not meet primary endpoint of EFSMedian EFS: 3 vs 3 mo(HR 0.93, 95% CI 0.71-1.22)
1Reported OS efficacy for ZUMA-7 is based on the 2023 update.
2Reported efficacy for TRANSFORM is based on the 2023 update.
====Prior treatment criteria====
*NCIC-CTG LY.12: Previous treatment with one anthracycline-containing chemotherapy regimen
*ZUMA-7: Failure of first-line chemoimmunotherapy including an anti-CD20 monoclonal antibody and an anthracycline-containing regimen
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1 or day -1
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
====Chemotherapy====
*Cytarabine (Ara-C) 2000 mg/m2 IV over 3 hours every 12 hours on day 2 (total dose per cycle: 4000 mg/m2)
*Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 1
21-day cycle for up to 3 cycles
====Subsequent treatment====
*NCIC-CTG LY.12 & TRANSFORM, responders: Stem-cell mobilization, then high-dose chemotherapy with autologous hematopoietic stem cell transplant consolidation (regimen not specified)
===Regimen variant #3===
Study 	Dates of enrollment	Evidence
Mey et al. 2006	2000-01 to 2004-06 	Phase 2
Note: The doses here were used after a mid-protocol amendment pertaining to the first cycle, and were intended for patients younger than 60 years of age.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycle 1: 40 mg PO once per day on days 3 to 5
**Cycles 2 to 4: 40 mg PO once per day on days 3 to 6
====Chemotherapy====
*Cytarabine (Ara-C) as follows:
**Cycle 1: 1000 mg/m2 IV over 2 hours every 12 hours on day 4 (total dose per cycle: 2000 mg/m2)
**Cycles 2 to 4: 2000 mg/m2 IV over 2 hours every 12 hours on day 4 (total dose per cycle: 4000 mg/m2)
*Cisplatin (Platinol) as follows:
**Cycle 1: 25 mg/m2/day IV continuous infusion over 72 hours, started on day 3 (total dose: 75 mg/m2)
**Cycles 2 to 4: 25 mg/m2/day IV continuous infusion over 96 hours, started on day 3 (total dose per cycle: 100 mg/m2)
21-day cycle for up to 4 cycles
====Subsequent treatment====
*Mey et al. 2006, patients with at least PR were allowed to undergo: high-dose chemotherapy with autologous stem-cell transplant consolidation (regimen not specified)
===Regimen variant #3===
Study 	Dates of enrollment	Evidence
Mey et al. 2006	2000-01 to 2004-06 	Phase 2
Note: The doses here were used after a mid-protocol amendment pertaining to the first cycle, and were intended for patients older than 60 years of age.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Dexamethasone (Decadron) as follows:
**Cycle 1: 40 mg PO once per day on days 3 to 5
**Cycles 2 to 4: 40 mg PO once per day on days 3 to 6
====Chemotherapy====
*Cytarabine (Ara-C) as follows:
**Cycle 1: 500 mg/m2 IV over 2 hours every 12 hours on day 4 (total dose per cycle: 1000 mg/m2)
**Cycles 2 to 4: 1000 mg/m2 IV over 2 hours every 12 hours on day 4 (total dose per cycle: 2000 mg/m2)
*Cisplatin (Platinol) as follows:
**Cycle 1: 25 mg/m2/day IV continuous infusion over 72 hours, started on day 3 (total dose: 75 mg/m2)
**Cycles 2 to 4: 25 mg/m2/day IV continuous infusion over 96 hours, started on day 3 (total dose per cycle: 100 mg/m2)
21-day cycle for up to 4 cycles
====Subsequent treatment====
*Mey et al. 2006, patients with at least PR were allowed to undergo: high-dose chemotherapy with autologous stem-cell transplant consolidation (regimen not specified)
===References===
#Mey UJ, Orlopp KS, Flieger D, Strehl JW, Ho AD, Hensel M, Bopp C, Gorschlüter M, Wilhelm M, Birkmann J, Kaiser U, Neubauer A, Florschütz A, Rabe C, Hahn C, Glasmacher AG, Schmidt-Wolf IG. Dexamethasone, high-dose cytarabine, and cisplatin in combination with rituximab as salvage treatment for patients with relapsed or refractory aggressive non-Hodgkin's lymphoma. Cancer Invest. 2006 Oct;24(6):593-600. link to original article dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00137995
#NCIC-CTG LY.12: Crump M, Kuruvilla J, Couban S, MacDonald DA, Kukreti V, Kouroukis CT, Rubinger M, Buckstein R, Imrie KR, Federico M, Di Renzo N, Howson-Jan K, Baetz T, Kaizer L, Voralia M, Olney HJ, Turner AR, Sussman J, Hay AE, Djurfeldt MS, Meyer RM, Chen BE, Shepherd LE. Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol. 2014 Nov 1;32(31):3490-6. Epub 2014 Sep 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00078949
#ORCHARRD: van Imhoff GW, McMillan A, Matasar MJ, Radford J, Ardeshna KM, Kuliczkowski K, Kim W, Hong X, Goerloev JS, Davies A, Barrigón MD, Ogura M, Leppä S, Fennessy M, Liao Q, van der Holt B, Lisby S, Hagenbeek A. Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: The ORCHARRD Study. J Clin Oncol. 2017 Feb 10;35(5):544-51. Epub 2016 Dec 28. link to original article link to data supplement dosing details in supplement have been reviewed by our editors EuroPMC NCT01014208
#ZUMA-7: Locke FL, Miklos DB, Jacobson CA, Perales MA, Kersten MJ, Oluwole OO, Ghobadi A, Rapoport AP, McGuirk J, Pagel JM, Muñoz J, Farooq U, van Meerten T, Reagan PM, Sureda A, Flinn IW, Vandenberghe P, Song KW, Dickinson M, Minnema MC, Riedell PA, Leslie LA, Chaganti S, Yang Y, Filosto S, Shah J, Schupp M, To C, Cheng P, Gordon LI, Westin JR; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):640-654. Epub 2021 Dec 11. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT03391466
##HRQoL analysis: Elsawy M, Chavez JC, Avivi I, Larouche JF, Wannesson L, Cwynarski K, Osman K, Davison K, Rudzki JD, Dahiya S, Dorritie K, Jaglowski S, Radford J, Morschhauser F, Cunningham D, Martin Garcia-Sancho A, Tzachanis D, Ulrickson ML, Karmali R, Kekre N, Thieblemont C, Enblad G, Dreger P, Malladi R, Joshi N, Wang WJ, Solem CT, Snider JT, Cheng P, To C, Kersten MJ. Patient-reported outcomes in ZUMA-7, a phase 3 study of axicabtagene ciloleucel in second-line large B-cell lymphoma. Blood. 2022 Nov 24;140(21):2248-2260. link to original article link to PMC article EuroPMC
##Q-TWiST analysis: Kersten MJ, Qiao Y, Shah R, Solem C, Snider JT, To C, Cheng P, Spooner C, Perales MA. Quality-Adjusted Time without Symptoms or Toxicity: Analysis of Axicabtagene Ciloleucel versus Standard of Care in Patients with Relapsed/Refractory Large B Cell Lymphoma. Transplant Cell Ther. 2023 May;29(5):335.e1-335.e8. Epub 2023 Jan 14. link to original article link to PMC article EuroPMC
##Update: Westin JR, Oluwole OO, Kersten MJ, Miklos DB, Perales MA, Ghobadi A, Rapoport AP, Sureda A, Jacobson CA, Farooq U, van Meerten T, Ulrickson M, Elsawy M, Leslie LA, Chaganti S, Dickinson M, Dorritie K, Reagan PM, McGuirk J, Song KW, Riedell PA, Minnema MC, Yang Y, Vardhanabhuti S, Filosto S, Cheng P, Shahani SA, Schupp M, To C, Locke FL; ZUMA-7 Investigators and Kite Members. Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma. N Engl J Med. 2023 Jul 13;389(2):148-157. Epub 2023 Jun 5. link to original article EuroPMC
#BELINDA: Bishop MR, Dickinson M, Purtill D, Barba P, Santoro A, Hamad N, Kato K, Sureda A, Greil R, Thieblemont C, Morschhauser F, Janz M, Flinn I, Rabitsch W, Kwong YL, Kersten MJ, Minnema MC, Holte H, Chan EHL, Martinez-Lopez J, Müller AMS, Maziarz RT, McGuirk JP, Bachy E, Le Gouill S, Dreyling M, Harigae H, Bond D, Andreadis C, McSweeney P, Kharfan-Dabaja M, Newsome S, Degtyarev E, Awasthi R, Del Corral C, Andreola G, Masood A, Schuster SJ, Jäger U, Borchmann P, Westin JR. Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):629-639. Epub 2021 Dec 14. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT03570892
#TRANSFORM: Kamdar M, Solomon SR, Arnason J, Johnston PB, Glass B, Bachanova V, Ibrahimi S, Mielke S, Mutsaers P, Hernandez-Ilizaliturri F, Izutsu K, Morschhauser F, Lunning M, Maloney DG, Crotta A, Montheard S, Previtali A, Stepan L, Ogasawara K, Mack T, Abramson JS; TRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022 Jun 18;399(10343):2294-2308. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03575351
##Update: Abramson JS, Solomon SR, Arnason J, Johnston PB, Glass B, Bachanova V, Ibrahimi S, Mielke S, Mutsaers P, Hernandez-Ilizaliturri F, Izutsu K, Morschhauser F, Lunning M, Crotta A, Montheard S, Previtali A, Ogasawara K, Kamdar M. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood. 2023 Apr 6;141(14):1675-1684. link to original article link to PMC article EuroPMC
==R-DHAP/R-VIM==
R-DHAP/R-VIM: Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin) alternating with Rituximab, VP-16 (Etoposide), Ifosfamide, Methotrexate
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Vellenga et al. 2007 (HOVON-44)	2000-2005 	Phase 3 (E-esc)	DHAP/VIM 	Longer PFSPFS24: 52% vs 31%(HR not reported, p<0.002)
Note: per the paper, "in case patients were non-responsive to R-DHAP but responsive to R-VIM, it was allowed to repeat the R-VIM regimen as the third cycle of reinduction chemotherapy." No statement was made as to whether Mesna was used in the VIM protocol.
====Targeted therapy, R-DHAP portion (cycles 1 & 3)====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 5
====Glucocorticoid therapy, R-DHAP portion (cycles 1 & 3)====
*Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4
====Chemotherapy, R-DHAP portion (cycles 1 & 3)====
*Cytarabine (Ara-C) 2000 mg/m2 IV over 3 hours every 12 hours on day 2 (total dose per cycle: 4000 mg/m2)
*Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 1
====Targeted therapy, R-VIM portion (cycle 2)====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 6
====Chemotherapy, R-VIM portion (cycle 2)====
*Etoposide (Vepesid) 90 mg/m2 IV once per day on days 1, 3, 5
*Ifosfamide (Ifex) 1200 mg/m2 IV once per day on days 1 to 5
*Methotrexate (MTX) 30 mg/m2 IV once per day on days 1 & 5
28-day cycle for 3 cycles
====Subsequent treatment====
*HOVON-44, responders: Stem-cell mobilization, then BEAM with autologous hematopoietic stem cell transplant
===References===
#HOVON-44: Vellenga E, van Putten WL, van 't Veer MB, Zijlstra JM, Fibbe WE, van Oers MH, Verdonck LF, Wijermans PW, van Imhoff GW, Lugtenburg PJ, Huijgens PC. Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: a prospective randomized HOVON trial. Blood. 2008 Jan 15;111(2):537-43. Epub 2007 Oct 30. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00012051
==R-EPOCH==
R-EPOCH: Rituximab, Etoposide, Prednisone, Oncovin (Vincristine), Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin)
===Regimen===
Study 	Dates of enrollment	Evidence
Jermann et al. 2004	1998-2001 	Phase 2
Note: this is not the dose-adjusted R-EPOCH regimen
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Etoposide (Vepesid) 65 mg/m2/day IV continuous infusion over 72 hours, started on day 2 (total dose per cycle: 195 mg/m2)
*Vincristine (Oncovin) 0.5 mg/m2/day IV continuous infusion over 72 hours, started on day 2 (total dose per cycle: 1.5 mg/m2)
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 5
*Doxorubicin (Adriamycin) 15 mg/m2/day IV continuous infusion over 72 hours, started on day 2 (total dose per cycle: 45 mg/m2)
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 14
21-day cycle for 4 to 6 cycles
====Subsequent treatment====
*Jermann et al. 2004, patients younger than 60 who achieved at least PR: High-dose chemotherapy with autologous hematopoietic stem-cell transplantation (regimen not specified)
===References===
#Jermann M, Jost LM, Taverna Ch, Jacky E, Honegger HP, Betticher DC, Egli F, Kroner T, Stahel RA. Rituximab-EPOCH, an effective salvage therapy for relapsed, refractory or transformed B-cell lymphomas: results of a phase II study. Ann Oncol. 2004 Mar;15(3):511-6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==R-ESHAP==
R-ESHAP: Rituximab, Etoposide, Solumedrol (Methylprednisolone) High-dose Ara-C (Cytarabine), Platinol (Cisplatin)
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Martín et al. 2008 	2000-2007 	Retrospective 	 	
Avilés et al. 2010 	Not reported 	Phase 3 (E-esc)	ESHAP 	Did not meet efficacy endpoints
Locke et al. 2021 (ZUMA-7)	2018-01-25 to 2019-10-04	Phase 3 (C) 	Axicabtagene ciloleucel	Shorter EFSMedian EFS: 2 vs 8.3 mo(HR 2.50, 95% CI 1.96-3.23)Seems to have shorter OS1Median OS: 31.1 vs NYR mo(HR 1.37, 95% CI 1.02-1.85)
1Reported OS efficacy for ZUMA-7 is based on the 2023 update.
Note: Regimen details are based on the ZUMA-7 protocol, which makes reference to Martin et al. 2008.
====Prior treatment criteria====
*ZUMA-7: Failure of first-line chemoimmunotherapy including an anti-CD20 monoclonal antibody and an anthracycline-containing regimen
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Etoposide (Vepesid) 40 mg/m2 IV once per day on days 1 to 4
*Cytarabine (Ara-C) 2000 mg/m2 IV once on day 5
*Cisplatin (Platinol) 25 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 100 mg/m2)
====Glucocorticoid therapy====
*Methylprednisolone (Solumedrol) 500 mg IV once per day on days 1 to 4 or 1 to 5
2 or 3 cycles
===References===
#Retrospective: Martín A, Conde E, Arnan M, Canales MA, Deben G, Sancho JM, Andreu R, Salar A, García-Sanchez P, Vázquez L, Nistal S, Requena MJ, Donato EM, González JA, León A, Ruiz C, Grande C, González-Barca E, Caballero MD; Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea. R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome: A GEL/TAMO study. Haematologica. 2008 Dec;93(12):1829-36. Epub 2008 Oct 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Avilés A, Neri N, Huerta-Guzmán J, de Jesús Nambo M. ESHAP versus rituximab-ESHAP in frail patients with refractory diffuse large B-cell lymphoma. Clin Lymphoma Myeloma Leuk. 2010 Apr;10(2):125-8. link to original article EuroPMC
#ZUMA-7: Locke FL, Miklos DB, Jacobson CA, Perales MA, Kersten MJ, Oluwole OO, Ghobadi A, Rapoport AP, McGuirk J, Pagel JM, Muñoz J, Farooq U, van Meerten T, Reagan PM, Sureda A, Flinn IW, Vandenberghe P, Song KW, Dickinson M, Minnema MC, Riedell PA, Leslie LA, Chaganti S, Yang Y, Filosto S, Shah J, Schupp M, To C, Cheng P, Gordon LI, Westin JR; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):640-654. Epub 2021 Dec 11. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT03391466
##HRQoL analysis: Elsawy M, Chavez JC, Avivi I, Larouche JF, Wannesson L, Cwynarski K, Osman K, Davison K, Rudzki JD, Dahiya S, Dorritie K, Jaglowski S, Radford J, Morschhauser F, Cunningham D, Martin Garcia-Sancho A, Tzachanis D, Ulrickson ML, Karmali R, Kekre N, Thieblemont C, Enblad G, Dreger P, Malladi R, Joshi N, Wang WJ, Solem CT, Snider JT, Cheng P, To C, Kersten MJ. Patient-reported outcomes in ZUMA-7, a phase 3 study of axicabtagene ciloleucel in second-line large B-cell lymphoma. Blood. 2022 Nov 24;140(21):2248-2260. link to original article link to PMC article EuroPMC
##Q-TWiST analysis: Kersten MJ, Qiao Y, Shah R, Solem C, Snider JT, To C, Cheng P, Spooner C, Perales MA. Quality-Adjusted Time without Symptoms or Toxicity: Analysis of Axicabtagene Ciloleucel versus Standard of Care in Patients with Relapsed/Refractory Large B Cell Lymphoma. Transplant Cell Ther. 2023 May;29(5):335.e1-335.e8. Epub 2023 Jan 14. link to original article link to PMC article EuroPMC
##Update: Westin JR, Oluwole OO, Kersten MJ, Miklos DB, Perales MA, Ghobadi A, Rapoport AP, Sureda A, Jacobson CA, Farooq U, van Meerten T, Ulrickson M, Elsawy M, Leslie LA, Chaganti S, Dickinson M, Dorritie K, Reagan PM, McGuirk J, Song KW, Riedell PA, Minnema MC, Yang Y, Vardhanabhuti S, Filosto S, Cheng P, Shahani SA, Schupp M, To C, Locke FL; ZUMA-7 Investigators and Kite Members. Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma. N Engl J Med. 2023 Jul 13;389(2):148-157. Epub 2023 Jun 5. link to original article EuroPMC
==R-GDP==
R-GDP: Rituximab, Gemcitabine, Dexamethasone, Platinol (Cisplatin)
===Regimen variant #1, 1 day of cisplatin/cycle===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Crump et al. 2014 (NCIC-CTG LY.12)	2003-2011 	Phase 3 (E-switch-ic)	R-DHAP 	Non-inferior RR after 2 cycles (primary endpoint)
Locke et al. 2021 (ZUMA-7) 	2018-01-25 to 2019-10-04	Phase 3 (C) 	Axi-cel 	Shorter EFSMedian EFS: 2 vs 8.3 mo(HR 2.50, 95% CI 1.96-3.23)Seems to have shorter OS1Median OS: 31.1 vs NYR mo(HR 1.37, 95% CI 1.02-1.85)
Kamdar et al. 2022 (TRANSFORM) 	2018-2020 	Phase 3 (C) 	Liso-cel 	Shorter EFS1Median EFS: 2.4 vs NYR mo(HR 2.78, 95% CI 1.92-4.17)
Bishop et al. 2021 (BELINDA) 	2019-2021 	Phase 3 (C) 	Tisagenlecleucel	Did not meet primary endpoint of EFSMedian EFS: 3 vs 3 mo(HR 0.93, 95% CI 0.71-1.22)
1Reported OS efficacy for ZUMA-7 is based on the 2023 update.
2Reported efficacy for TRANSFORM is based on the 2023 update.
====Prior treatment criteria====
*NCIC-CTG LY.12: Previous treatment with one anthracycline-containing chemotherapy regimen
*ZUMA-7: Failure of first-line chemoimmunotherapy including an anti-CD20 monoclonal antibody and an anthracycline-containing regimen
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
*Cisplatin (Platinol) 75 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
21-day cycle for up to 3 cycles
====Subsequent treatment====
*NCIC-CTG LY.12 & TRANSFORM, responders: Stem-cell mobilization, then high-dose chemotherapy with autologous hematopoietic stem cell transplant (regimen not specified)
===Regimen variant #2, 3 days of cisplatin/cycle===
Study 	Dates of enrollment	Evidence
Hou et al. 2012	2005-2010 	Non-randomized
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
*Cisplatin (Platinol) 25 mg/m2 IV once per day on days 1 to 3
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg IV once per day on days 1 to 4
21-day cycle for up to 6 cycles
===References===
#Hou Y, Wang HQ, Ba Y. Rituximab, gemcitabine, cisplatin, and dexamethasone in patients with refractory or relapsed aggressive B-cell lymphoma. Med Oncol. 2012 Dec;29(4):2409-16. Epub 2012 Apr 3. link to original article EuroPMC
#NCIC-CTG LY.12: Crump M, Kuruvilla J, Couban S, MacDonald DA, Kukreti V, Kouroukis CT, Rubinger M, Buckstein R, Imrie KR, Federico M, Di Renzo N, Howson-Jan K, Baetz T, Kaizer L, Voralia M, Olney HJ, Turner AR, Sussman J, Hay AE, Djurfeldt MS, Meyer RM, Chen BE, Shepherd LE. Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol. 2014 Nov 1;32(31):3490-6. Epub 2014 Sep 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00078949
#ZUMA-7: Locke FL, Miklos DB, Jacobson CA, Perales MA, Kersten MJ, Oluwole OO, Ghobadi A, Rapoport AP, McGuirk J, Pagel JM, Muñoz J, Farooq U, van Meerten T, Reagan PM, Sureda A, Flinn IW, Vandenberghe P, Song KW, Dickinson M, Minnema MC, Riedell PA, Leslie LA, Chaganti S, Yang Y, Filosto S, Shah J, Schupp M, To C, Cheng P, Gordon LI, Westin JR; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):640-654. Epub 2021 Dec 11. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT03391466
##HRQoL analysis: Elsawy M, Chavez JC, Avivi I, Larouche JF, Wannesson L, Cwynarski K, Osman K, Davison K, Rudzki JD, Dahiya S, Dorritie K, Jaglowski S, Radford J, Morschhauser F, Cunningham D, Martin Garcia-Sancho A, Tzachanis D, Ulrickson ML, Karmali R, Kekre N, Thieblemont C, Enblad G, Dreger P, Malladi R, Joshi N, Wang WJ, Solem CT, Snider JT, Cheng P, To C, Kersten MJ. Patient-reported outcomes in ZUMA-7, a phase 3 study of axicabtagene ciloleucel in second-line large B-cell lymphoma. Blood. 2022 Nov 24;140(21):2248-2260. link to original article link to PMC article EuroPMC
##Q-TWiST analysis: Kersten MJ, Qiao Y, Shah R, Solem C, Snider JT, To C, Cheng P, Spooner C, Perales MA. Quality-Adjusted Time without Symptoms or Toxicity: Analysis of Axicabtagene Ciloleucel versus Standard of Care in Patients with Relapsed/Refractory Large B Cell Lymphoma. Transplant Cell Ther. 2023 May;29(5):335.e1-335.e8. Epub 2023 Jan 14. link to original article link to PMC article EuroPMC
##Update: Westin JR, Oluwole OO, Kersten MJ, Miklos DB, Perales MA, Ghobadi A, Rapoport AP, Sureda A, Jacobson CA, Farooq U, van Meerten T, Ulrickson M, Elsawy M, Leslie LA, Chaganti S, Dickinson M, Dorritie K, Reagan PM, McGuirk J, Song KW, Riedell PA, Minnema MC, Yang Y, Vardhanabhuti S, Filosto S, Cheng P, Shahani SA, Schupp M, To C, Locke FL; ZUMA-7 Investigators and Kite Members. Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma. N Engl J Med. 2023 Jul 13;389(2):148-157. Epub 2023 Jun 5. link to original article EuroPMC
#BELINDA: Bishop MR, Dickinson M, Purtill D, Barba P, Santoro A, Hamad N, Kato K, Sureda A, Greil R, Thieblemont C, Morschhauser F, Janz M, Flinn I, Rabitsch W, Kwong YL, Kersten MJ, Minnema MC, Holte H, Chan EHL, Martinez-Lopez J, Müller AMS, Maziarz RT, McGuirk JP, Bachy E, Le Gouill S, Dreyling M, Harigae H, Bond D, Andreadis C, McSweeney P, Kharfan-Dabaja M, Newsome S, Degtyarev E, Awasthi R, Del Corral C, Andreola G, Masood A, Schuster SJ, Jäger U, Borchmann P, Westin JR. Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):629-639. Epub 2021 Dec 14. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT03570892
#TRANSFORM: Kamdar M, Solomon SR, Arnason J, Johnston PB, Glass B, Bachanova V, Ibrahimi S, Mielke S, Mutsaers P, Hernandez-Ilizaliturri F, Izutsu K, Morschhauser F, Lunning M, Maloney DG, Crotta A, Montheard S, Previtali A, Stepan L, Ogasawara K, Mack T, Abramson JS; TRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022 Jun 18;399(10343):2294-2308. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03575351
##Update: Abramson JS, Solomon SR, Arnason J, Johnston PB, Glass B, Bachanova V, Ibrahimi S, Mielke S, Mutsaers P, Hernandez-Ilizaliturri F, Izutsu K, Morschhauser F, Lunning M, Crotta A, Montheard S, Previtali A, Ogasawara K, Kamdar M. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood. 2023 Apr 6;141(14):1675-1684. link to original article link to PMC article EuroPMC
==R-GemOx==
R-GemOx: Rituximab, Gemcitabine, Oxaliplatin
===Regimen variant #1, q3wk===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Abramson et al. 2024 (STARGLO)	2021-02-23 to 2023-03-14	Phase 3 (C)	Glofit-GemOx	Shorter OS1Median OS: 12.9 vs 25.5 mo(HR 1.61, 95% CI 1.14-2.33)
1Reported efficacy is based on the updated analysis presented along with the primary results in Abramson et al. 2024
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm in this setting.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Gemcitabine (Gemzar) as follows:
**Cycle 1: 1000 mg/m2 IV once on day 2
**Cycles 2 to 8: 1000 mg/m2 IV once on day 1
*Oxaliplatin (Eloxatin) as follows:
**Cycle 1: 100 mg/m2 IV once on day 2
**Cycles 2 to 8: 100 mg/m2 IV once on day 1
21-day cycle for up to 8 cycles
===Regimen variant #2, q2wk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bishop et al. 2021 (BELINDA)	2019-2021 	Phase 3 (C)	Tisagenlecleucel	Did not meet primary endpoint of EFSMedian EFS: 3 vs 3 mo(HR 0.93, 95% CI 0.71-1.22)
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm in this setting.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Gemcitabine (Gemzar) 1000 mg/m2 IV once on day 2
*Oxaliplatin (Eloxatin) 100 mg/m2 IV once on day 1
15-day cycle for 2 or more cycles
====Subsequent treatment====
*BELINDA, responders: Stem-cell mobilization, then high-dose chemotherapy with autologous hematopoietic stem cell transplant consolidation (BEAM preferred)
===References===
#BELINDA: Bishop MR, Dickinson M, Purtill D, Barba P, Santoro A, Hamad N, Kato K, Sureda A, Greil R, Thieblemont C, Morschhauser F, Janz M, Flinn I, Rabitsch W, Kwong YL, Kersten MJ, Minnema MC, Holte H, Chan EHL, Martinez-Lopez J, Müller AMS, Maziarz RT, McGuirk JP, Bachy E, Le Gouill S, Dreyling M, Harigae H, Bond D, Andreadis C, McSweeney P, Kharfan-Dabaja M, Newsome S, Degtyarev E, Awasthi R, Del Corral C, Andreola G, Masood A, Schuster SJ, Jäger U, Borchmann P, Westin JR. Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):629-639. Epub 2021 Dec 14. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT03570892
#STARGLO: Abramson JS, Ku M, Hertzberg M, Huang HQ, Fox CP, Zhang H, Yoon DH, Kim WS, Abdulhaq H, Townsend W, Herbaux C, Zaucha JM, Zhang QY, Chang H, Liu Y, Cheah CY, Ghesquieres H, Simko S, Orellana-Noia V, Ta R, Relf J, Dixon M, Kallemeijn M, Mulvihill E, Huang H, Lundberg L, Gregory GP. Glofitamab plus gemcitabine and oxaliplatin (GemOx) versus rituximab-GemOx for relapsed or refractory diffuse large B-cell lymphoma (STARGLO): a global phase 3, randomised, open-label trial. Lancet. 2024 Nov 16;404(10466):1940-1954. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT04408638
==R-ICE==
R-ICE: Rituximab, Ifosfamide, Carboplatin, Etoposide
ICE-R: Ifosfamide, Carboplatin, Etoposide, Rituximab
===Regimen variant #1===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Gisselbrecht et al. 2010 (CORAL)	2003-2007 	Phase 3 (E-switch-ic) 	R-DHAP 	Did not meet primary endpoint of mobilization-adjusted response rate after 3 cycles
Fayad et al. 2015 (SG040-0005) 	2007-2009 	Randomized Phase 2b (C)	R-ICE & Dacetuzumab	Did not meet primary endpoint of CR rate
Locke et al. 2021 (ZUMA-7) 	2018-01-25 to 2019-10-04	Phase 3 (C) 	Axi-cel 	Shorter EFSMedian EFS: 2 vs 8.3 mo(HR 2.50, 95% CI 1.96-3.23)Seems to have shorter OS1Median OS: 31.1 vs NYR mo(HR 1.37, 95% CI 1.02-1.85)
Kamdar et al. 2022 (TRANSFORM) 	2018-2020 	Phase 3 (C) 	Liso-cel 	Shorter EFS1Median EFS: 2.4 vs NYR mo(HR 2.78, 95% CI 1.92-4.17)
Bishop et al. 2021 (BELINDA) 	2019-2021 	Phase 3 (C) 	Tisagenlecleucel 	Did not meet primary endpoint of EFSMedian EFS: 3 vs 3 mo(HR 0.93, 95% CI 0.71-1.22)
1Reported OS efficacy for ZUMA-7 is based on the 2023 update.
2Reported efficacy for TRANSFORM is based on the 2023 update.
Note: Gisselbrecht et al. 2010 referred to the non-randomized regimen described in variant #3 below, although it had slightly different day numbering. Doses were the same. ZUMA-7 & BELINDA described just one dose of rituximab per cycle, given on the day prior to chemotherapy. TRANSFORM also described one dose of rituximab per cycle, given on day 1.
====Prior treatment criteria====
*ZUMA-7: Failure of first-line chemoimmunotherapy including an anti-CD20 monoclonal antibody and an anthracycline-containing regimen
====Targeted therapy====
*Rituximab (Rituxan) as follows (given first before other chemotherapy; see note):
**Cycle 1: 375 mg/m2 IV once per day on days -1 & 1
**Cycles 2 & 3: 375 mg/m2 IV once on day 1
====Chemotherapy====
*Ifosfamide (Ifex) 5000 mg/m2 IV continuous infusion over 24 hours, started on day 2
*Carboplatin (Paraplatin) AUC 5 (maximum dose of 800 mg) IV once on day 2
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
====Supportive therapy====
*Mesna (Mesnex) given with ifosfamide (dose & schedule not specified)
* Granulocyte colony-stimulating factor was administered after R-ICE
21-day cycle for varying durations: 2 to 3 cycles (ZUMA-7); 3 cycles (BELINDA, CORAL, SG040-0005, TRANSFORM)
====Subsequent treatment====
*CORAL, PR/CR: BEAM with autologous hematopoietic stem cell transplant
</div>
===Regimen variant #2===
Study 	Dates of enrollment	Evidence	Efficacy
Zelenetz et al. 2003 	1993-2000 	Phase 2 	ORR: 81%
Kewalramani et al. 2004	Not reported 	Phase 2 	CR rate (primary endpoint): 53%, 95% CI 36-69
Note: The third cycle was intended to be followed by peripheral blood hematopoietic stem cell collection. ORR reported in Zelenetz et al. 2003 was for the subset of DLBCL patients who received R-ICE; it is unclear if these patients were exposed to rituximab previously. None of the patients in Kewalaramani et al. 2004 had previously received rituximab.
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days -2 & 1
**Cycles 2 & 3: 375 mg/m2 IV once on day 1
====Chemotherapy====
*Ifosfamide (Ifex) 5000 mg/m2 IV continuous infusion over 24 hours, started on day 4, mixed with mesna
*Carboplatin (Paraplatin) AUC 5 (maximum dose of 800 mg) IV bolus once on day 4
**Carboplatin AUC calculated based on a 12-hour creatinine clearance
*Etoposide (Vepesid) 100 mg/m2 IV bolus once per day on days 3 to 5
====Supportive therapy====
*(as described by Kewalramani et al. 2004):
*Mesna (Mesnex) 5000 mg/m2 IV continuous infusion over 24 hours, started on day 4, mixed with ifosfamide
*Acetaminophen (Tylenol) 650 mg PO once, given prior to rituximab
*Diphenhydramine (Benadryl) 50 mg IV once, given prior to rituximab
*Filgrastim (Neupogen) as follows:
**Cycles 1 & 2: 5 mcg/kg SC once per day on days 7 to 14 
**Cycle 3: 10 mcg/kg SC once per day, starting on day 7, continued until collection of peripheral blood hematopoietic stem cells
14-day cycle for 3 cycles
===References===
#Zelenetz AD, Hamlin P, Kewalramani T, Yahalom J, Nimer S, Moskowitz CH. Ifosfamide, carboplatin, etoposide (ICE)-based second-line chemotherapy for the management of relapsed and refractory aggressive non-Hodgkin's lymphoma. Ann Oncol. 2003;14 Suppl 1:i5-10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Kewalramani T, Zelenetz AD, Nimer SD, Portlock C, Straus D, Noy A, O'Connor O, Filippa DA, Teruya-Feldstein J, Gencarelli A, Qin J, Waxman A, Yahalom J, Moskowitz CH. Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood. 2004 May 15;103(10):3684-8. Epub 2004 Jan 22. link to original article dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00137995
#SG040-0005: Fayad L, Ansell SM, Advani R, Coiffier B, Stuart R, Bartlett NL, Forero-Torres A, Kuliczkowski K, Belada D, Ng E, Drachman JG. Dacetuzumab plus rituximab, ifosfamide, carboplatin and etoposide as salvage therapy for patients with diffuse large B-cell lymphoma relapsing after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone: a randomized, double-blind, placebo-controlled phase 2b trial. Leuk Lymphoma. 2015;56(9):2569-78. Epub 2015 Feb 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00529503
#ZUMA-7: Locke FL, Miklos DB, Jacobson CA, Perales MA, Kersten MJ, Oluwole OO, Ghobadi A, Rapoport AP, McGuirk J, Pagel JM, Muñoz J, Farooq U, van Meerten T, Reagan PM, Sureda A, Flinn IW, Vandenberghe P, Song KW, Dickinson M, Minnema MC, Riedell PA, Leslie LA, Chaganti S, Yang Y, Filosto S, Shah J, Schupp M, To C, Cheng P, Gordon LI, Westin JR; All ZUMA-7 Investigators and Contributing Kite Members. Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):640-654. Epub 2021 Dec 11. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT03391466
##HRQoL analysis: Elsawy M, Chavez JC, Avivi I, Larouche JF, Wannesson L, Cwynarski K, Osman K, Davison K, Rudzki JD, Dahiya S, Dorritie K, Jaglowski S, Radford J, Morschhauser F, Cunningham D, Martin Garcia-Sancho A, Tzachanis D, Ulrickson ML, Karmali R, Kekre N, Thieblemont C, Enblad G, Dreger P, Malladi R, Joshi N, Wang WJ, Solem CT, Snider JT, Cheng P, To C, Kersten MJ. Patient-reported outcomes in ZUMA-7, a phase 3 study of axicabtagene ciloleucel in second-line large B-cell lymphoma. Blood. 2022 Nov 24;140(21):2248-2260. link to original article link to PMC article EuroPMC
##Q-TWiST analysis: Kersten MJ, Qiao Y, Shah R, Solem C, Snider JT, To C, Cheng P, Spooner C, Perales MA. Quality-Adjusted Time without Symptoms or Toxicity: Analysis of Axicabtagene Ciloleucel versus Standard of Care in Patients with Relapsed/Refractory Large B Cell Lymphoma. Transplant Cell Ther. 2023 May;29(5):335.e1-335.e8. Epub 2023 Jan 14. link to original article link to PMC article EuroPMC
##Update: Westin JR, Oluwole OO, Kersten MJ, Miklos DB, Perales MA, Ghobadi A, Rapoport AP, Sureda A, Jacobson CA, Farooq U, van Meerten T, Ulrickson M, Elsawy M, Leslie LA, Chaganti S, Dickinson M, Dorritie K, Reagan PM, McGuirk J, Song KW, Riedell PA, Minnema MC, Yang Y, Vardhanabhuti S, Filosto S, Cheng P, Shahani SA, Schupp M, To C, Locke FL; ZUMA-7 Investigators and Kite Members. Survival with Axicabtagene Ciloleucel in Large B-Cell Lymphoma. N Engl J Med. 2023 Jul 13;389(2):148-157. Epub 2023 Jun 5. link to original article EuroPMC
#BELINDA: Bishop MR, Dickinson M, Purtill D, Barba P, Santoro A, Hamad N, Kato K, Sureda A, Greil R, Thieblemont C, Morschhauser F, Janz M, Flinn I, Rabitsch W, Kwong YL, Kersten MJ, Minnema MC, Holte H, Chan EHL, Martinez-Lopez J, Müller AMS, Maziarz RT, McGuirk JP, Bachy E, Le Gouill S, Dreyling M, Harigae H, Bond D, Andreadis C, McSweeney P, Kharfan-Dabaja M, Newsome S, Degtyarev E, Awasthi R, Del Corral C, Andreola G, Masood A, Schuster SJ, Jäger U, Borchmann P, Westin JR. Second-Line Tisagenlecleucel or Standard Care in Aggressive B-Cell Lymphoma. N Engl J Med. 2022 Feb 17;386(7):629-639. Epub 2021 Dec 14. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT03570892
#TRANSFORM: Kamdar M, Solomon SR, Arnason J, Johnston PB, Glass B, Bachanova V, Ibrahimi S, Mielke S, Mutsaers P, Hernandez-Ilizaliturri F, Izutsu K, Morschhauser F, Lunning M, Maloney DG, Crotta A, Montheard S, Previtali A, Stepan L, Ogasawara K, Mack T, Abramson JS; TRANSFORM Investigators. Lisocabtagene maraleucel versus standard of care with salvage chemotherapy followed by autologous stem cell transplantation as second-line treatment in patients with relapsed or refractory large B-cell lymphoma (TRANSFORM): results from an interim analysis of an open-label, randomised, phase 3 trial. Lancet. 2022 Jun 18;399(10343):2294-2308. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03575351
##Update: Abramson JS, Solomon SR, Arnason J, Johnston PB, Glass B, Bachanova V, Ibrahimi S, Mielke S, Mutsaers P, Hernandez-Ilizaliturri F, Izutsu K, Morschhauser F, Lunning M, Crotta A, Montheard S, Previtali A, Ogasawara K, Kamdar M. Lisocabtagene maraleucel as second-line therapy for large B-cell lymphoma: primary analysis of the phase 3 TRANSFORM study. Blood. 2023 Apr 6;141(14):1675-1684. link to original article link to PMC article EuroPMC
</div>
==RICER==
RICER: Rituximab, Ifosfamide, Carboplatin, Etoposide, Revlimid (Lenalidomide)
===Regimen===
Study 	Dates of enrollment	Evidence
Feldman et al. 2014 (RV-DLBCL-PI-0463)	2010-2012 	Phase 1/2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 7
====Chemotherapy====
*Ifosfamide (Ifex) 5000 mg/m2 IV continuous infusion over 24 hours, started on day 2, mixed with mesna
*Carboplatin (Paraplatin) AUC 5 (maximum dose of 800 mg) IV once on day 2
*Etoposide (Vepesid) 100 mg/m2 IV bolus once per day on days 2 to 4
====Supportive therapy====
*Mesna (Mesnex) 5000 mg/m2 IV continuous infusion over 24 hours, started on day 2, mixed with ifosfamide
*Aspirin 81 mg PO once per day from day 1 until platelets less than 50 x 109/L
*Low dose LMWH for patients intolerant of Aspirin
* Granulocyte colony-stimulating factor was administered after R-ICE
14-day cycle for 2 cycles
====Subsequent treatment====
*RV-DLBCL-PI-0463, responders: RICER continuation x 1 (3 cycles total) with hematopoietic stem cell collection 10 to 14 days afterwards, then BEAM with autologous hematopoietic stem cell transplant (details not described)
===References===
#RV-DLBCL-PI-0463: Feldman T, Mato AR, Chow KF, Protomastro EA, Yannotti KM, Bhattacharyya P, Yang X, Donato ML, Rowley SD, Carini C, Valentinetti M, Smith J, Gadaleta G, Bejot C, Stives S, Timberg M, Kdiry S, Pecora AL, Beaven AW, Goy A. Addition of lenalidomide to rituximab, ifosfamide, carboplatin, etoposide (RICER) in first-relapse/primary refractory diffuse large B-cell lymphoma. Br J Haematol. 2014 Jul;166(1):77-83. Epub 2014 Mar 25. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01241734
==R-IFE==
R-IFE: Rituximab, IFosfamide, Etoposide
===Regimen===
Study 	Dates of enrollment	Evidence
Pardal et al. 2014 (GELTAMO-2006)	2007-2009 	Phase 2
====Preceding treatment====
*Induction R-MegaCHOP x 3, with PET-positive disease at interim assessment
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Ifosfamide (Ifex) 3333 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 10,000 mg/m2)
*Etoposide (Vepesid) 150 mg/m2 IV over 12 hours once per day on days 1 to 3
====Supportive therapy====
*Mesna (Mesnex) given after R-IFE; details not supplied in manuscript
*Pegfilgrastim (Neulasta) given after each cycle
2 cycles (duration not specified)
====Subsequent treatment====
*GELTAMO-2006, responders: BEAM with autologous hematopoietic stem cell transplant consolidation
===References===
#GELTAMO-2006: Pardal E, Coronado M, Martín A, Grande C, Marín-Niebla A, Panizo C, Bello JL, Conde E, Hernández MT, Arranz R, Bargay J, González-Barca E, Pérez-Ceballos E, Montes-Moreno S, Caballero MD. Intensification treatment based on early FDG-PET in patients with high-risk diffuse large B-cell lymphoma: a phase II GELTAMO trial. Br J Haematol. 2014 Nov;167(3):327-36. Epub 2014 Jul 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01361191
==R-NIMP==
R-NIMP: Rituximab, Navelbine (Vinorelbine), Ifosfamide, Mitoxantrone, Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Gyan et al. 2013	2004-2010 	Phase 2 	68% (95% CI: 53–79)
Note: BSA was capped at 2 for all dose calculations.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 (maximum dose of 750 mg) IV once on day 1
====Chemotherapy====
*Vinorelbine (Navelbine) 25 mg/m2 (maximum dose of 50 mg) IV once per day on days 1 & 15
*Ifosfamide (Ifex) 1000 mg/m2/day (maximum dose of 2000 mg/day) IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 5000 mg/m2)
*Mitoxantrone (Novantrone) 10 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 1 mg/kg (route not specified) once per day on days 1 to 5
====Supportive therapy====
*Mesna (Mesnex) given with ifosfamide "at the same dose"; schedule not specified in the paper
*Recommended: Pegfilgrastim (Neulasta) 6 mg SC once on day 7
*Recommended: Epoietin alpha support for hemoglobin less than 10 g/dL
28-day cycle for 3 cycles
====Subsequent treatment====
*Gyan et al. 2013, responders, transplant-ineligible: R-NIMP continuation x 3 (6 cycles total)
*Gyan et al. 2013, responders, transplant-eligible: high-dose chemotherapy with autologous hematopoietic stem cell transplant (regimen not specified)
===References===
#Gyan E, Damotte D, Courby S, Sénécal D, Quittet P, Schmidt-Tanguy A, Banos A, Le Gouill S, Lamy T, Fontan J, Maisonneuve H, Alexis M, Dreyfus F, Tournilhac O, Laribi K, Solal-Céligny P, Arakelyan N, Cartron G, Gressin R; GOELAMS. High response rate and acceptable toxicity of a combination of rituximab, vinorelbine, ifosfamide, mitoxantrone and prednisone for the treatment of diffuse large B-cell lymphoma in first relapse: results of the R-NIMP GOELAMS study. Br J Haematol. 2013 Jul;162(2):240-9. Epub 2013 May 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=Consolidation after salvage therapy=
==BEAC, then auto HSCT==
BEAC: Rituximab, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Cyclophosphamide
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Philip et al. 1995 (PARMA)	1987-1994 	Phase 3 (E-esc)	DHAP x 4 	Seems to have longer OSOS60: 53% vs 32%(HR not reported, p=0.038)
====Preceding treatment====
*DHAP x 2; radiation was also given to sites of bulky disease (>5cm)
===References===
#PARMA pilot: Philip T, Chauvin F, Armitage J, Bron D, Hagenbeek A, Biron P, Spitzer G, Velasquez W, Weisenburger DD, Fernandez-Ranada J, Somers R, Rizzoli V, Harousseau JL, Sotto JJ, Cahn JY, Guilhot F, Biggs J, Sonneveld P, Misset JL, Manna A, Jagannath S, Guglielmi C, Chevreau C, Delmer A, Santini G, Coiffier B. Parma international protocol: pilot study of DHAP followed by involved-field radiotherapy and BEAC with autologous bone marrow transplantation. Blood. 1991 Apr 1;77(7):1587-92. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#PARMA: Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D, Sonneveld P, Gisselbrecht C, Cahn JY, Harousseau JL, Coiffier B, Biron P, Mandelli F, Chauvin F. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med. 1995 Dec 7;333(23):1540-5. link to original article EuroPMC
==BEAM, then allo HSCT==
BEAM: BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan
===Regimen===
Study 	Dates of enrollment	Evidence
Przepiorka et al. 1999	Not reported 	Phase 2
===References===
#Przepiorka D, van Besien K, Khouri I, Hagemeister F, Samuels B, Folloder J, Ueno NT, Molldrem J, Mehra R, Körbling M, Giralt S, Gajewski J, Donato M, Cleary K, Claxton D, Braunschweig I, Andersson B, Anderlini P, Champlin R. Carmustine, etoposide, cytarabine and melphalan as a preparative regimen for allogeneic transplantation for high-risk malignant lymphoma. Ann Oncol. 1999 May;10(5):527-32. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==BEAM, then auto HSCT==
BEAM: Rituximab, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Shimoni et al. 2012 (SHEBA-07-4466-AN-CTIL)	Not reported 	Randomized Phase 2 (C) 	Z-BEAM 	Did not meet primary endpoint of PFS24
Pardal et al. 2014 (GELTAMO-2006) 	2007-2009 	Phase 2 	 	
van Imhoff et al. 2016 (ORCHARRD) 	2010-2013 	Non-randomized part of phase 3 RCT	 	
====Preceding treatment====
*GELTAMO-2006: R-MegaCHOP induction x 3, then R-IFE salvage x 2
*ORCHARRD: Salvage O-DHAP x 3 versus R-DHAP x 3
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Vellenga et al. 2007 (HOVON-44) 	2000-2005 	Non-randomized part of phase 3 RCT
Gisselbrecht et al. 2010 (CORAL)	2003-2007 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*HOVON-44: DHAP/VIM x 3 versus R-DHAP/R-VIM x 3
*CORAL: R-ICE x 3 versus R-DHAP x 3
====Subsequent treatment====
*CORAL: Rituximab maintenance versus observation
===Regimen variant #3, 300/100q12/200/140===
Study 	Dates of enrollment	Evidence
Philip et al. 1987	1980-1985 	Non-randomized
===References===
#Philip T, Armitage JO, Spitzer G, Chauvin F, Jagannath S, Cahn JY, Colombat P, Goldstone AH, Gorin NC, Flesh M, Laporte JP, Maraninchi D, Pico J, Bosly A, Anderson C, Schots R, Biron P, Cabanillas F, Dicke K. High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma. N Engl J Med. 1987 Jun 11;316(24):1493-8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#HOVON-44: Vellenga E, van Putten WL, van 't Veer MB, Zijlstra JM, Fibbe WE, van Oers MH, Verdonck LF, Wijermans PW, van Imhoff GW, Lugtenburg PJ, Huijgens PC. Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: a prospective randomized HOVON trial. Blood. 2008 Jan 15;111(2):537-43. Epub 2007 Oct 30. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00012051
#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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00137995
#SHEBA-07-4466-AN-CTIL: Shimoni A, Avivi I, Rowe JM, Yeshurun M, Levi I, Or R, Patachenko P, Avigdor A, Zwas T, Nagler A. A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma. Cancer. 2012 Oct 1;118(19):4706-14. Epub 2012 Jan 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00491491
#GELTAMO-2006: Pardal E, Coronado M, Martín A, Grande C, Marín-Niebla A, Panizo C, Bello JL, Conde E, Hernández MT, Arranz R, Bargay J, González-Barca E, Pérez-Ceballos E, Montes-Moreno S, Caballero MD. Intensification treatment based on early FDG-PET in patients with high-risk diffuse large B-cell lymphoma: a phase II GELTAMO trial. Br J Haematol. 2014 Nov;167(3):327-36. Epub 2014 Jul 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01361191
#ORCHARRD: van Imhoff GW, McMillan A, Matasar MJ, Radford J, Ardeshna KM, Kuliczkowski K, Kim W, Hong X, Goerloev JS, Davies A, Barrigón MD, Ogura M, Leppä S, Fennessy M, Liao Q, van der Holt B, Lisby S, Hagenbeek A. Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: The ORCHARRD Study. J Clin Oncol. 2017 Feb 10;35(5):544-51. Epub 2016 Dec 28. link to original article link to data supplement dosing details in supplement have been reviewed by our editors EuroPMC NCT01014208
==BeEAM, then auto HSCT==
BeEAM: Bendamustine, Etoposide, Ara-C (Cytarabine), Melphalan
===Regimen===
Study 	Dates of enrollment	Evidence
Visani et al. 2011	2008-08 to 2010-06 	Phase 1/2, fewer than 20 pts in this subgroup
===References===
#Visani G, Malerba L, Stefani PM, Capria S, Galieni P, Gaudio F, Specchia G, Meloni G, Gherlinzoni F, Giardini C, Falcioni S, Cuberli F, Gobbi M, Sarina B, Santoro A, Ferrara F, Rocchi M, Ocio EM, Caballero MD, Isidori A. BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell transplantation is safe and effective for resistant/relapsed lymphoma patients. Blood. 2011 Sep 22;118(12):3419-25. Epub 2011 Aug 3. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC EudraCT 2008-002736-15
==Busulfan, Fludarabine, Ibritumomab tiuxetan, then allo HSCT==
===Regimen===
Study 	Dates of enrollment	Evidence
Bouabdallah et al. 2015 (ZEVALLO)	2008-2010 	Phase 2
===References===
#ZEVALLO: Bouabdallah K, Furst S, Asselineau J, Chevalier P, Tournilhac O, Ceballos P, Vigouroux S, Tabrizi R, Doussau A, Bouabdallah R, Mohty M, Le Gouill S, Blaise D, Milpied N. 90Y-ibritumomab tiuxetan, fludarabine, busulfan and antithymocyte globulin reduced-intensity allogeneic transplant conditioning for patients with advanced and high-risk B-cell lymphomas. Ann Oncol. 2015 Jan;26(1):193-8. Epub 2014 Oct 30. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00607854
==CBV, then auto HSCT==
CBV: Cyclophosphamide, BiCNU (Carmustine), VP-16 (Etoposide)
===Regimen===
Study 	Dates of enrollment	Evidence
Stiff et al. 1998	1990-04 to 1994-11 	Phase 2
===References===
#Stiff PJ, Dahlberg S, Forman SJ, McCall AR, Horning SJ, Nademanee AP, Blume KG, LeBlanc M, Fisher RI; SWOG. Autologous bone marrow transplantation for patients with relapsed or refractory diffuse aggressive non-Hodgkin's lymphoma: value of augmented preparative regimens--a Southwest Oncology Group trial. J Clin Oncol. 1998 Jan;16(1):48-55. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Cyclophosphamide & TBI, then auto HSCT==
Cy/TBI: Cyclophosphamide & Total Body Irradiation
===Regimen===
Study 	Dates of enrollment	Evidence
Phillips et al. 1984	1977-1982 	Non-randomized
===References===
#Phillips GL, Herzig RH, Lazarus HM, Fay JW, Wolff SN, Mill WB, Lin H, Thomas PR, Glasgow GP, Shina DC, Herzig GP. Treatment of resistant malignant lymphoma with cyclophosphamide, total body irradiation, and transplantation of cryopreserved autologous marrow. N Engl J Med. 1984 Jun 14;310(24):1557-61. link to original article EuroPMC
==FEAM, then auto HSCT==
FEAM: Fotemustine, Etoposide, Ara-C (Cytarabine), Melphalan
===Regimen===
Study 	Dates of enrollment	Evidence
Musso et al. 2009	2007-2008 	Phase 2
===References===
#Musso M, Scalone R, Marcacci G, Lanza F, Di Renzo N, Cascavilla N, Di Bartolomeo P, Crescimanno A, Perrone T, Pinto A. Fotemustine plus etoposide, cytarabine and melphalan (FEAM) as a new conditioning regimen for lymphoma patients undergoing auto-SCT: a multicenter feasibility study. Bone Marrow Transplant. 2010 Jul;45(7):1147-53. Epub 2009 Nov 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Fludarabine, Busulfan, Cyclophosphamide, then allo HSCT==
FluBuCy: Fludarabine, Busulfan, Cyclophosphamide
===Regimen variant #1, oral===
Study 	Dates of enrollment 	Evidence
Glass et al. 2014 (DSHNHL R3)	2004-06-16 to 2009-03-24	Phase 2
===Regimen variant #2, intravenous===
Study 	Dates of enrollment 	Evidence
Glass et al. 2014 (DSHNHL R3)	2004-06-16 to 2009-03-24	Phase 2
===References===
#DSHNHL R3: Glass B, Hasenkamp J, Wulf G, Dreger P, Pfreundschuh M, Gramatzki M, Silling G, Wilhelm C, Zeis M, Görlitz A, Pfeiffer S, Hilgers R, Truemper L, Schmitz N; German High-Grade Lymphoma Study Group. Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial. Lancet Oncol. 2014 Jun;15(7):757-66. Epub 2014 May 11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00785330
==LEED, then auto HSCT==
LEED: L-PAM (Melphalan), Endoxan (Cyclophosphamide), Etoposide, Dexamethasone
===Regimen===
Study 	Dates of enrollment	Evidence
van Imhoff et al. 2016 (ORCHARRD)	2010-2013 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*O-DHAP x 3 versus R-DHAP x 3
===References===
#ORCHARRD: van Imhoff GW, McMillan A, Matasar MJ, Radford J, Ardeshna KM, Kuliczkowski K, Kim W, Hong X, Goerloev JS, Davies A, Barrigón MD, Ogura M, Leppä S, Fennessy M, Liao Q, van der Holt B, Lisby S, Hagenbeek A. Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: The ORCHARRD Study. J Clin Oncol. 2017 Feb 10;35(5):544-51. Epub 2016 Dec 28. link to original article link to data supplement dosing details in supplement have been reviewed by our editors EuroPMC NCT01014208
==R-BEAM, then auto HSCT==
R-BEAM: Rituximab, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan
===Regimen variant #1, 750/300/800/800/140===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Vose et al. 2013 (BMT CTN 0401)	2006-2009 	Phase 3 (C)	B-BEAM 	Did not meet primary endpoint of PFS24
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
===Regimen variant #2, 750/300/1600/3200/140===
Study 	Dates of enrollment	Evidence
Kirschey et al. 2014 (Mz-135)	2002-2006 	Phase 2
A minimum number of 2 x 106/kg bw CD34-positive cells were required to proceed.
====Preceding treatment====
*R-DexaBEAM x 2
===References===
#BMT CTN 0401: Vose JM, Carter S, Burns LJ, Ayala E, Press OW, Moskowitz CH, Stadtmauer EA, Mineshi S, Ambinder R, Fenske T, Horowitz M, Fisher R, Tomblyn M. Phase III randomized study of rituximab/carmustine, etoposide, cytarabine, and melphalan (BEAM) compared with iodine-131 tositumomab/BEAM with autologous hematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: results from the BMT CTN 0401 trial. J Clin Oncol. 2013 May 1;31(13):1662-8. Epub 2013 Mar 11. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00329030
#Mz-135: Kirschey S, Flohr T, Wolf HH, Frickhofen N, Gramatzki M, Link H, Basara N, Peter N, Meyer RG, Schmitz N, Weidmann E, Banat A, Schulz A, Kolbe K, Derigs G, Theobald M, Hess G. Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: mature results of a phase II multicentre study. Br J Haematol. 2015 Mar;168(6):824-34. Epub 2014 Dec 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02099292
==R-TBI/Cy, then auto HSCT==
R-TBI/Cy: Rituximab, Total, Body, Irradiation, Cyclophosphamide
===Regimen===
Study 	Dates of enrollment	Evidence
Kirschey et al. 2014 (Mz-135)	2002-2006 	Phase 2
====Preceding treatment====
*R-DexaBEAM x 2
===References===
#Mz-135: Kirschey S, Flohr T, Wolf HH, Frickhofen N, Gramatzki M, Link H, Basara N, Peter N, Meyer RG, Schmitz N, Weidmann E, Banat A, Schulz A, Kolbe K, Derigs G, Theobald M, Hess G. Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: mature results of a phase II multicentre study. Br J Haematol. 2015 Mar;168(6):824-34. Epub 2014 Dec 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02099292
==Z-BEAM, then auto HSCT==
Z-BEAM: Zevalin (Ibritumomab tiuxetan), BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Shimoni et al. 2007 	2004-2006 	Phase 2 	 	
Shimoni et al. 2012 (SHEBA-07-4466-AN-CTIL)	Not reported 	Randomized Phase 2 (E-esc)	BEAM 	Did not meet primary endpoint of PFS24
Briones et al. 2013 (GELTAMO Z-BEAM LDCGB) 	2008-2010 	Phase 2 	 	
Patients in SHEBA-07-4466-AN-CTIL had primary induction failure or were chemosensitive to salvage therapy. Patients in GELTAMO Z-BEAM LDCGB had primary induction failure or were refractory to salvage therapy.
===References===
#Shimoni A, Zwas ST, Oksman Y, Hardan I, Shem-Tov N, Yerushalmi R, Avigdor A, Ben-Bassat I, Nagler A. Yttrium-90-ibritumomab tiuxetan (Zevalin) combined with high-dose BEAM chemotherapy and autologous stem cell transplantation for chemo-refractory aggressive non-Hodgkin's lymphoma. Exp Hematol. 2007 Apr;35(4):534-40. link to original article EuroPMC
#SHEBA-07-4466-AN-CTIL: Shimoni A, Avivi I, Rowe JM, Yeshurun M, Levi I, Or R, Patachenko P, Avigdor A, Zwas T, Nagler A. A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma. Cancer. 2012 Oct 1;118(19):4706-14. Epub 2012 Jan 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00491491
#GELTAMO Z-BEAM LDCGB: Briones J, Novelli S, García-Marco JA, Tomás JF, Bernal T, Grande C, Canales MA, Torres A, Moraleda JM, Panizo C, Jarque I, Palmero F, Hernsández M, González-Barca E, López D, Caballero D. Autologous stem cell transplantation after conditioning with Yttrium-90 ibritumomab tiuxetan plus beam in refractory non-Hodgkin diffuse large B-cell lymphoma: results of a prospective, multicenter, phase II clinical trial. Haematologica. 2014 Mar;99(3):505-10. Epub 2013 Oct 25. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC EudraCT 2007-003198-22
=Maintenance after salvage therapy=
==Lenalidomide monotherapy==
===Regimen variant #1, 25 mg 21/28, indefinite===
Study 	Dates of enrollment	Evidence	Efficacy
Ferreri et al. 2017 (RV-NHL-PI351)	2009-2015 	Phase 2 	PFS12 (primary endpoint): 70%, 95% CI 57-83
====Preceding treatment====
*Salvage Rituximab-containing chemotherapy
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycles
===Regimen variant #2, 25 mg 21/28 for 12 months===
Study 	Dates of enrollment	Evidence
Feldman et al. 2014 (RV-DLBCL-PI-0463)	2010-2012 	Phase 1/2, fewer than 20 pts
====Preceding treatment====
*BEAM with autologous hematopoietic stem cell transplant (details not described)
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycle for up to 13 cycles (1 year)
===References===
#RV-DLBCL-PI-0463: Feldman T, Mato AR, Chow KF, Protomastro EA, Yannotti KM, Bhattacharyya P, Yang X, Donato ML, Rowley SD, Carini C, Valentinetti M, Smith J, Gadaleta G, Bejot C, Stives S, Timberg M, Kdiry S, Pecora AL, Beaven AW, Goy A. Addition of lenalidomide to rituximab, ifosfamide, carboplatin, etoposide (RICER) in first-relapse/primary refractory diffuse large B-cell lymphoma. Br J Haematol. 2014 Jul;166(1):77-83. Epub 2014 Mar 25. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01241734
#RV-NHL-PI351: Ferreri AJ, Sassone M, Zaja F, Re A, Spina M, di Rocco A, Fabbri A, Stelitano C, Frezzato M, Rusconi C, Zambello R, Couto S, Ren Y, Arcari A, Bertoldero G, Nonis A, Scarfò L, Calimeri T, Cecchetti C, Chiozzotto M, Govi S, Ponzoni M. Lenalidomide maintenance in patients with relapsed diffuse large B-cell lymphoma who are not eligible for autologous stem cell transplantation: an open label, single-arm, multicentre phase 2 trial. Lancet Haematol. 2017 Mar;4(3):e137-e146. Epub 2017 Feb 17. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00799513
==Rituximab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Gisselbrecht et al. 2010 (CORAL)	2003-2007 	Phase 3 (E-esc)	Observation	Did not meet secondary endpoint of EFS1
1Reported efficacy is based on the 2012 update.
Note: Treatment begins on day +28.
====Preceding treatment====
*BEAM with autologous hematopoietic stem cell transplant
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
8-week cycle for 6 cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
=Relapsed or refractory, further lines of therapy=
Note: these are regimens that were generally given with non-curative intent. However, some of these regimens, such as CAR-T therapy, can function as a bridge to consolidation with one of the salvage consolidation regimens, above.
==Axicabtagene ciloleucel monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Efficacy
Locke et al. 2017 (ZUMA-1)	2015-11 to 2016-09 	Phase 1/2 (RT)	ORR: 83%; CR: 59%
Median OS: not reached
Median PFS: 6 months
Median duration of response: 11 months
====Preceding treatment====
*Lymphodepletion with FC
====Immunotherapy====
*Axicabtagene ciloleucel (Yescarta) target dose of 2 x 106 CAR T cells/kg IV once on day 0
====Supportive therapy====
*Acetaminophen (Tylenol) 650 mg PO once on day 0, approximately 60 minutes prior to axi-cel
*Diphenhydramine (Benadryl) 12.5 mg IV or PO once on day 0, approximately 60 minutes prior to axi-cel
 
One course; patients with initial response and disease progression at least 3 months later could be retreated
===References===
#ZUMA-1: Locke FL, Neelapu SS, Bartlett NL, Siddiqi T, Chavez JC, Hosing CM, Ghobadi A, Budde LE, Bot A, Rossi JM, Jiang Y, Xue AX, Elias M, Aycock J, Wiezorek J, Go WY. Phase 1 results of ZUMA-1: A multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017 Jan 4;25(1):285-295. Epub 2017 Jan 4. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02348216
##Update: Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi T, Lin Y, Timmerman JM, Stiff PJ, Friedberg JW, Flinn IW, Goy A, Hill BT, Smith MR, Deol A, Farooq U, McSweeney P, Munoz J, Avivi I, Castro JE, Westin JR, Chavez JC, Ghobadi A, Komanduri KV, Levy R, Jacobsen ED, Witzig TE, Reagan P, Bot A, Rossi J, Navale L, Jiang Y, Aycock J, Elias M, Chang D, Wiezorek J, Go WY. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017 Dec 28;377(26):2531-2544. Epub 2017 Dec 10. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
##Update: Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, Lin Y, Braunschweig I, Hill BT, Timmerman JM, Deol A, Reagan PM, Stiff P, Flinn IW, Farooq U, Goy A, McSweeney PA, Munoz J, Siddiqi T, Chavez JC, Herrera AF, Bartlett NL, Wiezorek JS, Navale L, Xue A, Jiang Y, Bot A, Rossi JM, Kim JJ, Go WY, Neelapu SS. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019 Jan;20(1):31-42. Epub 2018 Dec 2. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
##Update: Neelapu SS, Jacobson CA, Ghobadi A, Miklos DB, Lekakis LJ, Oluwole OO, Lin Y, Braunschweig I, Hill BT, Timmerman JM, Deol A, Reagan PM, Stiff P, Flinn IW, Farooq U, Goy AH, McSweeney PA, Munoz J, Siddiqi T, Chavez JC, Herrera AF, Bartlett NL, Bot AA, Shen RR, Dong J, Singh K, Miao H, Kim JJ, Zheng Y, Locke FL. Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma. Blood. 2023 May 11;141(19):2307-2315. link to original article link to PMC article EuroPMC
==Bendamustine monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Efficacy
Weidmann et al. 2002	Not reported 	Phase 2, fewer than 20 pts	ORR: 44%
====Chemotherapy====
*Bendamustine 120 mg/m2 IV once per day on days 1 & 2
21-day cycle for up to 6 cycles
===References===
#Weidmann E, Kim SZ, Rost A, Schuppert H, Seipelt G, Hoelzer D, Mitrou PS. Bendamustine is effective in relapsed or refractory aggressive non-Hodgkin's lymphoma. Ann Oncol. 2002 Aug;13(8):1285-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Bendamustine & Rituximab (BR)==
BR: Bendamustine & Rituximab
R-B: Rituximab & Bendamustine
===Regimen variant #1, 90 mg/m2 x 6 cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Sehn et al. 2019 (GO29365)	2014-2016 	Randomized Phase 2 (C)	BR & Polatuzumab vedotin	Seems to have lower CR rate
====Chemotherapy====
*Bendamustine as follows:
**Cycle 1: 90 mg/m2 IV once per day on days 2 & 3
**Cycles 2 to 6: 90 mg/m2 IV once per day on days 1 & 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
21-day cycle for up to 6 cycles
===Regimen variant #2, 120 mg/m2 x 6 cycles===
Study 	Dates of enrollment	Evidence
Vacirca et al. 2013 (PI-08904) 	2008-2011 	Phase 2
Ohmachi et al. 2013 (SymBio 2010001)	2010-2011 	Phase 2
Note: Bendamustine was given on days 2 & 3 in SymBio 2010001 and on days 1 & 2 in PI-08904.
====Chemotherapy====
*Bendamustine 120 mg/m2 IV once per day on days 1 & 2 OR on days 2 & 3
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Supportive therapy====
*Recommended PCP prophylaxis: Trimethoprim-Sulfamethoxazole (Bactrim DS)
*Recommended VZV prophylaxis: Acyclovir (Zovirax)
21-day cycle for up to 6 cycles
===Regimen variant #3, indefinite===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Dang et al. 2017 (B1931008)	2011-2013 	Phase 3 (C)	R-INO 	Did not meet primary endpoint of OSMedian OS: 9.5 vs 9.5 mo(HR 0.91, 95% CI 0.71-1.25)
====Chemotherapy====
*Bendamustine 120 mg/m2 IV once per day on days 1 & 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycles
===References===
#SymBio 2010001: Ohmachi K, Niitsu N, Uchida T, Kim SJ, Ando K, Takahashi N, Takahashi N, Uike N, Eom HS, Chae YS, Terauchi T, Tateishi U, Tatsumi M, Kim WS, Tobinai K, Suh C, Ogura M. Multicenter phase II study of bendamustine plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2013 Jun 10;31(17):2103-9. Epub 2013 May 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01118845
#PI-08904: Vacirca JL, Acs PI, Tabbara IA, Rosen PJ, Lee P, Lynam E. Bendamustine combined with rituximab for patients with relapsed or refractory diffuse large B cell lymphoma. Ann Hematol. 2014 Mar;93(3):403-9. Epub 2013 Aug 17. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00831597
#B1931008: Dang NH, Ogura M, Castaigne S, Fayad LE, Jerkeman M, Radford J, Pezzutto A, Bondarenko I, Stewart DA, Shnaidman M, Sullivan S, Vandendries E, Tobinai K, Ramchandren R, Hamlin PA, Giné E, Ando K. Randomized, phase 3 trial of inotuzumab ozogamicin plus rituximab versus chemotherapy plus rituximab for relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Br J Haematol. 2018 Aug;182(4):583-586. Epub 2017 Jul 5. link to original article link to PMC article dosing details in supplement have been reviewed by our editors EuroPMC NCT01232556
#GO29365: Sehn LH, Herrera AF, Flowers CR, Kamdar MK, McMillan A, Hertzberg M, Assouline S, Kim TM, Kim WS, Ozcan M, Hirata J, Penuel E, Paulson JN, Cheng J, Ku G, Matasar MJ. Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2020 Jan 10; 38(2):155-165. Epub 2019 Nov 6. link to original article link to PMC article link to EuroPMC NCT02257567
##Update: Sehn LH, Hertzberg M, Opat S, Herrera AF, Assouline S, Flowers CR, Kim TM, McMillan A, Ozcan M, Safar V, Salles G, Ku G, Hirata J, Chang YM, Musick L, Matasar MJ. Polatuzumab vedotin plus bendamustine and rituximab in relapsed/refractory DLBCL: survival update and new extension cohort data. Blood Adv. 2022 Jan 25;6(2):533-543. link to original article link to PMC article EuroPMC
==Bendamustine & Rituximab (BR) & Polatuzumab vedotin==
Pola-BR: Polatuzumab vedotin, Bendamustine, Rituximab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Sehn et al. 2019 (GO29365)	2014-2016 	Randomized Phase 2 (E-RT-esc)	BR 	Seems to have higher CR rate (primary endpoint)CR rate: 40% vs 17.5%Longer OS (secondary endpoint)Median OS: 12.4 vs 4.7 mo(HR 0.42, 95% CI 0.24-0.75)
====Chemotherapy====
*Bendamustine as follows:
**Cycle 1: 90 mg/m2 IV once per day on days 2 & 3
**Cycles 2 to 6: 90 mg/m2 IV once per day on days 1 & 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Antibody-drug conjugate therapy====
*Polatuzumab vedotin (Polivy) as follows:
**Cycle 1: 1.8 mg/kg IV over 90 minutes once on day 2
**Cycles 2 to 6: 1.8 mg/kg IV over 90 minutes once on day 1
21-day cycle for up to 6 cycles
===References===
#GO29365: Sehn LH, Herrera AF, Flowers CR, Kamdar MK, McMillan A, Hertzberg M, Assouline S, Kim TM, Kim WS, Ozcan M, Hirata J, Penuel E, Paulson JN, Cheng J, Ku G, Matasar MJ. Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2020 Jan 10; 38(2):155-165. Epub 2019 Nov 6. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors link to EuroPMC NCT02257567
##Update: Sehn LH, Hertzberg M, Opat S, Herrera AF, Assouline S, Flowers CR, Kim TM, McMillan A, Ozcan M, Safar V, Salles G, Ku G, Hirata J, Chang YM, Musick L, Matasar MJ. Polatuzumab vedotin plus bendamustine and rituximab in relapsed/refractory DLBCL: survival update and new extension cohort data. Blood Adv. 2022 Jan 25;6(2):533-543. link to original article link to PMC article EuroPMC
==Blinatumomab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Viardot et al. 2016 (MT103-208)	2012-2014 	Phase 2
Note: Two dosing schemas were evaluated; this was the preferred dosing regimen, per the authors.
====Immunotherapy====
*Blinatumomab (Blincyto) 9 mcg/day IV continuous infusion over 7 days, started on day 1, then 28 mcg/day IV continuous infusion over 7 days, started on day 8, then 112 mcg/day IV continuous infusion over 42 days, started on day 15 (total dose: 4963 mcg)
====Supportive therapy====
*Dexamethasone (Decadron) 20 mg PO 6 to 12 hours before infusion start and dose increases, 20 mg PO 1 hour before infusion start and dose increases, and 8 mg PO three times per day for 2 days following infusion start and dose increases
**Patients with neurologic symptoms or cytokine release syndrome received 8 mg IV or PO every 8 hours for up to 3 days, with a subsequent taper over 4 days
8-week course
====Subsequent treatment====
*Responders could receive a 4-week consolidation cycle after a 4-week treatment-free period. Patients relapsing within 2 years of treatment could receive another 8-week course.
===References===
#MT103-208: Viardot A, Goebeler ME, Hess G, Neumann S, Pfreundschuh M, Adrian N, Zettl F, Libicher M, Sayehli C, Stieglmaier J, Zhang A, Nagorsen D, Bargou RC. Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. Blood. 2016 Mar 17;127(11):1410-6. Epub 2016 Jan 11. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01741792
==Brentuximab vedotin monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Jacobsen et al. 2015 (SGN35-012CD30+B-NHL)	2011-08 to 2013-08 	Phase 2
Note: Jacobsen et al. 2015 treated patients with CD30+ non-Hodgkin lymphoma, as determined by IHC; the 2016 update described a subgroup with undetectable CD30.
====Antibody-drug conjugate therapy====
*Brentuximab vedotin (Adcetris) 1.8 mg/kg IV over 30 minutes once on day 1
21-day cycles
===References===
#SGN35-012CD30+B-NHL: Jacobsen ED, Sharman JP, Oki Y, Advani RH, Winter JN, Bello CM, Spitzer G, Palanca-Wessels MC, Kennedy DA, Levine P, Yang J, Bartlett NL. Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood. 2015 Feb 26;125(9):1394-402. Epub 2015 Jan 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01421667
##Update: Bartlett NL, Smith MR, Siddiqi T, Advani RH, O'Connor OA, Sharman JP, Feldman T, Savage KJ, Shustov AR, Diefenbach CS, Oki Y, Palanca-Wessels MC, Uttarwar M, Li M, Yang J, Jacobsen ED. Brentuximab vedotin activity in diffuse large B-cell lymphoma with CD30 undetectable by visual assessment of conventional immunohistochemistry. Leuk Lymphoma. 2017 Jul;58(7):1607-1616. Epub 2016 Nov 20. link to original article EuroPMC
==Epcoritamab monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Hutchings et al. 2021 (EPCORE NHL-1)	2020-06-19 to 2022-01-31	Phase 1/2 (RT)
Note: dates of enrollment are based on the dose-expansion cohort.
====Immunotherapy====
*Epcoritamab (Epkinly) as follows:
**Cycle 1: 0.16 mg SC once on day 1, then 0.8 mg SC once on day 8, then 48 mg SC once per day on days 15 & 22
**Cycles 2 & 3: 48 mg SC once per day on days 1, 8, 15, 22
**Cycles 4 to 9: 48 mg SC once per day on days 1 & 15
**Cycle 10 onwards: 48 mg SC once on day 1
====Supportive therapy====
*Prednisolone (Millipred) as follows:
**Cycle 1: 100 mg PO or IV once per day on days 1 to 4, 8 to 11, 15 to 18, 22 to 25, given 30 to 120 minutes prior to epcoritamab on treatment days 1, 8, 15, 22
*Diphenhydramine (Benadryl) as follows:
**Cycle 1: 50 mg PO or IV once per day on days 1, 8, 15, 22
*Acetaminophen (Tylenol) as follows:
**Cycle 1: 650 to 1000 mg PO once per day on days 1, 8, 15, 22
28-day cycles
===References===
#EPCORE NHL-1: Hutchings M, Mous R, Clausen MR, Johnson P, Linton KM, Chamuleau MED, Lewis DJ, Sureda Balari A, Cunningham D, Oliveri RS, Elliott B, DeMarco D, Azaryan A, Chiu C, Li T, Chen KM, Ahmadi T, Lugtenburg PJ. Dose escalation of subcutaneous epcoritamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma: an open-label, phase 1/2 study. Lancet. 2021 Sep 25;398(10306):1157-1169. Epub 2021 Sep 8. link to original article EuroPMC NCT03625037
##Update: Thieblemont C, Phillips T, Ghesquieres H, Cheah CY, Clausen MR, Cunningham D, Do YR, Feldman T, Gasiorowski R, Jurczak W, Kim TM, Lewis DJ, van der Poel M, Poon ML, Cota Stirner M, Kilavuz N, Chiu C, Chen M, Sacchi M, Elliott B, Ahmadi T, Hutchings M, Lugtenburg PJ. Epcoritamab, a Novel, Subcutaneous CD3xCD20 Bispecific T-Cell-Engaging Antibody, in Relapsed or Refractory Large B-Cell Lymphoma: Dose Expansion in a Phase I/II Trial. J Clin Oncol. 2023 Apr 20;41(12):2238-2247. Epub 2022 Dec 22. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
==Etoposide monotherapy==
===Regimen variant #1, IV (3 days/cycle)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Czuczman et al. 2017 (DLC-001)	2009-2013 	Phase 2/3 (C)	Lenalidomide	Might have lower ORR
====Chemotherapy====
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
28-day cycle for up to 6 cycles
===Regimen variant #2, IV (5 days/cycle)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Pettengell et al. 2012 (PIX301)	2004-2008 	Phase 3, fewer than 20 pts in this arm (C)	Pixantrone 	Seems to have lower composite CR/CRu rate
Czuczman et al. 2017 (DLC-001) 	2009-2013 	Phase 2/3 (C) 	Lenalidomide	Might have lower ORR
====Chemotherapy====
*Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
28-day cycle for up to 6 cycles
===Regimen variant #3, PO (10 days/cycle)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Czuczman et al. 2017 (DLC-001)	2009-2013 	Phase 2/3 (C)	Lenalidomide	Might have lower ORR
====Chemotherapy====
*Etoposide (Vepesid) 50 mg/m2 PO once per day on days 1 to 10
28-day cycle for up to 6 cycles
===Regimen variant #4, PO (14 days/cycle)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Czuczman et al. 2017 (DLC-001)	2009-2013 	Phase 2/3 (C)	Lenalidomide	Might have lower ORR
====Chemotherapy====
*Etoposide (Vepesid) 50 mg/m2 PO once per day on days 1 to 14
28-day cycle for up to 6 cycles
===Regimen variant #5, PO (21 days/cycle)===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hainsworth et al. 1992 	1988-1989 	Phase 2 	 	
Pettengell et al. 2012 (PIX301)	2004-2008 	Phase 3, fewer than 20 pts in this arm (C)	Pixantrone 	Seems to have lower composite CR/CRu rate
Czuczman et al. 2017 (DLC-001) 	2009-2013 	Phase 2/3 (C) 	Lenalidomide	Might have lower ORR
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Chemotherapy====
*Etoposide (Vepesid) 50 mg/m2 PO once per day on days 1 to 21
28-day cycle for up to 6 cycles
===References===
#Hainsworth JD, Johnson DH, Greco FA. Chronic etoposide schedules in the treatment of non-Hodgkin's lymphoma. Semin Oncol. 1992 Dec;19(6 Suppl 14):13-8. link to original article EuroPMC
#PIX301: Pettengell R, Coiffier B, Narayanan G, de Mendoza FH, Digumarti R, Gomez H, Zinzani PL, Schiller G, Rizzieri D, Boland G, Cernohous P, Wang L, Kuepfer C, Gorbatchevsky I, Singer JW. Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2012 Jul;13(7):696-706. Epub 2012 May 30. Erratum in: Lancet Oncol. 2012 Jul;13(7):e285. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00088530
#DLC-001: Czuczman MS, Trněný M, Davies A, Rule S, Linton KM, Wagner-Johnston N, Gascoyne RD, Slack GW, Brousset P, Eberhard DA, Hernandez-Ilizaliturri FJ, Salles G, Witzig TE, Zinzani PL, Wright GW, Staudt LM, Yang Y, Williams PM, Lih CJ, Russo J, Thakurta A, Hagner P, Fustier P, Song D, Lewis ID. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2017 Aug 1;23(15):4127-4137. Epub 2017 Apr 5. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT01197560
==Everolimus monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Witzig et al. 2011	2005-2008 	Phase 2
====Targeted therapy====
*Everolimus (Afinitor) 10 mg PO once per day on days 1 to 28, taken on an empty stomach
====Supportive therapy====
*"Patients could receive white blood cell growth factors, if neutropenia developed at physician's discretion. Erythropoietin treatment for anemia was permitted per standard guidelines."
28-day cycles
===References===
#Witzig TE, Reeder CB, LaPlant BR, Gupta M, Johnston PB, Micallef IN, Porrata LF, Ansell SM, Colgan JP, Jacobsen ED, Ghobrial IM, Habermann TM. A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia. 2011 Feb;25(2):341-7. Epub 2010 Dec 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==Everolimus & Rituximab==
===Regimen===
Study 	Dates of enrollment	Evidence
Barnes et al. 2013 (MGH 09-002)	2009-2010 	Phase 2
====Targeted therapy====
*Everolimus (Afinitor) as follows:
**Cycle 1: 5 mg PO once per day on days 1 to 14, then 10 mg PO once per day on days 15 to 28
**Cycles 2 to 6: 10 mg PO once per day
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
**Cycles 2 to 6: 375 mg/m2 IV once on day 1
28-day cycle for 6 cycles 
====Subsequent treatment====
*MGH 09-002, responders: option of de-intensification to everolimus alone for another 6 months
===References===
#MGH 09-002: Barnes JA, Jacobsen E, Feng Y, Freedman A, Hochberg EP, LaCasce AS, Armand P, Joyce R, Sohani AR, Rodig SJ, Neuberg D, Fisher DC, Abramson JS. Everolimus in combination with rituximab induces complete responses in heavily pretreated diffuse large B-cell lymphoma. Haematologica. 2013 Apr;98(4):615-9. Epub 2012 Nov 9. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00869999
==Gemcitabine monotherapy==
===Regimen variant #1, bi-weekly===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Czuczman et al. 2017 (DLC-001)	2009-2013 	Phase 2/3 (C)	Lenalidomide	Might have lower ORR
Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Chemotherapy====
*Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 15
28-day cycle for up to 6 cycles
===Regimen variant #2, 3 out of 4 weeks x 6===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Pettengell et al. 2012 (PIX301)	2004-2008 	Phase 3, fewer than 20 pts in this arm (C)	Pixantrone 	Seems to have lower composite CR/CRu rate
Czuczman et al. 2017 (DLC-001) 	2009-2013 	Phase 2/3 (C) 	Lenalidomide	Might have lower ORR
Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Chemotherapy====
*Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1, 8, 15
28-day cycle for up to 6 cycles
===Regimen variant #3, indefinite 3 out of 4 weeks===
Study 	Dates of enrollment	Evidence
Fosså et al. 1999	1995-1997 	Phase 2
====Chemotherapy====
*Gemcitabine (Gemzar) 1250 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
28-day cycles
====Dose and schedule modifications====
*If no hematologic or non-hematologic toxicities, gemcitabine could be optionally increased to 1500 mg/m2 from cycle 2 onwards
===References===
#Fosså A, Santoro A, Hiddemann W, Truemper L, Niederle N, Buksmaui S, Bonadonna G, Seeber S, Nowrousian MR. Gemcitabine as a single agent in the treatment of relapsed or refractory aggressive non-Hodgkin's lymphoma. J Clin Oncol. 1999 Dec;17(12):3786-92. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#PIX301: Pettengell R, Coiffier B, Narayanan G, de Mendoza FH, Digumarti R, Gomez H, Zinzani PL, Schiller G, Rizzieri D, Boland G, Cernohous P, Wang L, Kuepfer C, Gorbatchevsky I, Singer JW. Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2012 Jul;13(7):696-706. Epub 2012 May 30. Erratum in: Lancet Oncol. 2012 Jul;13(7):e285. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00088530
#DLC-001: Czuczman MS, Trněný M, Davies A, Rule S, Linton KM, Wagner-Johnston N, Gascoyne RD, Slack GW, Brousset P, Eberhard DA, Hernandez-Ilizaliturri FJ, Salles G, Witzig TE, Zinzani PL, Wright GW, Staudt LM, Yang Y, Williams PM, Lih CJ, Russo J, Thakurta A, Hagner P, Fustier P, Song D, Lewis ID. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2017 Aug 1;23(15):4127-4137. Epub 2017 Apr 5. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT01197560
==Gemcitabine & Rituximab==
R-G: Rituximab & Gemcitabine
===Regimen variant #1, 6 cycles maximum===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Pettengell et al. 2019 (PIX306)	2011-2018 	Phase 3 (C)	Pixantrone & Rituximab	Did not meet primary endpoint of PFS
====Chemotherapy====
*Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycle for up to 6 cycles
===Regimen variant #2, indefinite===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Dang et al. 2017 (B1931008)	2011-2013 	Phase 3 (C)	R-INO 	Did not meet primary endpoint of OSMedian OS: 9.5 vs 9.5 mo(HR 0.91, 95% CI 0.71-1.25)
====Chemotherapy====
*Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
**Cycle 2 onwards: 375 mg/m2 IV once on day 1
28-day cycles
===References===
#B1931008: Dang NH, Ogura M, Castaigne S, Fayad LE, Jerkeman M, Radford J, Pezzutto A, Bondarenko I, Stewart DA, Shnaidman M, Sullivan S, Vandendries E, Tobinai K, Ramchandren R, Hamlin PA, Giné E, Ando K. Randomized, phase 3 trial of inotuzumab ozogamicin plus rituximab versus chemotherapy plus rituximab for relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Br J Haematol. 2018 Aug;182(4):583-586. Epub 2017 Jul 5. link to original article link to PMC article dosing details in supplement have been reviewed by our editors EuroPMC NCT01232556
#PIX306: Pettengell R, Długosz-Danecka M, Andorsky D, Belada D, Georgiev P, Quick D, Singer JW, Singh SB, Pallis A, Egorov A, Salles G. Pixantrone plus rituximab versus gemcitabine plus rituximab in patients with relapsed aggressive B-cell non-Hodgkin lymphoma not eligible for stem cell transplantation: a phase 3, randomized, multicentre trial (PIX306). Br J Haematol. 2020 Jan;188(2):240-248. Epub 2019 Dec 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01321541
==Glofitamab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Dickinson et al. 2022 (NP30179)	2020-01 to 2021-09 	Phase 1/2 (RT)
====Immunotherapy====
*Glofitamab (Columvi) as follows:
**Cycle 1: 2.5 mg IV once on day 8, then 10 mg IV once on day 15
**Cycles 2 to 12: 30 mg IV once on day 1
====Immunosuppressive therapy====
*Obinutuzumab (Gazyva) as follows:
**Cycle 1: 1000 mg IV once on day 1
21-day cycle for 12 cycles
===References===
#NP30179: Dickinson MJ, Carlo-Stella C, Morschhauser F, Bachy E, Corradini P, Iacoboni G, Khan C, Wróbel T, Offner F, Trněný M, Wu SJ, Cartron G, Hertzberg M, Sureda A, Perez-Callejo D, Lundberg L, Relf J, Dixon M, Clark E, Humphrey K, Hutchings M. Glofitamab for Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2022 Dec 15;387(24):2220-2231. Epub 2022 Dec 11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03075696
==GVD==
GVD: Gemcitabine, Vinorelbine, Doxil (Pegylated liposomal doxorubicin)
===Regimen===
Study 	Dates of enrollment	Evidence
Bai et al. 2013	2006-05 to 2008-08 	Retrospective
====Chemotherapy====
*Gemcitabine (Gemzar) 800 mg/m2 IV once on day 1
*Vinorelbine (Navelbine) 15 mg/m2 IV once on day 1
*Pegylated liposomal doxorubicin (Doxil) 20 mg/m2 IV once on day 1
14-day cycles
===References===
#Retrospective: Bai B, Huang HQ, Cai QQ, Wang XX, Cai QC, Lin ZX, Gao Y, Xia Y, Bu Q, Guo Y. Promising long-term outcome of gemcitabine, vinorelbine, liposomal doxorubicin (GVD) in 14-day schedule as salvage regimen for patients with previously heavily treated Hodgkin's lymphoma and aggressive non-Hodgkin's lymphoma. Med Oncol. 2013 Mar;30(1):350. Epub 2013 Jan 18. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Ibritumomab tiuxetan protocol==
===Regimen===
Study 	Dates of enrollment	Evidence
Morschhauser et al. 2007	2001-2003 	Phase 2
====Radioconjugate therapy====
*Ibritumomab tiuxetan & Yttrium-90 (Zevalin)
===References===
#Morschhauser F, Illidge T, Huglo D, Martinelli G, Paganelli G, Zinzani PL, Rule S, Liberati AM, Milpied N, Hess G, Stein H, Kalmus J, Marcus R. Efficacy and safety of yttrium-90 ibritumomab tiuxetan in patients with relapsed or refractory diffuse large B-cell lymphoma not appropriate for autologous stem-cell transplantation. Blood. 2007 Jul 1;110(1):54-8. Epub 2007 Mar 26. link to original article EuroPMC
==Ibrutinib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Wilson et al. 2015 (PCYC-1106-CA)	2010-2012 	Phase 2
Note: Clinically meaningful responses were observed in the ABC subtype, only.
====Targeted therapy====
*Ibrutinib (Imbruvica) 560 mg PO once per day on days 1 to 28
28-day cycles
===References===
#PCYC-1106-CA: Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G, Lih CJ, Williams PM, Shaffer AL, Gerecitano J, de Vos S, Goy A, Kenkre VP, Barr PM, Blum KA, Shustov A, Advani R, Fowler NH, Vose JM, Elstrom RL, Habermann TM, Barrientos JC, McGreivy J, Fardis M, Chang BY, Clow F, Munneke B, Moussa D, Beaupre DM, Staudt LM. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015 Aug;21(8):922-6. Epub 2015 Jul 20. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00849654; NCT01325701
==Ifosfamide monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Case et al. 1991 (CALGB 8552) 	Not reported 	Phase 2 	 	
Pettengell et al. 2012 (PIX301)	2004-2008 	Phase 3, fewer than 20 pts in this arm (C)	Pixantrone	Seems to have lower composite CR/CRu rate
Note: Dose & schedule is as given in Pettengell et al. 2012. CALGB 8552 used a different dose & schedule. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
====Chemotherapy====
*Ifosfamide (Ifex) 3000 mg/m2 IV once per day on days 1 & 2
====Supportive therapy====
*Mesna (Mesnex) dose not specified
28-day cycle for up to 6 cycles
===References===
#CALGB 8552: Case DC Jr, Anderson J, Ervin TJ, Gottlieb A. Phase II trial of ifosfamide and mesna in previously treated patients with non-Hodgkin's lymphoma: Cancer and Leukemia Group B study 8552. Hematol Oncol. 1991 Jul-Oct;9(4-5):189-96. link to original article EuroPMC
#Review: Webb MS, Saltman DL, Connors JM, Goldie JH. A literature review of single agent treatment of multiply relapsed aggressive non-Hodgkin's lymphoma. Leuk Lymphoma. 2002 May;43(5):975-82. link to original article EuroPMC
#PIX301: Pettengell R, Coiffier B, Narayanan G, de Mendoza FH, Digumarti R, Gomez H, Zinzani PL, Schiller G, Rizzieri D, Boland G, Cernohous P, Wang L, Kuepfer C, Gorbatchevsky I, Singer JW. Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2012 Jul;13(7):696-706. Epub 2012 May 30. Erratum in: Lancet Oncol. 2012 Jul;13(7):e285. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00088530
==Lenalidomide monotherapy==
===Regimen variant #1, low dose===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Czuczman et al. 2017 (DLC-001)	2009-2013 	Phase 2/3 (E-switch-ooc)	Investigator's choice of:1a. Etoposide1b. Gemcitabine1c. Oxaliplatin1d. Rituximab	Might have higher ORR (primary endpoint)
====Eligibility criteria====
*CrCl 30 up to 60 mL/min/1.73m2
====Targeted therapy====
*Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
28-day cycles
===Regimen variant #2, normal dose===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Wiernik et al. 2008 (CC-5013-NHL-002)	2005-2006 	Phase 2 	 	ORR: 35%
Witzig et al. 2011 (NHL-003) 	2006-2008 	Phase 2 	 	ORR: 28%
Czuczman et al. 2017 (DLC-001) 	2009-2013 	Phase 2/3 (E-switch-ooc)	Investigator's choice of:1a. Etoposide1b. Gemcitabine1c. Oxaliplatin1d. Rituximab	Might have higher ORR (primary endpoint)
====Eligibility criteria====
*DLC-001: CrCl 60 mL/min/1.73m2 or more
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycles
===References===
#CC-5013-NHL-002: Wiernik PH, Lossos IS, Tuscano JM, Justice G, Vose JM, Cole CE, Lam W, McBride K, Wride K, Pietronigro D, Takeshita K, Ervin-Haynes A, Zeldis JB, Habermann TM. Lenalidomide monotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma. J Clin Oncol. 2008 Oct 20;26(30):4952-7. Epub 2008 Jul 7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00179660
#NHL-003: Witzig TE, Vose JM, Zinzani PL, Reeder CB, Buckstein R, Polikoff JA, Bouabdallah R, Haioun C, Tilly H, Guo P, Pietronigro D, Ervin-Haynes AL, Czuczman MS. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma. Ann Oncol. 2011 Jul;22(7):1622-7. Epub 2011 Jan 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00413036
#DLC-001: Czuczman MS, Trněný M, Davies A, Rule S, Linton KM, Wagner-Johnston N, Gascoyne RD, Slack GW, Brousset P, Eberhard DA, Hernandez-Ilizaliturri FJ, Salles G, Witzig TE, Zinzani PL, Wright GW, Staudt LM, Yang Y, Williams PM, Lih CJ, Russo J, Thakurta A, Hagner P, Fustier P, Song D, Lewis ID. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2017 Aug 1;23(15):4127-4137. Epub 2017 Apr 5. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01197560
==Lenalidomide & Rituximab (R2)==
===Regimen variant #1, indefinite===
Study 	Dates of enrollment	Evidence
Wang et al. 2013 (MDACC 2005-0461DLBCL)	2008-2011 	Phase 2
====Targeted therapy====
*Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycles
===Regimen variant #2, 4 cycles===
Study 	Dates of enrollment	Evidence
Zinzani et al. 2011 (REVLIRIT01)	2009 	Phase 2
====Targeted therapy====
*Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1 & 21
28-day cycle for 4 cycles
====Subsequent treatment====
*REVLIRIT01, SD or better: Lenalidomide maintenance
===References===
#REVLIRIT01: Zinzani PL, Pellegrini C, Gandolfi L, Stefoni V, Quirini F, Derenzini E, Broccoli A, Argnani L, Pileri S, Baccarani M. Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial. Clin Lymphoma Myeloma Leuk. 2011 Dec;11(6):462-6. Epub 2011 May 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00968331
##Update: Zinzani PL, Pellegrini C, Derenzini E, Argnani L, Pileri S. Long-term efficacy of the combination of lenalidomide and rituximab in elderly relapsed/refractory diffuse large B-cell lymphoma patients. Hematol Oncol. 2013 Dec;31(4):223-4. Epub 2013 Apr 26. link to original article EuroPMC
#MDACC 2005-0461DLBCL: Wang M, Fowler N, Wagner-Bartak N, Feng L, Romaguera J, Neelapu SS, Hagemeister F, Fanale M, Oki Y, Pro B, Shah J, Thomas S, Younes A, Hosing C, Zhang L, Newberry KJ, Desai M, Cheng N, Badillo M, Bejarano M, Chen Y, Young KH, Champlin R, Kwak L, Fayad L. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase II clinical trial. Leukemia. 2013 Sep;27(9):1902-9. Epub 2013 Apr 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00294632
==Lenalidomide & Tafasitamab==
===Regimen===
Study 	Dates of enrollment	Evidence
Salles et al. 2020 (L-MIND)	2016-2017 	Phase 2 (RT)
====Targeted therapy====
*Lenalidomide (Revlimid) as follows:
**Cycles 1 to 12: 25 mg PO once per day on days 1 to 21
*Tafasitamab (Monjuvi) as follows:
**Cycle 1: 12 mg/kg IV over 2 hours once per day on days 1, 4, 8, 15, 22
**Cycles 2 & 3: 12 mg/kg IV over 2 hours once per day on days 1, 8, 15, 22
**Cycle 4 onwards: 12 mg/kg IV over 2 hours once per day on days 1 & 15
28-day cycles
===References===
# L-MIND: Salles G, Duell J, González Barca E, Tournilhac O, Jurczak W, Liberati AM, Nagy Z, Obr A, Gaidano G, André M, Kalakonda N, Dreyling M, Weirather J, Dirnberger-Hertweck M, Ambarkhane S, Fingerle-Rowson G, Maddocks K. Tafasitamab plus lenalidomide in relapsed or refractory diffuse large B-cell lymphoma (L-MIND): a multicentre, prospective, single-arm, phase 2 study. Lancet Oncol. 2020 Jul;21(7):978-988. Epub 2020 Jun 5. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02399085
##Update: Duell J, Maddocks KJ, González-Barca E, Jurczak W, Liberati AM, De Vos S, Nagy Z, Obr A, Gaidano G, Abrisqueta P, Kalakonda N, André M, Dreyling M, Menne T, Tournilhac O, Augustin M, Rosenwald A, Dirnberger-Hertweck M, Weirather J, Ambarkhane S, Salles G. Long-term outcomes from the Phase II L-MIND study of tafasitamab (MOR208) plus lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma. Haematologica. 2021 Sep 1;106(9):2417-2426. link to original article link to PMC article EuroPMC
==Lisocabtagene maraleucel monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Abramson et al. 2020 (TRANSCEND NHL-001)	2016-01-11 to 2019-07-05	Phase 1 (RT)
Note: This was target dose level 2, which was tested during dose confirmation.
====Preceding treatment====
*Lymphodepletion with FC
====Immunotherapy====
*Lisocabtagene maraleucel (Breyanzi) target dose of 100 x 106 CAR T cells IV once on day 0
One course
===References===
#TRANSCEND NHL-001: Abramson JS, Palomba ML, Gordon LI, Lunning MA, Wang M, Arnason J, Mehta A, Purev E, Maloney DG, Andreadis C, Sehgal A, Solomon SR, Ghosh N, Albertson TM, Garcia J, Kostic A, Mallaney M, Ogasawara K, Newhall K, Kim Y, Li D, Siddiqi T. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet. 2020 Sep 19;396(10254):839-852. Epub 2020 Sep 1. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02631044
##Update: Abramson JS, Palomba ML, Gordon LI, Lunning M, Wang M, Arnason J, Purev E, Maloney DG, Andreadis C, Sehgal A, Solomon SR, Ghosh N, Dehner C, Kim Y, Ogasawara K, Kostic A, Siddiqi T. Two-year follow-up of lisocabtagene maraleucel in relapsed or refractory large B-cell lymphoma in TRANSCEND NHL 001. Blood. 2024 Feb 1;143(5):404-416. link to original article EuroPMC
==Loncastuximab tesirine monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence
Caimi et al. 2021 (LOTIS-2)	2018-2019 	Phase 2 (RT)
====Antibody-drug conjugate therapy====
*Loncastuximab tesirine (Zynlonta) as follows:
**Cycles 1 & 2: 0.15 mg/kg IV over 30 minutes once on day 1
**Cycles 3 to 18: 0.075 mg/kg IV over 30 minutes once on day 1
====Supportive therapy====
*Dexamethasone (Decadron) 4 mg IV or PO twice per day on days -1 to 2 (3 days total)
21-day cycles
===References===
#LOTIS-2: Caimi PF, Ai W, Alderuccio JP, Ardeshna KM, Hamadani M, Hess B, Kahl BS, Radford J, Solh M, Stathis A, Zinzani PL, Havenith K, Feingold J, He S, Qin Y, Ungar D, Zhang X, Carlo-Stella C. Loncastuximab tesirine in relapsed or refractory diffuse large B-cell lymphoma (LOTIS-2): a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol. 2021 Jun;22(6):790-800. Epub 2021 May 11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03589469
==Mitoxantrone monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Bajetta et al. 1988a 	Not reported in abstract	Phase 2 	 	
Pettengell et al. 2012 (PIX301)	2004-2008 	Phase 3, fewer than 20 pts in this arm (C)	Pixantrone	Seems to have lower composite CR/CRu rate
Note: The full manuscript for Bajetta et al. 1988a was not available for review.
====Chemotherapy====
*Mitoxantrone (Novantrone) 14 mg/m2 IV over 30 minutes once on day 1
21-day cycles
===References===
#Bajetta E, Buzzoni R, Valagussa P, Bonadonna G. Mitoxantrone: an active agent in refractory non-Hodgkin's lymphomas. Am J Clin Oncol. 1988 Apr;11(2):100-3. dosing details in abstract have been reviewed by our editors EuroPMC
#PIX301: Pettengell R, Coiffier B, Narayanan G, de Mendoza FH, Digumarti R, Gomez H, Zinzani PL, Schiller G, Rizzieri D, Boland G, Cernohous P, Wang L, Kuepfer C, Gorbatchevsky I, Singer JW. Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2012 Jul;13(7):696-706. Epub 2012 May 30. Erratum in: Lancet Oncol. 2012 Jul;13(7):e285. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00088530
==Obinutuzumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Salles et al. 2012 (GAUGUIN)	2008-2009 	Phase 1/2
Note: this was the phase 2 dosing reported in Morschhauser et al. 2013.
====Targeted therapy====
*Obinutuzumab (Gazyva) as follows:
**Cycle 1: 1600 mg (diluted to 10 mg/mL) IV once per day on days 1 & 8
**Cycles 2 to 8: 800 mg IV once on day 1
**Initial infusion rate is 50 mg/hour. In the absence of infusion-related reactions (IRRs), the rate is then increased by 50 mg/hour every 30 minutes, up to a maximum of 400 mg/hour.
====Supportive therapy====
*Acetaminophen (Tylenol) or paracetamol 650 to 1000 mg PO once per infusion, 30 minutes prior to obinutuzumab
*"An antihistamine" once per infusion, 30 minutes prior to obinutuzumab
**If there were no infusion-related reactions (IRRs) requiring medication or infusion interruption, antihistamine could be omitted for subsequent infusions
*Premedication with corticosteroids recommended for patients at high risk of infusion-related reactions (IRRs)
*Use of G-CSF allowed for severe neutropenia
*Antibiotic prophylaxis allowed
21-day cycle for 8 cycles
===References===
#GAUGUIN: Salles G, Morschhauser F, Lamy T, Milpied N, Thieblemont C, Tilly H, Bieska G, Asikanius E, Carlile D, Birkett J, Pisa P, Cartron G. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood. 2012 May 31;119(22):5126-32. Epub 2012 Mar 19. link to original article EuroPMC NCT00517530
##Subgroup analysis: Morschhauser FA, Cartron G, Thieblemont C, Solal-Céligny P, Haioun C, Bouabdallah R, Feugier P, Bouabdallah K, Asikanius E, Lei G, Wenger M, Wassner-Fritsch E, Salles GA. Obinutuzumab (GA101) monotherapy in relapsed/refractory diffuse large B-cell lymphoma or mantle-cell lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2912-9. Epub 2013 Jul 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Subgroup analysis: Salles GA, Morschhauser F, Solal-Céligny P, Thieblemont C, Lamy T, Tilly H, Gyan E, Lei G, Wenger M, Wassner-Fritsch E, Cartron G. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2920-6. Epub 2013 Jul 8. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
##Subgroup analysis: Cartron G, de Guibert S, Dilhuydy MS, Morschhauser F, Leblond V, Dupuis J, Mahe B, Bouabdallah R, Lei G, Wenger M, Wassner-Fritsch E, Hallek M. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014 Oct 2;124(14):2196-202. Epub 2014 Aug 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Ofatumumab monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Coiffier et al. 2013 (415 Study)	2007 to not reported	Phase 2
====Targeted therapy====
*Ofatumumab (Arzerra) as follows:
**Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once per day on days 8, 15, 22
**Cycle 2: 1000 mg IV once per day on days 1, 8, 15, 22
====Supportive therapy====
*Acetaminophen (Tylenol) (or equivalent) 1000 mg PO once per day on days 1, 8, 15, 22, given 30 minutes to 2 hours prior to ofatumumab
*Cetirizine (Zyrtec) (or equivalent) 10 mg PO once per day on days 1, 8, 15, 22, given 30 minutes to 2 hours prior to ofatumumab
*Prednisolone (Millipred) (or equivalent) 100 mg (route not specified) once per day on days 1 & 8, given 30 minutes to 2 hours prior to ofatumumab for first 2 infusions, only
28-day cycle for 2 cycles
===References===
#415 Study: Coiffier B, Radford J, Bosly A, Martinelli G, Verhoef G, Barca G, Davies A, Decaudin D, Gallop-Evans E, Padmanabhan-Iyer S, Van Eygen K, Wu KL, Gupta IV, Lin TS, Goldstein N, Jewell RC, Winter P, Lisby S; 415 study investigators. A multicentre, phase II trial of ofatumumab monotherapy in relapsed/progressive diffuse large B-cell lymphoma. Br J Haematol. 2013 Nov;163(3):334-42. Epub 2013 Aug 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00622388
==Oxaliplatin monotherapy==
===Regimen variant #1, 100 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Germann et al. 1999 	1988-1994 	Phase 2, fewer than 20 pts in this subgroup	 	
Pettengell et al. 2012 (PIX301)	2004-2008 	Phase 3, fewer than 20 pts in this arm (C) 	Pixantrone 	Seems to have lower composite CR/CRu rate
Czuczman et al. 2017 (DLC-001) 	2009-2013 	Phase 2/3 (C) 	Lenalidomide	Might have lower ORR
Note: Germann et al. gave a range of 100 to 130 mg/m2. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
====Chemotherapy====
*Oxaliplatin (Eloxatin) 100 mg/m2 IV once on day 1
21-day cycles (maximum of 6 cycles in PIX301 & DLC-001)
===Regimen variant #2, 130 mg/m2===
Study 	Dates of enrollment	Evidence 	Efficacy
Germann et al. 1999	1988-1994 	Phase 2, fewer than 20 pts in this subgroup	
Oki et al. 2005 	2001-2003 	Phase 2 	ORR: 27% (95% CI, 13–47)
Note: Germann et al. gave a range of 100 to 130 mg/m2.
====Chemotherapy====
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
21-day cycles
===References===
#Germann N, Brienza S, Rotarski M, Emile JF, Di Palma M, Musset M, Reynes M, Soulié P, Cvitkovic E, Misset JL. Preliminary results on the activity of oxaliplatin (L-OHP) in refractory/recurrent non-Hodgkin's lymphoma patients. Ann Oncol. 1999 Mar;10(3):351-4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Review: Webb MS, Saltman DL, Connors JM, Goldie JH. A literature review of single agent treatment of multiply relapsed aggressive non-Hodgkin's lymphoma. Leuk Lymphoma. 2002 May;43(5):975-82. link to original article EuroPMC
#Oki Y, McLaughlin P, Pro B, Hagemeister FB, Bleyer A, Loyer E, Younes A. Phase II study of oxaliplatin in patients with recurrent or refractory non-Hodgkin lymphoma. Cancer. 2005 Aug 15;104(4):781-7. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#PIX301: Pettengell R, Coiffier B, Narayanan G, de Mendoza FH, Digumarti R, Gomez H, Zinzani PL, Schiller G, Rizzieri D, Boland G, Cernohous P, Wang L, Kuepfer C, Gorbatchevsky I, Singer JW. Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2012 Jul;13(7):696-706. Epub 2012 May 30. Erratum in: Lancet Oncol. 2012 Jul;13(7):e285. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00088530
#DLC-001: Czuczman MS, Trněný M, Davies A, Rule S, Linton KM, Wagner-Johnston N, Gascoyne RD, Slack GW, Brousset P, Eberhard DA, Hernandez-Ilizaliturri FJ, Salles G, Witzig TE, Zinzani PL, Wright GW, Staudt LM, Yang Y, Williams PM, Lih CJ, Russo J, Thakurta A, Hagner P, Fustier P, Song D, Lewis ID. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2017 Aug 1;23(15):4127-4137. Epub 2017 Apr 5. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT01197560
==Panobinostat monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Assouline et al. 2016 (Q-CROC-02)	2010-2013 	Randomized Phase 2 (E-de-esc)	Panobinostat & Rituximab	Did not meet primary endpoint of ORR
Note: patients had a median of 2 prior treatments (range 1-8). The schedule shown below is an example.
====Targeted therapy====
*Panobinostat (Farydak) 30 mg PO once per day on days 1, 3, 5, 8, 10, 12, 15, 17, 19 (three times per week)
21-day cycles
===References===
#Q-CROC-02: Assouline SE, Nielsen TH, Yu S, Alcaide M, Chong L, MacDonald D, Tosikyan A, Kukreti V, Kezouh A, Petrogiannis-Haliotis T, Albuquerque M, Fornika D, Alamouti S, Froment R, Greenwood CM, Oros KK, Camglioglu E, Sharma A, Christodoulopoulos R, Rousseau C, Johnson N, Crump M, Morin RD, Mann KK. Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma. Blood. 2016 Jul 14;128(2):185-94. Epub 2016 May 10. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01238692
==Panobinostat & Rituximab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Assouline et al. 2016 (Q-CROC-02)	2010-2013 	Randomized Phase 2, fewer than 20 pts (E-esc)	Panobinostat	Did not meet primary endpoint of ORR
Note: patients had a median of 3 prior treatments (range 2-9). The schedule shown below is an example.
====Targeted therapy====
*Panobinostat (Farydak) 30 mg PO once per day on days 1, 3, 5, 8, 10, 12, 15, 17, 19 (three times per week)
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
21-day cycles
===References===
#Q-CROC-02: Assouline SE, Nielsen TH, Yu S, Alcaide M, Chong L, MacDonald D, Tosikyan A, Kukreti V, Kezouh A, Petrogiannis-Haliotis T, Albuquerque M, Fornika D, Alamouti S, Froment R, Greenwood CM, Oros KK, Camglioglu E, Sharma A, Christodoulopoulos R, Rousseau C, Johnson N, Crump M, Morin RD, Mann KK. Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma. Blood. 2016 Jul 14;128(2):185-94. Epub 2016 May 10. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01238692
==Pixantrone monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Pettengell et al. 2012 (PIX301)	2004-2008 	Phase 3 (E-switch-ic)	Investigator's choice of:1a. Etoposide1b. Gemcitabine1c. Ifosfamide1d. Mitoxantrone1e. Oxaliplatin1f. Vinorelbine	Seems to have higher CR/CRu rate (composite primary endpoint)
====Chemotherapy====
*Pixantrone (Pixuvri) 85 mg/m2 IV once per day on days 1, 8, 15
28-day cycle for up to 6 cycles
===References===
#PIX301: Pettengell R, Coiffier B, Narayanan G, de Mendoza FH, Digumarti R, Gomez H, Zinzani PL, Schiller G, Rizzieri D, Boland G, Cernohous P, Wang L, Kuepfer C, Gorbatchevsky I, Singer JW. Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2012 Jul;13(7):696-706. Epub 2012 May 30. Erratum in: Lancet Oncol. 2012 Jul;13(7):e285. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00088530
##Post-hoc analysis: Pettengell R, Sebban C, Zinzani PL, Derigs HG, Kravchenko S, Singer JW, Theocharous P, Wang L, Pavlyuk M, Makhloufi KM, Coiffier B. Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B-cell non-Hodgkin lymphoma: post-hoc analyses from a phase III trial. Br J Haematol. 2016 Sep;174(5):692-9. Epub 2016 Apr 26. link to original article link to PMC article EuroPMC
==Rituximab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Coiffier et al. 1998 	1996-1997 	Randomized Phase 2 (E-de-esc)	Rituximab; higher-dose	Did not meet primary endpoint of ORR
Czuczman et al. 2017 (DLC-001)	2009-2013 	Phase 2/3 (C) 	Lenalidomide 	Might have lower ORR
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
**Cycles 4, 6, 8, 10: 375 mg/m2 IV once on day 1
28-day cycle for 10 cycles (8 doses total)
===References===
#Coiffier B, Haioun C, Ketterer N, Engert A, Tilly H, Ma D, Johnson P, Lister A, Feuring-Buske M, Radford JA, Capdeville R, Diehl V, Reyes F. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood. 1998 Sep 15;92(6):1927-32. link to original article EuroPMC
#DLC-001: Czuczman MS, Trněný M, Davies A, Rule S, Linton KM, Wagner-Johnston N, Gascoyne RD, Slack GW, Brousset P, Eberhard DA, Hernandez-Ilizaliturri FJ, Salles G, Witzig TE, Zinzani PL, Wright GW, Staudt LM, Yang Y, Williams PM, Lih CJ, Russo J, Thakurta A, Hagner P, Fustier P, Song D, Lewis ID. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2017 Aug 1;23(15):4127-4137. Epub 2017 Apr 5. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC NCT01197560
==R-BL==
R-BL: Rituximab, Bendamustine, Lenalidomide
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Hitz et al. 2016 (SAKK 38/08)	Not reported 	Phase 2 	ORR: 61% (95% CI 45-76%)
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
*Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
====Chemotherapy====
*Bendamustine 70 mg/m2 IV once per day on days 1 & 2
28-day cycle for 6 cycles
===References===
#SAKK 38/08: Hitz F, Zucca E, Pabst T, Fischer N, Cairoli A, Samaras P, Caspar CB, Mach N, Krasniqi F, Schmidt A, Rothermundt C, Enoiu M, Eckhardt K, Berardi Vilei S, Rondeau S, Mey U. Rituximab, bendamustine and lenalidomide in patients with aggressive B-cell lymphoma not eligible for anthracycline-based therapy or intensive salvage chemotherapy - SAKK 38/08. Br J Haematol. 2016 Jul;174(2):255-63. Epub 2016 Mar 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00987493
==R-CVEP==
R-CVEP: Rituximab, Cyclophosphamide, Vorinostat, Etoposide, Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence
Straus et al. 2014 (MSK 08-045)	2008-2012 	Phase 1/2
Note: The MTD for vorinostat appears to have been 300 mg in this phase 1/2 trial. However, there was a discrepancy in the dosing units for vorinostat between the abstract (mg), figure (mg), and text (mg/m2). The authors have not been contacted to clarify this, given the age of the study.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
*Vorinostat (Zolinza) 300 mg PO once per day on days 1 to 10
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once per day on days 1 & 8
*Etoposide (Vepesid) 70 mg/m2 IV once on day 1, then 140 mg/m2 PO once per day on days 2 & 3
====Glucocorticoid therapy====
*Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 10
====Supportive therapy====
*Pegfilgrastim (Neulasta) once on day 11 or Filgrastim (Neupogen) (details not provided)
28-day cycle for 6 cycles
===References===
#MSK 08-045: Straus DJ, Hamlin PA, Matasar MJ, Lia Palomba M, Drullinsky PR, Zelenetz AD, Gerecitano JF, Noy A, Hamilton AM, Elstrom R, Wegner B, Wortman K, Cella D. Phase I/II trial of vorinostat with rituximab, cyclophosphamide, etoposide and prednisone as palliative treatment for elderly patients with relapsed or refractory diffuse large B-cell lymphoma not eligible for autologous stem cell transplantation. Br J Haematol. 2015 Mar;168(5):663-70. Epub 2014 Oct 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00667615
==R-GemOx==
R-GemOx: Rituximab, Gemcitabine, Oxaliplatin
GEMOX-R: GEMcitabine, OXaliplatin, Rituximab
===Regimen variant #1, 14-day cycles===
Study 	Dates of enrollment	Evidence
El Gnaoui et al. 2007	2002-2005 	Phase 2
Mounier et al. 2013 	2003-2009 	Phase 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Gemcitabine (Gemzar) 1000 mg/m2 IV at fixed dose rate over 100 minutes once on day 2
*Oxaliplatin (Eloxatin) 100 mg/m2 IV over 2 hours once on day 2
====Supportive therapy====
*Methylprednisolone (Solumedrol) 1 mg/kg IV once on day 1, prior to rituximab
*Acetaminophen (Tylenol) 1000 mg PO once on day 1, prior to rituximab
*Dexchlorpheniramine (Polaramine) 6 mg PO once on day 1, prior to rituximab
*Primary prophylaxis with G-CSF was not permitted
14-day cycle for up to 8 cycles
===Regimen variant #2, 21-day cycles===
Study 	Dates of enrollment	Evidence
López et al. 2008	2004-09 to 2006-09 	Phase 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Gemcitabine (Gemzar) 1000 mg/m2 IV once on day 1
*Oxaliplatin (Eloxatin) 100 mg/m2 IV once on day 1
21-day cycle for 6 to 8 cycles
===References===
#El Gnaoui T, Dupuis J, Belhadj K, Jais JP, Rahmouni A, Copie-Bergman C, Gaillard I, Diviné M, Tabah-Fisch I, Reyes F, Haioun C. Rituximab, gemcitabine and oxaliplatin: an effective salvage regimen for patients with relapsed or refractory B-cell lymphoma not candidates for high-dose therapy. Ann Oncol. 2007 Aug;18(8):1363-8. Epub 2007 May 11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#López A, Gutiérrez A, Palacios A, Blancas I, Navarrete M, Morey M, Perelló A, Alarcón J, Martínez J, Rodríguez J. GEMOX-R regimen is a highly effective salvage regimen in patients with refractory/relapsing diffuse large-cell lymphoma: a phase II study. Eur J Haematol. 2008 Feb;80(2):127-32. Epub 2007 Nov 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Mounier N, El-Gnaoui T, Tilly H, Canioni D, Sebban C, Casasnovas RO, Delarue R, Sonet A, Beaussart P, Petrella T, Castaigne S, Bologna S, Salles G, Rahmouni A, Gaulard P, Haioun C. Rituximab plus gemcitabine and oxaliplatin in refractory/relapsed patients with diffuse large B-cell lymphoma who are not candidates for high-dose therapy: a phase II Lymphoma Study Association trial. Haematologica. 2013 Nov;98(11):1726-31. Epub 2013 Jun 10. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00169195
==Selinexor monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Efficacy
Kalakonda et al. 2020 (SADAL)	2015-2019 	Phase 2b (RT)	ORR: 28%, 95% CI 20.7-37
====Targeted therapy====
*Selinexor (Xpovio) 60 mg PO once per day on days 1 & 3
7-day cycles
===References===
#SADAL: Kalakonda N, Maerevoet M, Cavallo F, Follows G, Goy A, Vermaat JSP, Casasnovas O, Hamad N, Zijlstra JM, Bakhshi S, Bouabdallah R, Choquet S, Gurion R, Hill B, Jaeger U, Sancho JM, Schuster M, Thieblemont C, De la Cruz F, Egyed M, Mishra S, Offner F, Vassilakopoulos TP, Warzocha K, McCarthy D, Ma X, Corona K, Saint-Martin JR, Chang H, Landesman Y, Joshi A, Wang H, Shah J, Shacham S, Kauffman M, Van Den Neste E, Canales MA. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020 Jul;7(7):e511-e522. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02227251
==Temsirolimus monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Smith et al. 2010 (NCI-6199)	Not reported 	Phase 2 	ORR: 28%
====Targeted therapy====
*Temsirolimus (Torisel) 25 mg IV over 30 minutes once on day 1
7-day cycle for at least 8 cycles
===References===
#NCI-6199: Smith SM, van Besien K, Karrison T, Dancey J, McLaughlin P, Younes A, Smith S, Stiff P, Lester E, Modi S, Doyle LA, Vokes EE, Pro B. Temsirolimus has activity in non-mantle cell non-Hodgkin's lymphoma subtypes: The University of Chicago phase II consortium. J Clin Oncol. 2010 Nov 1;28(31):4740-6. Epub 2010 Sep 13. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00290472
==Tisagenlecleucel monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Efficacy
Schuster et al. 2017 (UPCC 13413)	2014-2016 	Phase 2 	
Schuster et al. 2018 (JULIET) 	2015-07-29 to 2017-11-02	Phase 2 (RT)	ORR: 59% (95% CI, 44-72)
Note: The FDA-recommended range is 0.6 to 6 x 108 CTL019 transduced viable T-cells.
====Preceding treatment====
*Lymphodepleting therapy with FC or Bendamustine
====Immunotherapy====
*Tisagenlecleucel (Kymriah) 1 to 5 x 108 CTL019 transduced viable T-cells IV once on day 0
One course
===References===
#UPCC 13413: Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak Ö, Brogdon JL, Pruteanu-Malinici I, Bhoj V, Landsburg D, Wasik M, Levine BL, Lacey SF, Melenhorst JJ, Porter DL, June CH. Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. N Engl J Med. 2017 Dec 28;377(26):2545-2554. Epub 2017 Dec 10. link to original article link to PMC article EuroPMC NCT02030834
#JULIET: Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, Jäger U, Jaglowski S, Andreadis C, Westin JR, Fleury I, Bachanova V, Foley SR, Ho PJ, Mielke S, Magenau JM, Holte H, Pantano S, Pacaud LB, Awasthi R, Chu J, Anak Ö, Salles G, Maziarz RT; JULIET Investigators. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019 Jan 3;380(1):45-56. Epub 2018 Dec 1. link to original article dosing details in supplement have been reviewed by our editors EuroPMC NCT02445248
##Update: Schuster SJ, Tam CS, Borchmann P, Worel N, McGuirk JP, Holte H, Waller EK, Jaglowski S, Bishop MR, Damon LE, Foley SR, Westin JR, Fleury I, Ho PJ, Mielke S, Teshima T, Janakiram M, Hsu JM, Izutsu K, Kersten MJ, Ghosh M, Wagner-Johnston N, Kato K, Corradini P, Martinez-Prieto M, Han X, Tiwari R, Salles G, Maziarz RT. Long-term clinical outcomes of tisagenlecleucel in patients with relapsed or refractory aggressive B-cell lymphomas (JULIET): a multicentre, open-label, single-arm, phase 2 study. Lancet Oncol. 2021 Oct;22(10):1403-1415. Epub 2021 Sep 10. link to original article EuroPMC
==TTR==
TTR: Taxol (Paclitaxel), Topotecan, Rituximab
===Regimen===
Study 	Dates of enrollment	Evidence
Westin et al. 2014	1999-2003 	Phase 2
====Chemotherapy====
*Paclitaxel (Taxol) 200 mg/m2 IV once on day 2
*Topotecan (Hycamtin) 1 mg/m2 IV once per day on days 2 to 6
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Supportive therapy====
*Filgrastim (Neupogen) 5 mcg/kg SC once per day from day 7 until neutrophil recovery
*Dexamethasone (Decadron) 20 mg IV once on day 2, given 30 minutes prior to paclitaxel
*Diphenhydramine (Benadryl) 50 mg IV once on day 2, given 30 minutes prior to paclitaxel
21-day cycle for up to 6 cycles
===References===
#Westin JR, McLaughlin P, Romaguera J, Hagemeister FB, Pro B, Dang NH, Samaniego F, Rodriguez MA, Fayad L, Oki Y, Fanale M, Fowler N, Nastoupil L, Feng L, Loyer E, Younes A. Paclitaxel, topotecan and rituximab: long term outcomes of an effective salvage programme for relapsed or refractory aggressive B-cell non-Hodgkin lymphoma. Br J Haematol. 2014 Oct;167(2):177-84. Epub 2014 Jul 8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==Vinorelbine monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Balzarotti et al. 1996 	1992-1994 	Non-randomized, fewer than 20 pts in this subgroup	 	
Pettengell et al. 2012 (PIX301)	2004-2008 	Phase 3, fewer than 20 pts in this arm (C) 	Pixantrone	Seems to have lower composite CR/CRu rate
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
====Chemotherapy====
*Vinorelbine (Navelbine) 30 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycle for up to 6 cycles
===References===
#Balzarotti M, Santoro A, Tondini C, Fornier M, Bonadonna G. Activity of single agent vinorelbine in pretreated non-Hodgkin's lymphoma. Ann Oncol. 1996 Nov;7(9):970-2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#Review: Webb MS, Saltman DL, Connors JM, Goldie JH. A literature review of single agent treatment of multiply relapsed aggressive non-Hodgkin's lymphoma. Leuk Lymphoma. 2002 May;43(5):975-82. link to original article EuroPMC
#PIX301: Pettengell R, Coiffier B, Narayanan G, de Mendoza FH, Digumarti R, Gomez H, Zinzani PL, Schiller G, Rizzieri D, Boland G, Cernohous P, Wang L, Kuepfer C, Gorbatchevsky I, Singer JW. Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2012 Jul;13(7):696-706. Epub 2012 May 30. Erratum in: Lancet Oncol. 2012 Jul;13(7):e285. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00088530
##Post-hoc analysis: Pettengell R, Sebban C, Zinzani PL, Derigs HG, Kravchenko S, Singer JW, Theocharous P, Wang L, Pavlyuk M, Makhloufi KM, Coiffier B. Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B-cell non-Hodgkin lymphoma: post-hoc analyses from a phase III trial. Br J Haematol. 2016 Sep;174(5):692-9. Epub 2016 Apr 26. link to original article link to PMC article EuroPMC
==ViPOR==
ViPOR: Venetoclax, ibrutinib, Prednisone, Obinutuzumab, Revlimid (Lenalidomide)
===Regimen===
Study 	Dates of enrollment	Evidence
Melani et al. 2024 (NCI 17-C-0127)	2018-02 to 2021-06 	Phase 1b/2
Note: this was the RP2D.
====Targeted therapy====
*Venetoclax (Venclexta) as follows:
**Cycle 1: 50 mg PO once per day on days 2 to 5, then 200 mg PO once per day on days 6 to 8, then 600 mg PO once per day on days 9 to 11, then 800 mg PO once per day on days 12 to 14
**Cycles 2 to 6: 800 mg PO once per day on days 2 to 14
*Ibrutinib (Imbruvica) 560 mg PO once per day on days 1 to 14
*Obinutuzumab (Gazyva) 1000 mg IV once per day on days 1 & 2
*Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 14
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 7
21-day cycle for 6 cycles
===References===
#NCI 17-C-0127: Melani C, Lakhotia R, Pittaluga S, Phelan JD, Huang DW, Wright G, Simard J, Muppidi J, Thomas CJ, Ceribelli M, Tosto FA, Yang Y, Xu W, Davies-Hill T, Pack SD, Peer CJ, Arisa O, Mena E, Lindenberg L, Bergvall E, Portell CA, Farah RJ, Lee ST, Pradhan A, Morrison C, Tadese A, Juanitez AM, Lu C, Jacob A, Simmons H, Figg WD, Steinberg SM, Jaffe ES, Roschewski M, Staudt LM, Wilson WH. Combination Targeted Therapy in Relapsed Diffuse Large B-Cell Lymphoma. N Engl J Med. 2024 Jun 20;390(23):2143-2155. link to original article link to PMC article contains dosing details in manuscript and supplement EuroPMC NCT03223610
=Maintenance after further lines of therapy=
==Lenalidomide monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Zinzani et al. 2011 (REVLIRIT01)	2009 	Phase 2
====Preceding treatment====
*Lenalidomide & Rituximab x 4
====Targeted therapy====
*Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
28-day cycle for 9 cycles
===References===
#REVLIRIT01: Zinzani PL, Pellegrini C, Gandolfi L, Stefoni V, Quirini F, Derenzini E, Broccoli A, Argnani L, Pileri S, Baccarani M. Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial. Clin Lymphoma Myeloma Leuk. 2011 Dec;11(6):462-6. Epub 2011 May 4. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00968331
##Update: Zinzani PL, Pellegrini C, Derenzini E, Argnani L, Pileri S. Long-term efficacy of the combination of lenalidomide and rituximab in elderly relapsed/refractory diffuse large B-cell lymphoma patients. Hematol Oncol. 2013 Dec;31(4):223-4. Epub 2013 Apr 26. link to original article EuroPMC
=Response criteria=
*Lugano Classification criteria (2014) link to PMC article EuroPMC
*International Harmonization Project on Lymphoma revised criteria (2007) EuroPMC
*NCI Sponsored International Working Group criteria (1999) EuroPMC
=Prognosis=
==IPI and age-adjusted IPI (1993)==
To be completed
#A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med. 1993 Sep 30;329(14):987-94. link to original article EuroPMC
==Revised International Prognostic Index, R-IPI (2006)==
To be completed
#Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, Klasa R, Savage KJ, Shenkier T, Sutherland J, Gascoyne RD, Connors JM. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2007 Mar 1;109(5):1857-61. Epub 2006 Nov 14. link to original article EuroPMC
==CNS-IPI (2016)==
===Risk factors===
*Age greater than 60 years
*Elevated LDH
*ECOG PS greater than 1
*Advanced stage (III or IV)
*Involvement of more than one extranodal site
*Involvement of the kidney and/or adrenal glands
===Risk stratification===
*Low risk: 0 or 1 risk factors (2-year rate of CNS disease less than 5%)
*Intermediate risk: 2 or 3 risk factors (2-year rate of CNS disease less than 5%)
*High risk: 4 to 6 risk factors (2-year rate of CNS disease greater than 10%)
===References===
#Schmitz N, Zeynalova S, Nickelsen M, Kansara R, Villa D, Sehn LH, Glass B, Scott DW, Gascoyne RD, Connors JM, Ziepert M, Pfreundschuh M, Loeffler M, Savage KJ. CNS International Prognostic Index: a risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2016 Sep 10;34(26):3150-3156. Epub 2016 Jul 5. link to original article EuroPMC
Category:Diffuse large B-cell lymphoma regimens
Category:Disease-specific pages
Category:Aggressive non-Hodgkin lymphomas
Category:B-cell lymphomas