Mantle cell lymphoma

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Last updated on 2024-09-06:83 regimens on this page
108 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.
==BSH==
*2024: Eyre et al. Diagnosis and management of mantle cell lymphoma: a British Society for Haematology guideline EuroPMC
==ESMO==
*2017: Dreyling et al. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2014: Dreyling et al. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. EuroPMC
==NCCN==
*NCCN does not currently have guidelines at this granular level; please see NCCN Guidelines - B-cell Lymphomas.
=First-line therapy, pre-phase=
==CVP (Prednisolone)==
CVP: Cyclophosphamide, Oncovin (Vincristine), Prednisolone
===Regimen===
Study 	Dates of enrollment	Evidence
Le Gouill et al. 2017 (LyMa)	2008-2012 	Non-randomized part of phase 3 RCT
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
====Chemotherapy====
*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) 80 mg/m2 PO once per day on days 1 to 5
21-day course
====Subsequent treatment====
*Induction R-DHAC x 4 or R-DHAOx x 4 or R-DHAP x 4
===References===
# LyMa: Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, Damaj G, Gastinne T, Ribrag V, Feugier P, Casasnovas O, Zerazhi H, Haioun C, Maisonneuve H, Houot R, Jardin F, Van Den Neste E, Tournilhac O, Le Dû K, Morschhauser F, Cartron G, Fornecker LM, Canioni D, Callanan M, Béné MC, Salles G, Tilly H, Lamy T, Gressin R, Hermine O; LYSA. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017 Sep 28;377(13):1250-1260. link to original article link to protocol dosing details in supplement have been reviewed by our editors EuroPMC NCT00921414
=First-line therapy, randomized data=
==Bendamustine & Rituximab (BR)==
BR: Bendamustine, Rituximab
RB: Rituximab, Bendamustine
===Regimen variant #1, 6 cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Rummel et al. 2013 (StiL NHL1) 	2003-2008 	Phase 3 (E-switch-ic) 	R-CHOP 	Longer1 PFS (primary endpoint)Median PFS: 69.5 vs 31.2 mo(HR 0.58, 95% CI 0.44-0.74)
Chen et al. 2016 (SWOG S1106) 	2012-2013 	Randomized Phase 2 (E-de-esc)	R-Hyper-CVAD/R-MA 	Did not meet primary endpoint of PFS24
Awaiting publication (ECHO) 	2017-2025 	Phase 3 (C) 	BR & Acalabrutinib 	Shorter PFS2 (primary endpoint)Median PFS: 49.6 vs 66.4 mo(HR 1.37, 95% CI 1.06-1.75)
Awaiting publication (MANGROVE)	2019-2027 	Phase 3 (C) 	Rituximab & Zanubrutinib	TBD if different primary endpoint of PFS
1StiL NHL1 was a non-inferiority trial.
2Reported efficacy for ECHO is based on the FDA notice; full results have not been published yet, to our knowledge.
====Chemotherapy====
*Bendamustine 90 mg/m2 IV once per day on days 1 & 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Supportive therapy====
*Antiemetics, antipyretics, and antibiotics according to local standard of care
*Prophylactic use of G-CSF allowed according ASCO guidelines (2006)
28-day cycle for up to 6 cycles
====Subsequent treatment====
*SWOG S1106, responders: BEAM, then auto HSCT or CBV, then auto HSCT or cyclophosphamide, etoposide, TBI, then auto HSCT consolidation, depending on age and center
===Regimen variant #2, 8 cycles===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Flinn et al. 2014 (BRIGHT)	2009-2012 	Phase 3 (E-switch-ic)	1a. R-CHOP1b. R-CVP	Longer PFS1 (secondary endpoint)PFS60: 65.5% vs 55.8%(HR 0.61, 95% CI 0.45-0.85)
1Reported efficacy is based on the 2019 update.
====Chemotherapy====
*Bendamustine 90 mg/m2 IV once per day on days 1 & 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Supportive therapy====
*Antiemetics, antipyretics, and antibiotics according to local standard of care
*Prophylactic use of G-CSF allowed according ASCO guidelines (2006)
28-day cycle for up to 8 cycles
===References===
# StiL NHL1: Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Dürk H, Ballo H, Stauch M, Roller F, Barth J, Hoelzer D, Hinke A, Brugger W; StiL. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 6;381(9873):1203-10. Epub 2013 Feb 20. Erratum in: Lancet. 2013 Apr 6;381(9873):1184. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00991211
# BRIGHT: Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014 May 8;123(19):2944-52. Epub 2014 Mar 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00877006
##HRQoL analysis: Burke JM, van der Jagt RH, Kahl BS, Wood P, Hawkins TE, MacDonald D, Hertzberg M, Simpson D, Craig M, Kolibaba K, Issa S, Munteanu M, Victor TW, Flinn IW. Differences in Quality of Life Between Bendamustine-Rituximab and R-CHOP/R-CVP in Patients With Previously Untreated Advanced Indolent Non-Hodgkin Lymphoma or Mantle Cell Lymphoma. Clin Lymphoma Myeloma Leuk. 2016 Apr;16(4):182-190.e1. Epub 2016 Jan 15. link to original article EuroPMC
## Update: Flinn IW, van der Jagt R, Kahl B, Wood P, Hawkins T, MacDonald D, Simpson D, Kolibaba K, Issa S, Chang J, Trotman J, Hallman D, Chen L, Burke JM. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol. 2019 Apr 20;37(12):984-991. Epub 2019 Feb 27. link to original article link to PMC article EuroPMC
# SWOG S1106: Chen RW, Li H, Bernstein SH, Kahwash S, Rimsza LM, Forman SJ, Constine L, Shea TC, Cashen AF, Blum KA, Fenske TS, Barr PM, Phillips T, Leblanc M, Fisher RI, Cheson BD, Smith SM, Faham M, Wilkins J, Leonard JP, Kahl BS, Friedberg JW. RB but not R-HCVAD is a feasible induction regimen prior to auto-HCT in frontline MCL: results of SWOG Study S1106. Br J Haematol. 2017 Mar;176(5):759-769. Epub 2016 Dec 19. link to original article link to PMC article does not contain dosing details EuroPMC NCT01412879
## Update: Kamdar M, Li H, Chen RW, Rimsza LM, Leblanc ML, Fenske TS, Shea TC, Barr PM, Phillips TJ, Leonard JP, Kahl BS, Friedberg JW, Smith SM. Five-year outcomes of the S1106 study of R-hyper-CVAD vs R-bendamustine in transplant-eligible patients with mantle cell lymphoma. Blood Adv. 2019 Oct 22;3(20):3132-3135. link to original article link to PMC article EuroPMC
#ECHO: NCT02972840
#ENRICH: ISRCTN11038174
#MANGROVE: NCT04002297 dosing details on CT.gov have been reviewed by our editors
==Bendamustine & Rituximab (BR) & Acalabrutinib==
BR & Acalabrutinib: Bendamustine, Rituximab, Acalabrutinib
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Awaiting publication (ECHO)	2017-2025 	Phase 3 (E-RT-esc)	BR 	Longer PFS1 (primary endpoint)Median PFS: 66.4 vs 49.6 mo(HR 0.73, 95% CI 0.57-0.94)
1Reported efficacy is based on the FDA notice; full results have not been published yet, to our knowledge.
====Chemotherapy====
*Bendamustine as follows:
**Cycles 1 to 6: 90 mg/m2 IV once per day on days 1 & 2
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycles 1 to 6: 375 mg/m2 IV once on day 1
*Acalabrutinib (Calquence) 100 mg PO once per day
28-day cycles
===References===
#ECHO: NCT02972840
==IR-CHOP/R-DHAOx==
IR-CHOP/R-DHAOx: Ibrutinib, Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne alternating with Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Oxaliplatin
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Dreyling et al. 2024 (TRIANGLE)	2016-07-29 to 2020-12-28	Phase 3 (C)	1a. R-CHOP/R-DHAP, then ASCT1b. R-CHOP/R-DHAOx, then ASCT	Longer FFS1 (primary endpoint)FFS36: 88% vs 72%(HR 0.52, 98.3% CI 0.00-0.86)
1Reported efficacy is for the group that underwent ASCT after induction; comparison between the two ibrutinib groups is not yet reported.
====Targeted therapy, IR-CHOP portion (cycles 1, 3, 5)====
*Ibrutinib (Imbruvica) 560 mg PO once per day on days 1 to 19
*Rituximab (Rituxan) 375 mg/m2 IV once on day 0 or 1
====Chemotherapy, IR-CHOP portion (cycles 1, 3, 5)====
*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, IR-CHOP portion (cycles 1, 3, 5)====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
====Targeted therapy, R-DHAOx portion (cycles 2, 4, 6)====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 0 or 1
====Glucocorticoid therapy, R-DHAOx portion (cycles 2, 4, 6)====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
====Chemotherapy, R-DHAOx portion (cycles 2, 4, 6)====
*Cytarabine (Ara-C) 2000 mg/m2 IV over 3 hours every 12 hours on day 2 (total dose per cycle: 4000 mg/m2)
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
21-day cycle for 6 cycles
====Subsequent treatment====
*ASCT consolidation followed by Ibrutinib maintenance versus Ibrutinib maintenance
===References===
#TRIANGLE: Dreyling M, Doorduijn J, Giné E, Jerkeman M, Walewski J, Hutchings M, Mey U, Riise J, Trneny M, Vergote V, Shpilberg O, Gomes da Silva M, Leppä S, Jiang L, Stilgenbauer S, Kerkhoff A, Jachimowicz RD, Celli M, Hess G, Arcaini L, Visco C, van Meerten T, Wirths S, Zinzani PL, Novak U, Herhaus P, Benedetti F, Sonnevi K, Hanoun C, Hänel M, Dierlamm J, Pott C, Klapper W, Gözel D, Schmidt C, Unterhalt M, Ladetto M, Hoster E. Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network. Lancet. 2024 May 25;403(10441):2293-2306. Epub 2024 May 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02858258
==IR-CHOP/R-DHAP==
IR-CHOP/R-DHAP: Ibrutinib, Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne alternating with Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin)
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Dreyling et al. 2024 (TRIANGLE)	2016-07-29 to 2020-12-28	Phase 3 (C)	1a. R-CHOP/R-DHAP, then ASCT1b. R-CHOP/R-DHAOx, then ASCT	Longer FFS1 (primary endpoint)FFS36: 88% vs 72%(HR 0.52, 98.3% CI 0-0.86)
1Reported efficacy is for the group that underwent ASCT after induction; comparison between the two ibrutinib groups is not yet reported.
====Targeted therapy, IR-CHOP portion (cycles 1, 3, 5)====
*Ibrutinib (Imbruvica) 560 mg PO once per day on days 1 to 19
*Rituximab (Rituxan) 375 mg/m2 IV once on day 0 or 1
====Chemotherapy, IR-CHOP portion (cycles 1, 3, 5)====
*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, IR-CHOP portion (cycles 1, 3, 5)====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
====Targeted therapy, R-DHAP portion (cycles 2, 4, 6)====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 0 or 1
====Glucocorticoid therapy, R-DHAP portion (cycles 2, 4, 6)====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
====Chemotherapy, R-DHAP portion (cycles 2, 4, 6)====
*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 6 cycles
====Subsequent treatment====
*ASCT consolidation followed by Ibrutinib maintenance versus Ibrutinib maintenance
===References===
#TRIANGLE: Dreyling M, Doorduijn J, Giné E, Jerkeman M, Walewski J, Hutchings M, Mey U, Riise J, Trneny M, Vergote V, Shpilberg O, Gomes da Silva M, Leppä S, Jiang L, Stilgenbauer S, Kerkhoff A, Jachimowicz RD, Celli M, Hess G, Arcaini L, Visco C, van Meerten T, Wirths S, Zinzani PL, Novak U, Herhaus P, Benedetti F, Sonnevi K, Hanoun C, Hänel M, Dierlamm J, Pott C, Klapper W, Gözel D, Schmidt C, Unterhalt M, Ladetto M, Hoster E. Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network. Lancet. 2024 May 25;403(10441):2293-2306. Epub 2024 May 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02858258
==R-CHOP==
R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone
===Example orders===
*Example orders for R-CHOP in lymphoma
===Regimen variant #1, prednisone 100 mg===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Kluin-Nelemans et al. 2012 (MCLelderly)	2004-2010 	Phase 3 (C)	R-FC 	Longer OS (secondary endpoint)OS48: 62% vs 47%(HR 0.67, 95% CI 0.50-0.88)Did not meet primary endpoint of CR rate
Hermine et al. 2016 (MCL Younger) 	2004-2010 	Phase 3 (C)	See link 	See link
Flinn et al. 2014 (BRIGHT) 	2009-2012 	Phase 3 (C)	BR 	Seems to have non-inferior CR rate
====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====
*Antiemetics, antipyretics, and antibiotics per local standard of care
*G-CSF "according to the American Society of Clinical Oncology guidelines"
21-day cycle for varying durations: 6 cycles (MCL Younger); 6 to 8 cycles (BRIGHT); 8 cycles (MCLelderly)
====Subsequent treatment====
*MCLelderly: Rituximab versus interferon alfa maintenance
*MCL Younger: Dexa-BEAM, then Cy/TBI auto HSCT
===Regimen variant #2, prednisone 100 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Lenz et al. 2005 	2000-2002 	Phase 3 (E-esc)	CHOP 	Higher ORR (co-primary endpoint)
Robak et al. 2015 (LYM-3002)	2008-2011 	Phase 3 (C) 	VR-CAP 	Shorter OS1
1Reported efficacy for LYM-3002 is based on the 2018 update.
Note: there is a slight difference between the two studies in terms of rituximab timing.
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day -1 (Lenz et al. 2005) or day 1 (LYM-3002)
====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 (Lenz et al. 2005) or up to 8 cycles (LYM-3002)
===Regimen variant #3, uncapped vincristine===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Rummel et al. 2013 (StiL NHL1)	2003-2008 	Phase 3 (C)	BR 	Shorter PFS
====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 IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
21-day cycle for up to maximum of 6 cycles
===Regimen variant #4, 3 cycles, rituximab in cycle 3 only===
Study 	Dates of enrollment	Evidence
Delarue et al. 2012	2000-2003 	Phase 2
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 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 IV once on day 1
====Glucocorticoid therapy====
*Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
====CNS therapy, prophylaxis====
Intrathecal prophylaxis with the following was given per physician discretion; no timeframe or total number of doses is described:
*Methotrexate (MTX) 15 mg IT
*Cytarabine (Ara-C) 40 mg IT
*Corticosteroids
21-day cycle for up to 3 cycles
====Subsequent treatment====
*R-DHAP consolidation; patients who progress after first 2 cycles go directly to R-DHAP
===Regimen variant #5, 4 cycles===
Study 	Dates of enrollment	Evidence
Smith et al. 2012 (ECOG E1499)	2003-2005 	Phase 2
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
====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
21-day cycle for 4 cycles
====Subsequent treatment====
*Ibritumomab tiuxetan consolidation, in 4 to 8 weeks
===References===
# Lenz G, Dreyling M, Hoster E, Wörmann B, Dührsen U, Metzner B, Eimermacher H, Neubauer A, Wandt H, Steinhauer H, Martin S, Heidemann E, Aldaoud A, Parwaresch R, Hasford J, Unterhalt M, Hiddemann W; German Low Grade Lymphoma Study Group. Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG). J Clin Oncol. 2005 Mar 20;23(9):1984-92. Epub 2005 Jan 24. link to original article EuroPMC
# Delarue R, Haioun C, Ribrag V, Brice P, Delmer A, Tilly H, Salles G, Van Hoof A, Casasnovas O, Brousse N, Lefrere F, Hermine O; Groupe d'Etude des Lymphomes de l'Adulte. CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d'Etude des Lymphomes de l'Adulte. Blood. 2013 Jan 3;121(1):48-53. Epub 2012 Jun 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# MCLelderly: Kluin-Nelemans HC, Hoster E, Hermine O, Walewski J, Trneny M, Geisler CH, Stilgenbauer S, Thieblemont C, Vehling-Kaiser U, Doorduijn JK, Coiffier B, Forstpointner R, Tilly H, Kanz L, Feugier P, Szymczyk M, Hallek M, Kremers S, Lepeu G, Sanhes L, Zijlstra JM, Bouabdallah R, Lugtenburg PJ, Macro M, Pfreundschuh M, Procházka V, Di Raimondo F, Ribrag V, Uppenkamp M, André M, Klapper W, Hiddemann W, Unterhalt M, Dreyling MH. Treatment of older patients with mantle-cell lymphoma. N Engl J Med. 2012 Aug 9;367(6):520-31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00209209
## Update: Kluin-Nelemans HC, Hoster E, Hermine O, Walewski J, Geisler CH, Trneny M, Stilgenbauer S, Kaiser F, Doorduijn JK, Salles G, Szymczyk M, Tilly H, Kanz L, Schmidt C, Feugier P, Thieblemont C, Zijlstra JM, Ribrag V, Klapper W, Pott C, Unterhalt M, Dreyling MH. Treatment of Older Patients With Mantle Cell Lymphoma (MCL): Long-Term Follow-Up of the Randomized European MCL Elderly Trial. J Clin Oncol. 2020 Jan 20;38(3):248-256. Epub 2019 Dec 5. link to original article EuroPMC
# ECOG E1499: Smith MR, Li H, Gordon L, Gascoyne RD, Paietta E, Forero-Torres A, Kahl BS, Advani R, Hong F, Horning SJ. Phase II study of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy followed by yttrium-90-ibritumomab tiuxetan in untreated mantle-cell lymphoma: Eastern Cooperative Oncology Group Study E1499. J Clin Oncol. 2012 Sep 1;30(25):3119-26. Epub 2012 Jul 30. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00070447
## Update: Smith MR, Hong F, Li H, Gordon LI, Gascoyne RD, Paietta EM, Advani RH, Forero-Torres A, Horning SJ, Kahl BS. Mantle cell lymphoma initial therapy with abbreviated R-CHOP followed by (90)Y-ibritumomab tiuxetan: 10-year follow-up of the phase 2 ECOG-ACRIN study E1499. Leukemia. 2017 Feb;31(2):517-519. Epub 2016 Oct 26. link to original article link to PMC article EuroPMC
# StiL NHL1: Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Dürk H, Ballo H, Stauch M, Roller F, Barth J, Hoelzer D, Hinke A, Brugger W; StiL. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013 Apr 6;381(9873):1203-10. Epub 2013 Feb 20. Erratum in: Lancet. 2013 Apr 6;381(9873):1184. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00991211
## Update: Abstract: Mathias J. Rummel, MD, Georg Maschmeyer, MD, Arnold Ganser, Andrea Heider, PhD, Ulrich von Grünhagen, MD, PhD5, Christoph Losem, Gerhard Heil, MD, Manfred Welslau, Christina Balser, MD, Ulrich Kaiser, MD, Eckhart Weidmann, Heinz Dürk, MD, Hans Peter Böck, Martina Beate Stauch, MD, Jürgen Barth, Wolfgang Blau, MD, Alexander Burchardt, MD, Frank Kauff, PhD, Axel Hinke, PhD and Wolfram Brugger, MD. Bendamustine Plus Rituximab (B-R) Versus CHOP Plus Rituximab (CHOP-R) As First-Line Treatment in Patients with Indolent and Mantle Cell Lymphomas (MCL) – 7 Year Updated Results from the StiL NHL1 Study. Blood 2014 124:4407. link to abstract
# BRIGHT: Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014 May 8;123(19):2944-52. Epub 2014 Mar 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00877006
##HRQoL analysis: Burke JM, van der Jagt RH, Kahl BS, Wood P, Hawkins TE, MacDonald D, Hertzberg M, Simpson D, Craig M, Kolibaba K, Issa S, Munteanu M, Victor TW, Flinn IW. Differences in Quality of Life Between Bendamustine-Rituximab and R-CHOP/R-CVP in Patients With Previously Untreated Advanced Indolent Non-Hodgkin Lymphoma or Mantle Cell Lymphoma. Clin Lymphoma Myeloma Leuk. 2016 Apr;16(4):182-190.e1. Epub 2016 Jan 15. link to original article EuroPMC
## Update: Flinn IW, van der Jagt R, Kahl B, Wood P, Hawkins T, MacDonald D, Simpson D, Kolibaba K, Issa S, Chang J, Trotman J, Hallman D, Chen L, Burke JM. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol. 2019 Apr 20;37(12):984-991. Epub 2019 Feb 27. link to original article link to PMC article EuroPMC
# LYM-3002: Robak T, Huang H, Jin J, Zhu J, Liu T, Samoilova O, Pylypenko H, Verhoef G, Siritanaratkul N, Osmanov E, Alexeeva J, Pereira J, Drach J, Mayer J, Hong X, Okamoto R, Pei L, Rooney B, van de Velde H, Cavalli F; the LYM-3002 Investigators. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N Engl J Med. 2015 Mar 5;372(10):944-953. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00722137
## Update: Robak T, Jin J, Pylypenko H, Verhoef G, Siritanaratkul N, Drach J, Raderer M, Mayer J, Pereira J, Tumyan G, Okamoto R, Nakahara S, Hu P, Appiani C, Nemat S, Cavalli F; LYM-3002 investigators. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. Lancet Oncol. 2018 Nov;19(11):1449-58. Epub 2018 Oct 18. link to original article EuroPMC
# MCL Younger: Hermine O, Hoster E, Walewski J, Bosly A, Stilgenbauer S, Thieblemont C, Szymczyk M, Bouabdallah R, Kneba M, Hallek M, Salles G, Feugier P, Ribrag V, Birkmann J, Forstpointner R, Haioun C, Hänel M, Casasnovas RO, Finke J, Peter N, Bouabdallah K, Sebban C, Fischer T, Dührsen U, Metzner B, Maschmeyer G, Kanz L, Schmidt C, Delarue R, Brousse N, Klapper W, Macintyre E, Delfau-Larue MH, Pott C, Hiddemann W, Unterhalt M, Dreyling M; European Mantle Cell Lymphoma Network. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016 Aug 6;388(10044):565-75. Epub 2016 Jun 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00209222
##Update: Hermine O, Jiang L, Walewski J, Bosly A, Thieblemont C, Szymczyk M, Pott C, Salles G, Feugier P, Hübel K, Haioun C, Casasnovas RO, Schmidt C, Bouabdallah K, Ribrag V, Kanz L, Dürig J, Metzner B, Sibon D, Cheminant M, Burroni B, Klapper W, Hiddemann W, Unterhalt M, Hoster E, Dreyling M; European Mantle Cell Lymphoma Network. High-Dose Cytarabine and Autologous Stem-Cell Transplantation in Mantle Cell Lymphoma: Long-Term Follow-Up of the Randomized Mantle Cell Lymphoma Younger Trial of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2023 Jan 20;41(3):479-484. Epub 2022 Dec 5. link to original article EuroPMC
==R-CHOP (Prednisolone)==
R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisolone
===Example orders===
*Example orders for R-CHOP in lymphoma
===Regimen===
Study 	Dates of enrollment	Evidence
Van 't Veer et al. 2008 (HOVON 45)	2002-2005 	Phase 2
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
====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 IV once on day 1
====Glucocorticoid therapy====
*Prednisolone (Millipred) 100 mg PO once per day on days 1 to 5
21-day cycle for 3 cycles
====Subsequent treatment====
*HOVON 45, patients with at least PR: R-HiDAC consolidation
===References===
# HOVON 45: Van 't Veer MB, de Jong D, MacKenzie M, Kluin-Nelemans HC, van Oers MH, Zijlstra J, Hagenbeek A, van Putten WL. High-dose Ara-C and BEAM with autograft rescue in R-CHOP responsive mantle cell lymphoma patients. Br J Haematol. 2009 Feb;144(4):524-30. Epub 2008 Nov 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==R-CHOP-14 (Prednisolone)==
R-CHOP-14: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisolone every 14 days
===Regimen===
Study 	Dates of enrollment	Evidence
Le Gouill et al. 2017 (LyMa)	2008-2012 	Non-randomized part of phase 3 RCT
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
====Preceding treatment====
*Induction R-DHAC x 4 or R-DHAOx x 4 or R-DHAP x 4, with PR
====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) 80 mg/m2 PO once per day on days 1 to 5
====Supportive therapy====
*Not specified
14-day cycle for 4 cycles
====Subsequent treatment====
*R-BEAM with autologous HSCT consolidation
===References===
# LyMa: Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, Damaj G, Gastinne T, Ribrag V, Feugier P, Casasnovas O, Zerazhi H, Haioun C, Maisonneuve H, Houot R, Jardin F, Van Den Neste E, Tournilhac O, Le Dû K, Morschhauser F, Cartron G, Fornecker LM, Canioni D, Callanan M, Béné MC, Salles G, Tilly H, Lamy T, Gressin R, Hermine O; LYSA. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017 Sep 28;377(13):1250-1260. link to original article link to protocol dosing details in supplement have been reviewed by our editors EuroPMC NCT00921414
==R-CHOP/R-DHAOx==
R-CHOP/R-DHAOx: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne alternating with Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Oxaliplatin
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Dreyling et al. 2024 (TRIANGLE)	2016-07-29 to 2020-12-28	Phase 3 (C)	1a. IR-CHOP/R-DHAP, then ASCT, then ibrutinib x 2y1b. IR-CHOP/R-DHAOx, then ASCT, then ibrutinib x 2y	Shorter FFS
Dreyling et al. 2024 (TRIANGLE)	2016-07-29 to 2020-12-28	Phase 3 (C)	2a. IR-CHOP/R-DHAP, then ibrutinib x 2y2b. IR-CHOP/R-DHAOx, then ibrutinib x 2y 	Did not meet primary endpoint of FFS
====Targeted therapy, R-CHOP portion (cycles 1, 3, 5)====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 0 or 1
====Chemotherapy, R-CHOP portion (cycles 1, 3, 5)====
*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, R-CHOP portion (cycles 1, 3, 5)====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
====Targeted therapy, R-DHAOx portion (cycles 2, 4, 6)====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 0 or 1
====Glucocorticoid therapy, R-DHAOx portion (cycles 2, 4, 6)====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
====Chemotherapy, R-DHAOx portion (cycles 2, 4, 6)====
*Cytarabine (Ara-C) 2000 mg/m2 IV over 3 hours every 12 hours on day 2 (total dose per cycle: 4000 mg/m2)
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
21-day cycle for 6 cycles
====Subsequent treatment====
*TRIANGLE: ASCT consolidation
===References===
#TRIANGLE: Dreyling M, Doorduijn J, Giné E, Jerkeman M, Walewski J, Hutchings M, Mey U, Riise J, Trneny M, Vergote V, Shpilberg O, Gomes da Silva M, Leppä S, Jiang L, Stilgenbauer S, Kerkhoff A, Jachimowicz RD, Celli M, Hess G, Arcaini L, Visco C, van Meerten T, Wirths S, Zinzani PL, Novak U, Herhaus P, Benedetti F, Sonnevi K, Hanoun C, Hänel M, Dierlamm J, Pott C, Klapper W, Gözel D, Schmidt C, Unterhalt M, Ladetto M, Hoster E. Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network. Lancet. 2024 May 25;403(10441):2293-2306. Epub 2024 May 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02858258
==R-CHOP/R-DHAP==
R-CHOP/R-DHAP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne alternating with Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin)
===Regimen===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Hermine et al. 2016 (MCL Younger)	2004-2010 	Phase 3 (E-esc)	See link 	See link
Dreyling et al. 2024 (TRIANGLE) 	2016-07-29 to 2020-12-28	Phase 3 (C) 	1a. IR-CHOP/R-DHAP, then ASCT, then ibrutinib x 2y1b. IR-CHOP/R-DHAOx, then ASCT, then ibrutinib x 2y	Shorter FFS
Dreyling et al. 2024 (TRIANGLE) 	2016-07-29 to 2020-12-28	Phase 3 (C) 	2a. IR-CHOP/R-DHAP, then ibrutinib x 2y2b. IR-CHOP/R-DHAOx, then ibrutinib x 2y 	Did not meet primary endpoint of FFS
====Targeted therapy, R-CHOP portion (cycles 1, 3, 5)====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 0 or 1
====Chemotherapy, R-CHOP portion (cycles 1, 3, 5)====
*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, R-CHOP portion (cycles 1, 3, 5)====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
====Targeted therapy, R-DHAP portion (cycles 2, 4, 6)====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 0 or 1
====Glucocorticoid therapy, R-DHAP portion (cycles 2, 4, 6)====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
====Chemotherapy, R-DHAP portion (cycles 2, 4, 6)====
*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 6 cycles
====Subsequent treatment====
*MCL Younger: Cytarabine, Melphalan, TBI with autologous hematopoietic stem cell transplant consolidation
*TRIANGLE: ASCT consolidation
===References===
# MCL Younger: Hermine O, Hoster E, Walewski J, Bosly A, Stilgenbauer S, Thieblemont C, Szymczyk M, Bouabdallah R, Kneba M, Hallek M, Salles G, Feugier P, Ribrag V, Birkmann J, Forstpointner R, Haioun C, Hänel M, Casasnovas RO, Finke J, Peter N, Bouabdallah K, Sebban C, Fischer T, Dührsen U, Metzner B, Maschmeyer G, Kanz L, Schmidt C, Delarue R, Brousse N, Klapper W, Macintyre E, Delfau-Larue MH, Pott C, Hiddemann W, Unterhalt M, Dreyling M; European Mantle Cell Lymphoma Network. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016 Aug 6;388(10044):565-75. Epub 2016 Jun 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00209222
##Update: Hermine O, Jiang L, Walewski J, Bosly A, Thieblemont C, Szymczyk M, Pott C, Salles G, Feugier P, Hübel K, Haioun C, Casasnovas RO, Schmidt C, Bouabdallah K, Ribrag V, Kanz L, Dürig J, Metzner B, Sibon D, Cheminant M, Burroni B, Klapper W, Hiddemann W, Unterhalt M, Hoster E, Dreyling M; European Mantle Cell Lymphoma Network. High-Dose Cytarabine and Autologous Stem-Cell Transplantation in Mantle Cell Lymphoma: Long-Term Follow-Up of the Randomized Mantle Cell Lymphoma Younger Trial of the European Mantle Cell Lymphoma Network. J Clin Oncol. 2023 Jan 20;41(3):479-484. Epub 2022 Dec 5. link to original article EuroPMC
#TRIANGLE: Dreyling M, Doorduijn J, Giné E, Jerkeman M, Walewski J, Hutchings M, Mey U, Riise J, Trneny M, Vergote V, Shpilberg O, Gomes da Silva M, Leppä S, Jiang L, Stilgenbauer S, Kerkhoff A, Jachimowicz RD, Celli M, Hess G, Arcaini L, Visco C, van Meerten T, Wirths S, Zinzani PL, Novak U, Herhaus P, Benedetti F, Sonnevi K, Hanoun C, Hänel M, Dierlamm J, Pott C, Klapper W, Gözel D, Schmidt C, Unterhalt M, Ladetto M, Hoster E. Ibrutinib combined with immunochemotherapy with or without autologous stem-cell transplantation versus immunochemotherapy and autologous stem-cell transplantation in previously untreated patients with mantle cell lymphoma (TRIANGLE): a three-arm, randomised, open-label, phase 3 superiority trial of the European Mantle Cell Lymphoma Network. Lancet. 2024 May 25;403(10441):2293-2306. Epub 2024 May 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02858258
==R-CVP==
R-CVP: Rituximab, Cyclophosphamide, Vincristine, Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Flinn et al. 2014 (BRIGHT)	2009-2012 	Phase 3 (C)	BR 	Seems to have non-inferior CR rate
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 or 1000 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====
*Antiemetics, antipyretics, and antibiotics per local standard of care
*G-CSF "according to the American Society of Clinical Oncology guidelines"
21-day cycle for up to 8 cycles
===References===
# BRIGHT: Flinn IW, van der Jagt R, Kahl BS, Wood P, Hawkins TE, Macdonald D, Hertzberg M, Kwan YL, Simpson D, Craig M, Kolibaba K, Issa S, Clementi R, Hallman DM, Munteanu M, Chen L, Burke JM. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study. Blood. 2014 May 8;123(19):2944-52. Epub 2014 Mar 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00877006
##HRQoL analysis: Burke JM, van der Jagt RH, Kahl BS, Wood P, Hawkins TE, MacDonald D, Hertzberg M, Simpson D, Craig M, Kolibaba K, Issa S, Munteanu M, Victor TW, Flinn IW. Differences in Quality of Life Between Bendamustine-Rituximab and R-CHOP/R-CVP in Patients With Previously Untreated Advanced Indolent Non-Hodgkin Lymphoma or Mantle Cell Lymphoma. Clin Lymphoma Myeloma Leuk. 2016 Apr;16(4):182-190.e1. Epub 2016 Jan 15. link to original article EuroPMC
## Update: Flinn IW, van der Jagt R, Kahl B, Wood P, Hawkins T, MacDonald D, Simpson D, Kolibaba K, Issa S, Chang J, Trotman J, Hallman D, Chen L, Burke JM. First-line treatment of patients with indolent non-Hodgkin lymphoma or mantle-cell lymphoma with bendamustine plus rituximab versus R-CHOP or R-CVP: results of the BRIGHT 5-year follow-up study. J Clin Oncol. 2019 Apr 20;37(12):984-991. Epub 2019 Feb 27. link to original article link to PMC article EuroPMC
==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
Romaguera et al. 2005 	1999-2002 	Phase 2 	 	
Wang et al. 2008 	Not reported 	Phase 2 	 	
Bernstein et al. 2013 (SWOG S0213)	2002-2006 	Phase 2 	 	
Merli et al. 2012 	2005-2010 	Phase 2 	 	
Chen et al. 2016 (SWOG S1106) 	2012-2013 	Randomized Phase 2 (E-esc)	BR 	Did not meet primary endpoint of PFS24
Note: Romaguera et al. 2005 had slightly different doxorubicin dosages in the text vs. table 1. SWOG S0213 used the original protocol as specified in Romaguera et al. 2005.
====Targeted therapy, both portions (cycles 1 to 8)====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1, given first
**Patients with peripheral blood involvement could have the cycle 1 dose of rituximab delayed or omitted by clinician discretion
====Chemotherapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")====
*Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 3 hours every 12 hours on days 2 to 4, given second (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, given 12 hours after the last dose of cyclophosphamide on day 5
*Doxorubicin (Adriamycin) 16.67 mg/m2/day IV continuous infusion over 72 hours, started on day 5 (total dose per cycle: 50 mg/m2)
====Glucocorticoid therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")====
*Dexamethasone (Decadron) 40 mg IV or PO once per day on days 2 to 5, 12 to 15
====Supportive therapy, Hyper-CVAD portion (cycles 1, 3, 5, 7; "Part A")====
*Mesna (Mesnex) 600 mg/m2/day IV continuous infusion over 76 hours, started on day 2, 1 hour prior to cyclophosphamide and completed 12 hours after the last dose of cyclophosphamide 
***"Over 76 hours" is not exactly specified in Romaguera et al. 2005; Wang et al. 2008. It is based on the assumption that "completed 12 hours after the last dose of cyclophosphamide" means that it would finish 12 hours after the last dose of cyclophosphamide completes.
====Chemotherapy, MA portion (cycles 2, 4, 6, 8; "Part B")====
*Methotrexate (MTX) by the following renal function-based criteria:
**Creatinine 1.5 mg/dL or less: 200 mg/m2 IV over 2 hours once on day 2, then 800 mg/m2 IV over 22 hours (total dose per cycle: 1000 mg/m2)
**Creatinine more than 1.5 mg/dL: 100 mg/m2 IV over 2 hours once on day 2, then 400 mg/m2 IV over 22 hours (total dose per cycle: 500 mg/m2)
***Urine alkalinized to pH of 6.8 or more prior to the start of methotrexate and kept within that range until methotrexate is cleared
*Cytarabine (Ara-C) by the following age- and renal function-based criteria:
**60 years old or younger AND creatinine 1.5 mg/dL or less: 3000 mg/m2 IV over 2 hours every 12 hours on days 3 & 4 (total dose per cycle: 12,000 mg/m2)
**Older than 60 years old OR creatinine more than 1.5 mg/dL: 1000 mg/m2 IV over 2 hours every 12 hours on days 3 & 4 (total dose per cycle: 4000 mg/m2)
====Supportive therapy, MA portion (cycles 2, 4, 6, 8; "Part B")====
*Leucovorin (Folinic acid) 50 mg PO once on day 3, 12 hours after methotrexate is complete, then 15 mg PO every 6 hours for 8 doses. If serum methotrexate level at 24 hours is greater than 1000 nmol/L or at 48 hours is greater than 100 nmol/L, dose is increased to 100 mg IV Q3H.
* Prednisolone 1% ophthalmic solution 2 drops in each eye four times per day on days 3 to 9 was started on the day of the start of cytarabine infusion and was continued for 7 days to prevent chemical conjunctivitis.
====Supportive therapy, both portions (cycles 1 to 8)====
All growth factors and antibiotics given for 10 days, starting 24 to 36 hours after doxorubicin infusion is complete in A cycles and not specified in B cycles
*Filgrastim (Neupogen) 5 mcg/kg SC once per day 
*Valacyclovir (Valtrex) 500 mg PO once per day
*Fluconazole (Diflucan) 100 mg PO once per day
*ONE of the following fluoroquinolones:
**Levofloxacin (Levaquin) 500 mg PO once per day
**Ciprofloxacin (Cipro) 500 mg PO twice per day
*Erythropoietin was permitted throughout therapy
21-day cycle for 8 cycles
====Subsequent treatment====
*Merli et al. 2012, responders: autologous HSCT (regimen not specified) consolidation
===References===
# Romaguera JE, Fayad L, Rodriguez MA, Broglio KR, Hagemeister FB, Pro B, McLaughlin P, Younes A, Samaniego F, Goy A, Sarris AH, Dang NH, Wang M, Beasley V, Medeiros LJ, Katz RL, Gagneja H, Samuels BI, Smith TL, Cabanillas FF. High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine. J Clin Oncol. 2005 Oct 1;23(28):7013-23. Epub 2005 Sep 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Romaguera JE, Fayad LE, Feng L, Hartig K, Weaver P, Rodriguez MA, Hagemeister FB, Pro B, McLaughlin P, Younes A, Samaniego F, Goy A, Cabanillas F, Kantarjian H, Kwak L, Wang M. Ten-year follow-up after intense chemoimmunotherapy with Rituximab-HyperCVAD alternating with Rituximab-high dose methotrexate/cytarabine (R-MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma. Br J Haematol. 2010 Jul;150(2):200-8. Epub 2010 May 26. Review. Erratum in: Br J Haematol.n 2010 Oct;151(1):111. link to original article EuroPMC
## Update: Chihara D, Cheah CY, Westin JR, Fayad LE, Rodriguez MA, Hagemeister FB, Pro B, McLaughlin P, Younes A, Samaniego F, Goy A, Cabanillas F, Kantarjian H, Kwak LW, Wang ML, Romaguera JE. Rituximab plus hyper-CVAD alternating with MTX/Ara-C in patients with newly diagnosed mantle cell lymphoma: 15-year follow-up of a phase II study from the MD Anderson Cancer Center. Br J Haematol. 2016 Jan;172(1):80-8. Epub 2015 Dec 9. link to original article link to PMC article EuroPMC
# Wang M, Fayad L, Cabanillas F, Hagemeister F, McLaughlin P, Rodriguez MA, Kwak LW, Zhou Y, Kantarjian H, Romaguera J. Phase 2 trial of rituximab plus hyper-CVAD alternating with rituximab plus methotrexate-cytarabine for relapsed or refractory aggressive mantle cell lymphoma. Cancer. 2008 Nov 15;113(10):2734-41. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Merli F, Luminari S, Ilariucci F, Petrini M, Visco C, Ambrosetti A, Stelitano C, Caracciolo F, Di Renzo N, Angrilli F, Carella AM, Capodanno I, Barbolini E, Galimberti S, Federico M. Rituximab plus HyperCVAD alternating with high dose cytarabine and methotrexate for the initial treatment of patients with mantle cell lymphoma, a multicentre trial from Gruppo Italiano Studio Linfomi. Br J Haematol. 2012 Feb;156(3):346-53. Epub 2011 Dec 7. link to original article EuroPMC
# SWOG S0213: Bernstein SH, Epner E, Unger JM, Leblanc M, Cebula E, Burack R, Rimsza L, Miller TP, Fisher RI. A phase II multicenter trial of hyperCVAD MTX/Ara-C and rituximab in patients with previously untreated mantle cell lymphoma; SWOG 0213. Ann Oncol. 2013 Jun;24(6):1587-93. Epub 2013 Mar 15. link to original article link to PMC article EuroPMC NCT00041132
# SWOG S1106: Chen RW, Li H, Bernstein SH, Kahwash S, Rimsza LM, Forman SJ, Constine L, Shea TC, Cashen AF, Blum KA, Fenske TS, Barr PM, Phillips T, Leblanc M, Fisher RI, Cheson BD, Smith SM, Faham M, Wilkins J, Leonard JP, Kahl BS, Friedberg JW. RB but not R-HCVAD is a feasible induction regimen prior to auto-HCT in frontline MCL: results of SWOG Study S1106. Br J Haematol. 2017 Mar;176(5):759-769. Epub 2016 Dec 19. link to original article link to PMC article does not contain dosing details; refers to Bernstein et al. 2013 EuroPMC NCT01412879
## Update: Kamdar M, Li H, Chen RW, Rimsza LM, Leblanc ML, Fenske TS, Shea TC, Barr PM, Phillips TJ, Leonard JP, Kahl BS, Friedberg JW, Smith SM. Five-year outcomes of the S1106 study of R-hyper-CVAD vs R-bendamustine in transplant-eligible patients with mantle cell lymphoma. Blood Adv. 2019 Oct 22;3(20):3132-3135. link to original article link to PMC article EuroPMC
==VR-CAP==
VR-CAP: Velcade (Bortezomib), Rituximab, Cyclophosphamide, Adriamycin (Doxorubicin), Prednisone
VcR-CAP: Velcade (Bortezomib), Rituximab, Cyclophosphamide, Adriamycin (Doxorubicin), Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Robak et al. 2015 (LYM-3002)	2008-2011 	Phase 3 (E-RT-switch-ooc)	R-CHOP 	Longer PFS (primary endpoint)Median PFS: 24.7 vs 14.4 mo(HR 0.63, 95% CI 0.50-0.79)Longer OS1 (secondary endpoint)Median OS: 90.7 vs 55.7 mo(HR 0.66, 95% CI 0.51-0.85)
1Reported efficacy is based on the 2018 update.
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11, given first 
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1, given second
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 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 up to 8 cycles
===References===
# LYM-3002: Robak T, Huang H, Jin J, Zhu J, Liu T, Samoilova O, Pylypenko H, Verhoef G, Siritanaratkul N, Osmanov E, Alexeeva J, Pereira J, Drach J, Mayer J, Hong X, Okamoto R, Pei L, Rooney B, van de Velde H, Cavalli F; the LYM-3002 Investigators. Bortezomib-based therapy for newly diagnosed mantle-cell lymphoma. N Engl J Med. 2015 Mar 5;372(10):944-953. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00722137
## Update: Robak T, Jin J, Pylypenko H, Verhoef G, Siritanaratkul N, Drach J, Raderer M, Mayer J, Pereira J, Tumyan G, Okamoto R, Nakahara S, Hu P, Appiani C, Nemat S, Cavalli F; LYM-3002 investigators. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. Lancet Oncol. 2018 Nov;19(11):1449-58. Epub 2018 Oct 18. link to original article EuroPMC
=First-line therapy, non-randomized or retrospective data=
==BR/RC==
BR/RC: Bendamustine & Rituximab alternating with Rituximab & Cytarabine
BR/CR: Bendamustine & Rituximab alternating with Cytarabine & Rituximab
RB/RC: Rituximab & Bendamustine alternating with Rituximab & Cytarabine
===Regimen variant #1, sequential===
Study 	Dates of enrollment	Evidence
Armand et al. 2016 (DFCI 12-168)	2012-2014 	Phase 2
====Chemotherapy, BR portion (cycles 1 to 3)====
*Bendamustine 90 mg/m2 IV once per day on days 1 & 2
====Chemotherapy, RC portion (cycles 4 to 6)====
*Cytarabine (Ara-C) by the following complex criteria:
**60 years old or younger AND Cr less than 1.3 AND NO preexisting neurotoxicity: 3000 mg/m2 IV twice per day on days 1 & 2
**Older than 60 years old AND Cr less than 1.3 AND NO preexisting neurotoxicity: 2000 mg/m2 IV twice per day on days 1 & 2
**Older than 60 years old AND either renal dysfunction (Cr 1.3 to 2.0) OR preexisting neurotoxicity: 1500 mg/m2 IV twice per day on days 1 & 2
**Older than 60 years old AND renal dysfunction (Cr 1.3 to 2.0) AND preexisting neurotoxicity: 1000 mg/m2 IV twice per day on days 1 & 2
====Targeted therapy, both portions (cycles 1 to 6)====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycle for 3 cycles, then 21-day cycle for 3 cycles
====Subsequent treatment====
*Auto HSCT consolidation
===Regimen variant #2, alternating===
Study 	Dates of enrollment	Evidence
Merryman et al. 2020 (WUSTL 201603149)	2016-2018 	Phase 2
Note: Merryman et al. 2020 is an update for DFCI 12-168 and the primary publication for WUSTL 201603149.
====Chemotherapy, BR portion (cycles 1, 3, 5)====
*Bendamustine 90 mg/m2 IV once per day on days 1 & 2
====Targeted therapy, BR portion (cycles 1, 3, 5)====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy, RC portion (cycles 2, 4, 6)====
*Cytarabine (Ara-C) by the following age- and renal function-based criteria:
**60 years old or younger AND eGFR 60 mL/min/1.73m2 or more: 3000 mg/m2 IV twice per day on days 1 & 2
**Older than 60 years old OR eGFR 40 to 59 mL/min/1.73m2: 2000 mg/m2 IV twice per day on days 1 & 2
====Targeted therapy, RC portion (cycles 2, 4, 6)====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycle, then 21-day cycle, then 28-day cycle, then 21-day cycle, then 28-day cycle, then 21-day cycle
====Subsequent treatment====
*Auto HSCT consolidation
===References===
# DFCI 12-168: Armand P, Redd R, Bsat J, Mayuram S, Giardino A, Fisher DC, LaCasce AS, Jacobson C, Davids MS, Brown JR, Weng L, Wilkins J, Faham M, Freedman AS, Joyce R, Jacobsen ED. A phase 2 study of rituximab-bendamustine and rituximab-cytarabine for transplant-eligible patients with mantle cell lymphoma. Br J Haematol. 2016 Apr;173(1):89-95. Epub 2016 Jan 5. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01661881
##Update: Merryman RW, Edwin N, Redd R, Bsat J, Chase M, LaCasce A, Freedman A, Jacobson C, Fisher D, Ng S, Crombie J, Kim A, Odejide O, Davids MS, Brown JR, Jacene H, Cashen A, Bartlett NL, Mehta-Shah N, Ghobadi A, Kahl B, Joyce R, Armand P, Jacobsen E. Rituximab/bendamustine and rituximab/cytarabine induction therapy for transplant-eligible mantle cell lymphoma. Blood Adv. 2020 Mar 10;4(5):858-867. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01661881
#WUSTL 201603149: Merryman RW, Edwin N, Redd R, Bsat J, Chase M, LaCasce A, Freedman A, Jacobson C, Fisher D, Ng S, Crombie J, Kim A, Odejide O, Davids MS, Brown JR, Jacene H, Cashen A, Bartlett NL, Mehta-Shah N, Ghobadi A, Kahl B, Joyce R, Armand P, Jacobsen E. Rituximab/bendamustine and rituximab/cytarabine induction therapy for transplant-eligible mantle cell lymphoma. Blood Adv. 2020 Mar 10;4(5):858-867. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02728531
==Chlorambucil & Rituximab (RClb)==
===Regimen===
Study 	Dates of enrollment	Evidence
Sachanas et al. 2011	2004-06 to 2008-08 	Phase 2
====Chemotherapy====
*Chlorambucil (Leukeran) as follows:
**Cycles 1 to 8: 10 mg PO once per day on days 2 to 11
**Cycles 9 to 12: 10 mg PO once per day on days 1 to 10
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycles 1 to 8: 375 mg/m2 IV once on day 1
28-day cycle for 12 cycles
====Subsequent treatment====
*Sachanas et al. 2011, PR/CR: Rituximab maintenance
===References===
# Sachanas S, Pangalis GA, Vassilakopoulos TP, Korkolopoulou P, Kontopidou FN, Athanasoulia M, Yiakoumis X, Kalpadakis C, Georgiou G, Masouridis S, Moschogiannis M, Tsirkinidis P, Pappis V, Kokoris SI, Siakantaris MP, Panayiotidis P, Angelopoulou MK. Combination of rituximab with chlorambucil as first line treatment in patients with mantle cell lymphoma: a highly effective regimen. Leuk Lymphoma. 2011 Mar;52(3):387-93. Epub 2010 Dec 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Cladribine monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Inwards et al. 2008 (NCCTG 95-80-53)	2003-2005 	Phase 2
====Chemotherapy====
*Cladribine (Leustatin) 5 mg/m2 IV over 2 hours once per day on days 1 to 5 
28-day cycle for up to 6 cycles
===References===
# NCCTG 95-80-53: Inwards DJ, Fishkin PA, Hillman DW, Brown DW, Ansell SM, Kurtin PJ, Fonseca R, Morton RF, Veeder MH, Witzig TE. Long-term results of the treatment of patients with mantle cell lymphoma with cladribine (2-CDA) alone (95-80-53) or 2-CDA and rituximab (N0189) in the North Central Cancer Treatment Group. Cancer. 2008 Jul 1;113(1):108-16. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==Cladribine & Rituximab==
===Regimen===
Study 	Dates of enrollment	Evidence
Inwards et al. 2008 (NCCTG N0189)	2003-2005 	Phase 2
====Chemotherapy====
*Cladribine (Leustatin) 5 mg/m2 IV over 2 hours once per day on days 1 to 5
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Supportive therapy====
*Pegfilgrastim (Neulasta) 6 mg SC once on day 6
OR
*Filgrastim (Neupogen) (dose not specified) SC once per day on days 6 to 15
28-day cycle for up to 6 cycles
===References===
# NCCTG N0189: Inwards DJ, Fishkin PA, Hillman DW, Brown DW, Ansell SM, Kurtin PJ, Fonseca R, Morton RF, Veeder MH, Witzig TE. Long-term results of the treatment of patients with mantle cell lymphoma with cladribine (2-CDA) alone (95-80-53) or 2-CDA and rituximab (N0189) in the North Central Cancer Treatment Group. Cancer. 2008 Jul 1;113(1):108-16. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==Lenalidomide & Rituximab (R2)==
LR: Lenalidomide & Rituximab
===Regimen===
Study 	Dates of enrollment	Evidence
Ruan et al. 2015 (Cornell 1103011566)	2011-2014 	Phase 2
Note: Lenalidomide dose was increased in cycle 2 only if no dose-limiting adverse events in cycle 1.
====Targeted therapy====
*Lenalidomide (Revlimid) as follows:
**Cycle 1: 20 mg PO once per day on days 1 to 21 
**Cycles 2 to 12: 25 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
**Cycles 4, 6, 8, 10, 12: 375 mg/m2 IV once on day 1
====Supportive therapy====
*Thromboprophylaxis: Aspirin or low molecular weight heparin unless on treatment for known thrombosis
28-day cycle for 12 cycles
====Subsequent treatment====
*Lenalidomide & rituximab maintenance
===References===
# Cornell 1103011566: Ruan J, Martin P, Shah B, Schuster SJ, Smith SM, Furman RR, Christos P, Rodriguez A, Svoboda J, Lewis J, Katz O, Coleman M, Leonard JP. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015 Nov 5;373(19):1835-44. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01472562
## Update: Ruan J, Martin P, Christos P, Cerchietti L, Tam W, Shah B, Schuster SJ, Rodriguez A, Hyman D, Calvo-Vidal MN, Smith SM, Svoboda J, Furman RR, Coleman M, Leonard JP. Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma. Blood. 2018 Nov 8;132(19):2016-2025. Epub 2018 Sep 4. link to original article link to PMC article EuroPMC
==R-BAC==
R-BAC: Rituximab, Bendamustine, Ara-C (Cytarabine)
===Regimen variant #1, 375/70/500 ("RBAC500")===
Study 	Dates of enrollment	Evidence
Visco et al. 2016 (FIL-RBAC500)	2012-2014 	Phase 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1 
====Chemotherapy====
*Bendamustine 70 mg/m2 IV once per day on days 2 & 3
*Cytarabine (Ara-C) 500 mg/m2 IV once per day on days 2 to 4
28-day cycle for up to 6 cycles
===Regimen variant #2, 375/70/800===
Study 	Dates of enrollment	Evidence
Visco et al. 2013 (VI-1903)	2009-2011 	Phase 2
Note: up to 6 cycles were given for newly diagnosed patients under the age of 80, who tolerated treatment, or had regression of disease between cycles 2 and 4.
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once on day 1 
**Cycles 2 to 4 up to 6: 375 mg/m2 IV once on day 2
====Chemotherapy====
*Bendamustine 70 mg/m2 IV once per day on days 2 & 3
*Cytarabine (Ara-C) 800 mg/m2 IV over 2 hours once per day on days 2 to 4, starting 2 hours after bendamustine on days 2 & 3
28-day cycle for 4 to 6 cycles (see note)
===References===
# VI-1903: Visco C, Finotto S, Zambello R, Paolini R, Menin A, Zanotti R, Zaja F, Semenzato G, Pizzolo G, D'Amore ES, Rodeghiero F. Combination of rituximab, bendamustine, and cytarabine for patients with mantle-cell non-Hodgkin lymphoma ineligible for intensive regimens or autologous transplantation. J Clin Oncol. 2013 Apr 10;31(11):1442-9. Epub 2013 Feb 11. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00992134
# FIL-RBAC500: Visco C, Chiappella A, Nassi L, Patti C, Ferrero S, Barbero D, Evangelista A, Spina M, Molinari A, Rigacci L, Tani M, Di Rocco A, Pinotti G, Fabbri A, Zambello R, Finotto S, Gotti M, Carella AM, Salvi F, Pileri SA, Ladetto M, Ciccone G, Gaidano G, Ruggeri M, Martelli M, Vitolo U. Rituximab, bendamustine, and low-dose cytarabine as induction therapy in elderly patients with mantle cell lymphoma: a multicentre, phase 2 trial from Fondazione Italiana Linfomi. Lancet Haematol. 2017 Jan;4(1):e15-e23. Epub 2016 Dec 2. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT01662050
==maxi-R-CHOP/R-HiDAC==
maxi-R-CHOP/R-HiDAC: maximum-strength Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne alternating with Rituximab, High-Dose Ara-C (Cytarabine)
===Regimen===
Study 	Dates of enrollment	Evidence
Geisler et al. 2008 (NLG MCL2)	2000-2006 	Phase 2
Note: This was also known as the "Nordic regimen". Protocol originally started rituximab during cycle 4, but the protocol was amended to start it on cycle 2.
====Targeted therapy, maxi-R-CHOP portion (cycles 1, 3, 5)====
*Rituximab (Rituxan) as follows:
**Cycles 3 & 5: 375 mg/m2 IV once on day 1 
====Chemotherapy, maxi-R-CHOP portion (cycles 1, 3, 5)====
*Cyclophosphamide (Cytoxan) 1200 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
*Vincristine (Oncovin) 2 mg IV once on day 1
====Glucocorticoid therapy, maxi-R-CHOP portion (cycles 1, 3, 5)====
*Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
====Targeted therapy, R-HiDAC portion (cycles 2, 4, 6)====
*Rituximab (Rituxan) as follows:
**Cycles 2 & 4: 375 mg/m2 IV once on day 1 
**Cycle 6: 375 mg/m2 IV once per day on days 1 & 9
====Chemotherapy, R-HiDAC portion (cycles 2, 4, 6)====
*Cytarabine (Ara-C) by the following age-based criteria:
**60 years old or younger: 3000 mg/m2 IV over 3 hours every 12 hours on days 1 & 2 (total dose per cycle: 12,000 mg/m2)
**Older than 60 years old: 2000 mg/m2 IV over 3 hours every 12 hours on days 1 & 2 (total dose per cycle: 8000 mg/m2)
====Supportive therapy, R-HiDAC portion (cycles 2, 4, 6)====
*Filgrastim (Neupogen) given during cycle 6 as part of stem cell mobilization, with at least 2 million CD34+ cells/kg harvested
21-day cycle for 6 cycles
====Subsequent treatment====
*BEAC with autologous HSCT or BEAM with autologous HSCT consolidation, within 1 to 2 weeks. If transplant was delayed, an additional 1 to 2 cycles of chemotherapy with maxi-R-CHOP or R-HiDAC could be given.
===References===
# NLG MCL2: Geisler CH, Kolstad A, Laurell A, Andersen NS, Pedersen LB, Jerkeman M, Eriksson M, Nordström M, Kimby E, Boesen AM, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Akerman M, Ehinger M, Sundström C, Langholm R, Delabie J, Karjalainen-Lindsberg ML, Brown P, Elonen E; Nordic Lymphoma Group. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008 Oct 1;112(7):2687-93. Epub 2008 Jul 14. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN87866680
## Update: Geisler CH, Kolstad A, Laurell A, Jerkeman M, Räty R, Andersen NS, Pedersen LB, Eriksson M, Nordström M, Kimby E, Bentzen H, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Ehinger M, Sundström C, Delabie J, Karjalainen-Lindsberg ML, Brown P, Elonen E; Nordic Lymphoma Group. Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem-cell support: still very long survival but late relapses do occur. Br J Haematol. 2012 Aug;158(3):355-62. Epub 2012 May 29. Erratum in: Br J Haematol. 2012 Sep;158(6):815-6. link to original article EuroPMC
## Update: Eskelund CW, Kolstad A, Jerkeman M, Räty R, Laurell A, Eloranta S, Smedby KE, Husby S, Pedersen LB, Andersen NS, Eriksson M, Kimby E, Bentzen H, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Ehinger M, Sundström C, Delabie J, Karjalainen-Lindsberg ML, Workman CT, Garde C, Elonen E, Brown P, Grønbaek K, Geisler CH. 15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016 Nov;175(3):410-418. Epub 2016 Jul 5. link to original article EuroPMC
==R-CODOX-M/R-IVAC==
R-CODOX-M/R-IVAC: Rituximab, Cyclophosphamide, Oncovin (Vincristine), DOXorubicin, Methotrexate alternating with Rituximab, Ifosfamide, Vepesid (etoposide), Ara-C (Cytarabine)
R-MACLO/R-IVAM: Rituximab, MTX (Methotrexate), Adriamycin (Doxorubicin), Cyclophosphamide, Leucovorin (Folinic acid), Oncovin (Vincristine) alternating with Rituximab, Ifosfamide, VP-16 (Etoposide), Ara-C (Cytarabine), Mesna
===Regimen variant #1===
Study 	Dates of enrollment	Evidence
Lossos et al. 2010 (UM-MCL1)	2004-2013 	Phase 2
====Targeted therapy, both portions (cycles 1 to 4)====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy, R-CODOX-M portion (cycles 1 & 3)====
*Doxorubicin (Adriamycin) 45 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 800 mg/m2 IV once on day 1, then 200 mg/m2 IV once per day on days 2 to 5
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1 & 8
*Methotrexate (MTX) 1200 mg/m2 IV over 60 minutes once on day 10, then 5520 mg/m2 IV continuous infusion over 23 hours (total dose per cycle: 6720 mg/m2)
====Supportive therapy, R-CODOX-M portion (cycles 1 & 3)====
*Leucovorin (Folinic acid) 180 mg/m2 IV once 12 hours after methotrexate is complete, then 12 mg/m2 IV every 6 hours for at least 10 doses or until serum methotrexate level is less than 50 nmol/L
*G-CSF given starting on day 13, continued until ANC greater than 1500/μL for two consecutive days
====Chemotherapy, R-IVAC portion (cycles 2 & 4)====
*Cytarabine (Ara-C) 2000 mg/m2 IV every 12 hours on days 1 & 2 (total dose per cycle: 8000 mg/m2)
*Etoposide (Vepesid) 60 mg/m2 IV once per day on days 1 to 5
*Ifosfamide (Ifex) 1500 mg/m2 IV once per day on days 1 to 5
====Supportive therapy, R-IVAC portion (cycles 2 & 4)====
*Mesna (Mesnex) 360 mg/m2 IV every 3 hours on days 1 to 5, starting prior to ifosfamide (total dose per cycle: 14,400 mg/m2)
*G-CSF starting on day 7, continued until ANC greater than 1500/μL for two consecutive days
4 cycles; cycles 2 & 4 start after count recovery, and cycle 3 begins after count recovery + 2 weeks
====Subsequent treatment====
*UM-MCL1, patients achieving a CR: Thalidomide maintenance
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Lossos et al. 2010 (UM-MCL2)	2004-2013 	Phase 2
Note: The only difference between this protocol and protocol #1 above is the dose of the MTX and the maintenance portion. It is unclear from the text whether the total dose of MTX is reduced to 3000 mg/m2 or if the 23 hour infusional portion is reduced to 3000 mg/m2.
====Targeted therapy, both portions (cycles 1 to 4)====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy, R-CODOX-M portion (cycles 1 & 3)====
*Doxorubicin (Adriamycin) 45 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 800 mg/m2 IV once on day 1, then 200 mg/m2 IV once per day on days 2 to 5
*Vincristine (Oncovin) 1.5 mg/m2 (maximum dose of 2 mg) IV once per day on days 1 & 8
*Methotrexate (MTX) 1200 mg/m2 IV over 60 minutes once on day 10, then 3000 mg/m2 IV continuous infusion over 23 hours (total dose per cycle: 4200 mg/m2)
====Supportive therapy, R-CODOX-M portion (cycles 1 & 3)====
*Leucovorin (Folinic acid) 180 mg/m2 IV once 12 hours after methotrexate is complete, then 12 mg/m2 IV every 6 hours for at least 10 doses or until serum methotrexate level is less than 50 nmol/L
*G-CSF given starting on day 13, continued until ANC greater than 1500/μL for two consecutive days
====Chemotherapy, R-IVAC portion (cycles 2 & 4)====
*Cytarabine (Ara-C) 2000 mg/m2 IV every 12 hours on days 1 & 2 (total dose per cycle: 8000 mg/m2)
*Etoposide (Vepesid) 60 mg/m2 IV once per day on days 1 to 5
*Ifosfamide (Ifex) 1500 mg/m2 IV once per day on days 1 to 5
====Supportive therapy, R-IVAC portion (cycles 2 & 4)====
*G-CSF given starting on day 7, continued until ANC greater than 1500/μL for two consecutive days
*Mesna (Mesnex) 360 mg/m2 IV every 3 hours on days 1 to 5, starting prior to ifosfamide (total dose per cycle: 14,400 mg/m2)
Total of 4 cycles, with next cycle to start after count recovery + 2 weeks
====Subsequent treatment====
*UM-MCL2, patients achieving a CR: Rituximab maintenance
===References===
# UM-MCL1: Lossos IS, Hosein PJ, Morgensztern D, Coleman F, Escalón MP, Byrne GE Jr, Rosenblatt JD, Walker GR. High rate and prolonged duration of complete remissions induced by rituximab, methotrexate, doxorubicin, cyclophosphamide, vincristine, ifosfamide, etoposide, cytarabine, and thalidomide (R-MACLO-IVAM-T), a modification of the National Cancer Institute 89-C-41 regimen, in patients with newly diagnosed mantle cell lymphoma. Leuk Lymphoma. 2010 Mar;51(3):406-14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00450801
## Update: Hosein PJ, Sandoval-Sus JD, Goodman D, Arteaga AG, Reis I, Hoffman J, Stefanovic A, Rosenblatt JD, Lossos IS. Updated survival analysis of two sequential prospective trials of R-MACLO-IVAM followed by maintenance for newly diagnosed mantle cell lymphoma. Am J Hematol. 2015 Jun;90(6):E111-6. Epub 2015 Apr 2. link to original article link to PMC article EuroPMC
# UM-MCL2: Lossos IS, Hosein PJ, Morgensztern D, Coleman F, Escalón MP, Byrne GE Jr, Rosenblatt JD, Walker GR. High rate and prolonged duration of complete remissions induced by rituximab, methotrexate, doxorubicin, cyclophosphamide, vincristine, ifosfamide, etoposide, cytarabine, and thalidomide (R-MACLO-IVAM-T), a modification of the National Cancer Institute 89-C-41 regimen, in patients with newly diagnosed mantle cell lymphoma. Leuk Lymphoma. 2010 Mar;51(3):406-14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00878254
## Update: Hosein PJ, Sandoval-Sus JD, Goodman D, Arteaga AG, Reis I, Hoffman J, Stefanovic A, Rosenblatt JD, Lossos IS. Updated survival analysis of two sequential prospective trials of R-MACLO-IVAM followed by maintenance for newly diagnosed mantle cell lymphoma. Am J Hematol. 2015 Jun;90(6):E111-6. Epub 2015 Apr 2. link to original article link to PMC article EuroPMC
==R-DHAC==
R-DHAC: Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Carboplatin
===Regimen===
Study 	Dates of enrollment	Evidence
Le Gouill et al. 2017 (LyMa)	2008-2012 	Non-randomized part of phase 3 RCT
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
====Preceding treatment====
*Pre-phase CVP x 1 (optional)
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg IV 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)
*Carboplatin (Paraplatin) AUC 5 IV once on day 1
21-day cycle for 4 cycles
====Subsequent treatment====
*LyMa, CR: R-BEAM with autologous HSCT consolidation
*LyMa, PR: R-CHOP-14 salvage x 4
===References===
# LyMa: Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, Damaj G, Gastinne T, Ribrag V, Feugier P, Casasnovas O, Zerazhi H, Haioun C, Maisonneuve H, Houot R, Jardin F, Van Den Neste E, Tournilhac O, Le Dû K, Morschhauser F, Cartron G, Fornecker LM, Canioni D, Callanan M, Béné MC, Salles G, Tilly H, Lamy T, Gressin R, Hermine O; LYSA. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017 Sep 28;377(13):1250-1260. link to original article link to protocol dosing details in supplement have been reviewed by our editors EuroPMC NCT00921414
==R-DHAOx==
R-DHAOx: Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Oxaliplatin
===Regimen===
Study 	Dates of enrollment	Evidence
Le Gouill et al. 2017 (LyMa)	2008-2012 	Non-randomized part of phase 3 RCT
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
====Preceding treatment====
*Pre-phase CVP x 1 (optional)
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg IV 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)
*Oxaliplatin (Eloxatin) 130 mg/m2 IV once on day 1
21-day cycle for 4 cycles
====Subsequent treatment====
*LyMa, CR: R-BEAM with autologous HSCT consolidation
*LyMa, PR: R-CHOP-14 salvage x 4
===References===
# LyMa: Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, Damaj G, Gastinne T, Ribrag V, Feugier P, Casasnovas O, Zerazhi H, Haioun C, Maisonneuve H, Houot R, Jardin F, Van Den Neste E, Tournilhac O, Le Dû K, Morschhauser F, Cartron G, Fornecker LM, Canioni D, Callanan M, Béné MC, Salles G, Tilly H, Lamy T, Gressin R, Hermine O; LYSA. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017 Sep 28;377(13):1250-1260. link to original article link to protocol dosing details in supplement have been reviewed by our editors EuroPMC NCT00921414
==R-DHAP==
R-DHAP: Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin)
===Regimen variant #1, 3 cycles===
Study 	Dates of enrollment	Evidence
Delarue et al. 2012	2000-2003 	Phase 2
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. The authors did not clearly specify the total dose/schedule of cytarabine; below is the dosing used in the NCIC-CTG LY.12 trial
====Preceding treatment====
*R-CHOP induction x 2 to 3 cycles
====Targeted therapy====
*Rituximab (Rituxan) 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 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
====CNS therapy, prophylaxis====
Intrathecal prophylaxis with the following was given per physician discretion; no timeframe or total number of doses is described:
*Methotrexate (MTX) 15 mg IT
*Cytarabine (Ara-C) 40 mg IT
*Corticosteroids
21-day cycle for 3 cycles
====Subsequent treatment====
*TAM6 with auto HSCT consolidation
===Regimen variant #2, 4 cycles===
Study 	Dates of enrollment	Evidence
Le Gouill et al. 2017 (LyMa)	2008-2012 	Non-randomized part of phase 3 RCT
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
====Preceding treatment====
*Pre-phase CVP x 1 (optional)
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg IV 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
21-day cycle for 4 cycles
====Subsequent treatment====
*LyMa, CR: R-BEAM with autologous HSCT consolidation
*LyMa, PR: R-CHOP-14 salvage x 4
===References===
# Case series: de Guibert S, Jaccard A, Bernard M, Turlure P, Bordessoule D, Lamy T. Rituximab and DHAP followed by intensive therapy with autologous stem-cell transplantation as first-line therapy for mantle cell lymphoma. Haematologica. 2006 Mar;91(3):425-6. link to original article does not contain dosing details EuroPMC
# Delarue R, Haioun C, Ribrag V, Brice P, Delmer A, Tilly H, Salles G, Van Hoof A, Casasnovas O, Brousse N, Lefrere F, Hermine O; Groupe d'Etude des Lymphomes de l'Adulte. CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d'Etude des Lymphomes de l'Adulte. Blood. 2013 Jan 3;121(1):48-53. Epub 2012 Jun 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# LyMa: Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, Damaj G, Gastinne T, Ribrag V, Feugier P, Casasnovas O, Zerazhi H, Haioun C, Maisonneuve H, Houot R, Jardin F, Van Den Neste E, Tournilhac O, Le Dû K, Morschhauser F, Cartron G, Fornecker LM, Canioni D, Callanan M, Béné MC, Salles G, Tilly H, Lamy T, Gressin R, Hermine O; LYSA. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017 Sep 28;377(13):1250-1260. link to original article link to protocol dosing details in supplement have been reviewed by our editors EuroPMC NCT00921414
==R-HiDAC==
R-HiDAC: Rituximab & High Dose Ara-C (Cytarabine)
===Regimen===
Study 	Dates of enrollment	Evidence
Van 't Veer et al. 2008 (HOVON 45)	2002-2005 	Phase 2
====Preceding treatment====
*R-CHOP induction x 3
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 11
====Chemotherapy====
*Cytarabine (Ara-C) 2000 mg/m2 IV every 12 hours on days 1 to 4 (total dose: 16,000 mg/m2)
11-day course
====Subsequent treatment====
*Stem cells were collected after this cycle with G-CSF given to "enhance" collection. Patients then proceeded to BEAM with autologous HSCT consolidation
===References===
# HOVON 45: Van 't Veer MB, de Jong D, MacKenzie M, Kluin-Nelemans HC, van Oers MH, Zijlstra J, Hagenbeek A, van Putten WL. High-dose Ara-C and BEAM with autograft rescue in R-CHOP responsive mantle cell lymphoma patients. Br J Haematol. 2009 Feb;144(4):524-30. Epub 2008 Nov 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==R-M-CHOP==
R-M-CHOP: Rituximab, MTX (Methotrexate), Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin, Prednisone
===Regimen===
Study 	Dates of enrollment	Evidence
Damon et al. 2009 (CALGB 59909)	2001-2004 	Phase 2
Note: this is the induction portion ("Treatments 1 & 2") of CALGB 59909. Median days between treatment 1 & 2 was 23 days, with a range of 16 to 41 days observed.
====Targeted therapy====
*Rituximab (Rituxan) by the following laboratory-based criteria:
**Circulating mantle cells up to 10,000 cells/μL: 375 mg/m2 IV once on day 1 
====Chemotherapy====
*Methotrexate (MTX) 300 mg/m2 IV over 4 hours once on day 2
*Cyclophosphamide (Cytoxan) 2000 mg/m2 IV over 2 hours once on day 3
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 3
*Vincristine (Oncovin) by the following age-based criteria:
**Up to 40 years old: 1.4 mg/m2 IV once on day 3
**Older than 40: 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 3
====Glucocorticoid therapy====
*Prednisone (Sterapred) 100 mg/m2 PO once per day on days 3 to 7
====CNS therapy====
If cerebrospinal fluid (CSF) contained disease with CSF WBC count more than or equal to 5 cells/μL:
*Methotrexate (MTX) 12 mg IT x 10 total doses during treatments 1 to 3; not given concurrently with intrathecal methotrexate or cytarabine
If CSF contained greater than 5 cells/μL: 
*In addition to intrathecal chemotherapy above, patient also received 200 cGy x 12 fractions (total dose 2400 cGy) cranial radiation 
====Supportive therapy====
*Leucovorin (Folinic acid) 50 mg/m2 IV every 6 hours for 3 doses, starting 24 hours after completion of methotrexate, then 10 mg/m2 IV or PO every 6 hours until serum methotrexate level less than 50 nmol/L
*Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 4, to continue until ANC greater than 10,000/μL once or greater than 5000/μL twice 
*Levofloxacin (Levaquin) 500 mg PO once per day, starting on day 6, to continue until ANC is greater than or equal to 1500/μL
*Fluconazole (Diflucan) 200 mg PO once per day, starting on day 6, to continue until ANC is greater than or equal to 1500/μL
2 cycles, with interval between cycle 1 & 2 based on count recovery
====Subsequent treatment====
*CALGB 59909, patients with less than or equal to 15% involvement by disease in bone marrow biopsy after cycle 2: EAR with stem cell mobilization, 4 weeks after treatment 2, if ANC greater than or equal to 1000/μL, platelets greater than or equal to 100 x 109/L, Cr less than 2 mg/dL, total bilirubin less than 2x upper limit of normal, and AST less than 3x upper limit of normal. 
*CALGB 59909, patients with bone marrow biopsy after treatment 2 with greater than 15% involvement by disease: repeat treatment 2 (identified as "treatment 2.5")
**Patients with greater than 15% bone marrow involvement by disease after treatment 2.5 were removed from protocol
===References===
# CALGB 59909: Damon LE, Johnson JL, Niedzwiecki D, Cheson BD, Hurd DD, Bartlett NL, Lacasce AS, Blum KA, Byrd JC, Kelly M, Stock W, Linker CA, Canellos GP. Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. J Clin Oncol. 2009 Dec 20;27(36):6101-8. Epub 2009 Nov 16. link to original article dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC NCT00020943
==RiPAD+C==
RiPAD+C: Rituximab, PS-341 (Bortezomib), Adriamycin (Doxorubicin), Dexamethasone, Chlorambucil
===Regimen===
Study 	Dates of enrollment	Evidence
Houot et al. 2011 (ManteauRiBVD)	2007-2008 	Phase 2
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days 1 & 8
**Cycles 2 to 6: 375 mg/m2 IV once on day 1
*Bortezomib (Velcade) 1.3 mg/m2 (route not specified) once per day on days 1, 4, 8, 11
====Chemotherapy====
*Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36 mg/m2)
*Chlorambucil (Leukeran) 12 mg PO once per day on days 20 to 29
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg (route not specified) twice per day on days 1 to 4
35-day cycle for up to 6 cycles
===References===
# ManteauRiBVD: Houot R, Le Gouill S, Ojeda Uribe M, Mounier C, Courby S, Dartigeas C, Bouabdallah K, Alexis Vigier M, Moles MP, Tournilhac O, Arakelyan N, Rodon P, El Yamani A, Sutton L, Fornecker L, Assouline D, Harousseau JL, Maisonneuve H, Caulet-Maugendre S, Gressin R; GOELAMS. Combination of rituximab, bortezomib, doxorubicin, dexamethasone and chlorambucil (RiPAD+C) as first-line therapy for elderly mantle cell lymphoma patients: results of a phase II trial from the GOELAMS. Ann Oncol. 2012 Jun;23(6):1555-61. Epub 2011 Oct 19. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00740415
==R-VAD+C==
R-VAD+C: Rituximab, Vincristine, Adriamycin (Doxorubicin), Dexamethasone, Chlorambucil
===Regimen===
Study 	Dates of enrollment	Evidence
Gressin et al. 2010 (GOELAMS LM2001)	2003-09 to 2005-12 	Phase 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*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)
*Doxorubicin (Adriamycin) 9 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 36 mg/m2)
*Chlorambucil (Leukeran) 12 mg PO once per day on days 20 to 29
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 20 mg IV or PO twice per day on days 1 to 4
35-day cycle for 4 to 8 cycles
====Subsequent treatment====
*GOELAMS LM2001, transplant-eligible patients with more than partial response after 4 cycles: High-dose melphalan & TBI, then autologous HSCT consolidation, 4 weeks after the 6th cycle
===References===
# GOELAMS LM2001: Gressin R, Caulet-Maugendre S, Deconinck E, Tournilhac O, Gyan E, Moles MP, El Yamani A, Cornillon J, Rossi JF, Le Gouill S, Lepeu G, Damaj G, Celigny PS, Maisonneuve H, Corront B, Vilque JP, Casassus P, Lamy T, Colonna M, Colombat P; GOELAMS. Evaluation of the (R)VAD+C regimen for the treatment of newly diagnosed mantle cell lymphoma: combined results of two prospective phase II trials from the French GOELAMS Group. Haematologica. 2010 Aug;95(8):1350-7. Epub 2010 Mar 10. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00285389
==Rituximab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Ghielmini et al. 2004 (SAKK 35/98MCL)	1998-2002 	Non-randomized part of phase 3 RCT
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
7-day cycle for 4 cycles
====Subsequent treatment====
*Rituximab maintenance versus no further treatment
===References===
# SAKK 35/98MCL: Ghielmini M, Schmitz SF, Cogliatti S, Bertoni F, Waltzer U, Fey MF, Betticher DC, Schefer H, Pichert G, Stahel R, Ketterer N, Bargetzi M, Cerny T; Swiss Group for Clinical Cancer Research. Effect of single-agent rituximab given at the standard schedule or as prolonged treatment in patients with mantle cell lymphoma: a study of the Swiss Group for Clinical Cancer Research (SAKK). J Clin Oncol. 2005 Feb 1;23(4):705-11. Epub 2004 Dec 14. link to original article EuroPMC NCT00003280
==VcR-CVAD==
VcR-CVAD: Velcade (Bortezomib), Rituximab, Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone
===Regimen===
Study 	Dates of enrollment 	Evidence
Chang et al. 2011 	2005-2008 	Phase 2
Chang et al. 2014 (ECOG E1405)	2007 to not reported	Phase 2
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1 & 4
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 3 hours every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m2)
*Vincristine (Oncovin) 1 mg IV once on day 3
*Doxorubicin (Adriamycin) 50 mg/m2/day IV continuous infusion over 48 hours, started on day 1 (total dose per cycle: 100 mg/m2)
====Glucocorticoid therapy====
*Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
====Supportive therapy====
*Mesna (Mesnex) dose not specified Chang et al. 2011; not mentioned in Chang et al. 2014
*Growth factor support with one of the following:
**Filgrastim (Neupogen) 5 mcg/kg SC once per day, started on day 5 or 6 and continued until absolute neutrophil count was at least 2000/μL past nadir
**Pegfilgrastim (Neulasta) 6 mg SC once on day 5 or 6
21-day cycle for 6 cycles
====Subsequent treatment====
*ECOG E1405, at least PR: Rituximab maintenance or high-dose therapy with autologous HSCT (regimen not specified) consolidation, patient choice
===References===
# Chang JE, Peterson C, Choi S, Eickhoff JC, Kim K, Yang DT, Gilbert LA, Rogers ES, Werndli JE, Huie MS, McFarland TA, Volk M, Blank J, Callander NS, Longo WL, Kahl BS; Wisconsin Oncology Network. VcR-CVAD induction chemotherapy followed by maintenance rituximab in mantle cell lymphoma: a Wisconsin Oncology Network study. Br J Haematol. 2011 Oct;155(2):190-7. Epub 2011 Aug 16. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# ECOG E1405: Chang JE, Li H, Smith MR, Gascoyne RD, Paietta EM, Yang DT, Advani RH, Horning SJ, Kahl BS. Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405). Blood. 2014 Mar 13;123(11):1665-73. Epub 2014 Jan 23. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00433537
==VR-CHOP==
VR-CHOP: Velcade (Bortezomib), Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne
===Regimen===
Study 	Dates of enrollment	Evidence
Ruan et al. 2010 (Cornell 0309006313)	2004-2007 	Phase 2
Till et al. 2015 (SWOG S0601) 	2006-2008 	Phase 2
Note: Doses here are the phase II dose of bortezomib and the R-CHOP protocol as specified in the phase I report by Furman et al. 2010
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1 & 4, given first on day 1
*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====
*Acetaminophen (Tylenol) (dose/route not specified) once on day 1, prior to rituximab
*Diphenhydramine (Benadryl) (dose/route not specified) once on day 1, prior to rituximab
21-day cycle for 6 cycles
====Subsequent treatment====
*SWOG S0601: Bortezomib maintenance
===References===
# Cornell 0309006313: Ruan J, Martin P, Furman RR, Lee SM, Cheung K, Vose JM, Lacasce A, Morrison J, Elstrom R, Ely S, Chadburn A, Cesarman E, Coleman M, Leonard JP. Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. J Clin Oncol. 2011 Feb 20;29(6):690-7. Epub 2010 Dec 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00151320
# SWOG S0601: Till BG, Li H, Bernstein SH, Fisher RI, Burack WR, Rimsza LM, Floyd JD, DaSilva MA, Moore DF Jr, Pozdnyakova O, Smith SM, LeBlanc M, Friedberg JW. Phase II trial of R-CHOP plus bortezomib induction therapy followed by bortezomib maintenance for newly diagnosed mantle cell lymphoma: SWOG S0601. Br J Haematol. 2016 Jan;172(2):208-18. Epub 2015 Oct 22. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00376961
==Watchful waiting==
===Regimen===
Study 	Dates of enrollment	Evidence
Martin et al. 2009	1997-2007 	Retrospective
Cohen et al. 2016 	2004-2011 	Retrospective
===References===
# Retrospective: Martin P, Chadburn A, Christos P, Weil K, Furman RR, Ruan J, Elstrom R, Niesvizky R, Ely S, Diliberto M, Melnick A, Knowles DM, Chen-Kiang S, Coleman M, Leonard JP. Outcome of deferred initial therapy in mantle-cell lymphoma. J Clin Oncol. 2009 Mar 10;27(8):1209-13. Epub 2009 Feb 2. link to original article EuroPMC
# Retrospective: Cohen JB, Han X, Jemal A, Ward EM, Flowers CR. Deferred therapy is associated with improved overall survival in patients with newly diagnosed mantle cell lymphoma. Cancer. 2016 Aug 1;122(15):2356-63. Epub 2016 May 6. link to original article EuroPMC
</div>
=Consolidation after first-line therapy=
==BEAC, then auto HSCT==
BEAC: Rituximab, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Cyclophosphamide
===Regimen===
Study 	Dates of enrollment	Evidence
Geisler et al. 2008 (NLG MCL2)	2000-2006 	Phase 2
====Preceding treatment====
*maxi-R-CHOP/R-HiDAC induction x 6 to 8
===References===
# NLG MCL2: Geisler CH, Kolstad A, Laurell A, Andersen NS, Pedersen LB, Jerkeman M, Eriksson M, Nordström M, Kimby E, Boesen AM, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Akerman M, Ehinger M, Sundström C, Langholm R, Delabie J, Karjalainen-Lindsberg ML, Brown P, Elonen E; Nordic Lymphoma Group. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008 Oct 1;112(7):2687-93. Epub 2008 Jul 14. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN87866680
## Update: Geisler CH, Kolstad A, Laurell A, Jerkeman M, Räty R, Andersen NS, Pedersen LB, Eriksson M, Nordström M, Kimby E, Bentzen H, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Ehinger M, Sundström C, Delabie J, Karjalainen-Lindsberg ML, Brown P, Elonen E; Nordic Lymphoma Group. Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem-cell support: still very long survival but late relapses do occur. Br J Haematol. 2012 Aug;158(3):355-62. Epub 2012 May 29. Erratum in: Br J Haematol. 2012 Sep;158(6):815-6. link to original article EuroPMC
## Update: Eskelund CW, Kolstad A, Jerkeman M, Räty R, Laurell A, Eloranta S, Smedby KE, Husby S, Pedersen LB, Andersen NS, Eriksson M, Kimby E, Bentzen H, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Ehinger M, Sundström C, Delabie J, Karjalainen-Lindsberg ML, Workman CT, Garde C, Elonen E, Brown P, Grønbaek K, Geisler CH. 15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016 Nov;175(3):410-418. Epub 2016 Jul 5. link to original article EuroPMC
==BEAM, then auto HSCT==
BEAM: Rituximab, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan
===Regimen variant #1===
Study 	Dates of enrollment	Evidence
Geisler et al. 2008 (NLG MCL2)	2000-2006 	Phase 2
====Preceding treatment====
*maxi-R-CHOP/R-HiDAC induction x 6 to 8
===Regimen variant #2===
Study 	Dates of enrollment	Evidence
Van 't Veer et al. 2008 (HOVON 45)	2002-2005 	Phase 2
====Preceding treatment====
*R-CHOP induction x 3, then R-HiDAC consolidation x 1
===References===
# NLG MCL2: Geisler CH, Kolstad A, Laurell A, Andersen NS, Pedersen LB, Jerkeman M, Eriksson M, Nordström M, Kimby E, Boesen AM, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Akerman M, Ehinger M, Sundström C, Langholm R, Delabie J, Karjalainen-Lindsberg ML, Brown P, Elonen E; Nordic Lymphoma Group. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008 Oct 1;112(7):2687-93. Epub 2008 Jul 14. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN87866680
## Update: Geisler CH, Kolstad A, Laurell A, Jerkeman M, Räty R, Andersen NS, Pedersen LB, Eriksson M, Nordström M, Kimby E, Bentzen H, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Ehinger M, Sundström C, Delabie J, Karjalainen-Lindsberg ML, Brown P, Elonen E; Nordic Lymphoma Group. Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem-cell support: still very long survival but late relapses do occur. Br J Haematol. 2012 Aug;158(3):355-62. Epub 2012 May 29. Erratum in: Br J Haematol. 2012 Sep;158(6):815-6. link to original article EuroPMC
## Update: Eskelund CW, Kolstad A, Jerkeman M, Räty R, Laurell A, Eloranta S, Smedby KE, Husby S, Pedersen LB, Andersen NS, Eriksson M, Kimby E, Bentzen H, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Ehinger M, Sundström C, Delabie J, Karjalainen-Lindsberg ML, Workman CT, Garde C, Elonen E, Brown P, Grønbaek K, Geisler CH. 15-year follow-up of the Second Nordic Mantle Cell Lymphoma trial (MCL2): prolonged remissions without survival plateau. Br J Haematol. 2016 Nov;175(3):410-418. Epub 2016 Jul 5. link to original article EuroPMC
# HOVON 45: Van 't Veer MB, de Jong D, MacKenzie M, Kluin-Nelemans HC, van Oers MH, Zijlstra J, Hagenbeek A, van Putten WL. High-dose Ara-C and BEAM with autograft rescue in R-CHOP responsive mantle cell lymphoma patients. Br J Haematol. 2009 Feb;144(4):524-30. Epub 2008 Nov 26. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# SWOG S1106: Chen RW, Li H, Bernstein SH, Kahwash S, Rimsza LM, Forman SJ, Constine L, Shea TC, Cashen AF, Blum KA, Fenske TS, Barr PM, Phillips T, Leblanc M, Fisher RI, Cheson BD, Smith SM, Faham M, Wilkins J, Leonard JP, Kahl BS, Friedberg JW. RB but not R-HCVAD is a feasible induction regimen prior to auto-HCT in frontline MCL: results of SWOG Study S1106. Br J Haematol. 2017 Mar;176(5):759-769. Epub 2016 Dec 19. link to original article link to PMC article does not contain dosing details EuroPMC NCT01412879
## Update: Kamdar M, Li H, Chen RW, Rimsza LM, Leblanc ML, Fenske TS, Shea TC, Barr PM, Phillips TJ, Leonard JP, Kahl BS, Friedberg JW, Smith SM. Five-year outcomes of the S1106 study of R-hyper-CVAD vs R-bendamustine in transplant-eligible patients with mantle cell lymphoma. Blood Adv. 2019 Oct 22;3(20):3132-3135. link to original article link to PMC article EuroPMC
==CBV, then auto HSCT==
CBV: Cyclophosphamide, BiCNU (Carmustine), VP-16 (Etoposide)
===Regimen===
Study 	Dates of enrollment	Evidence
Damon et al. 2009 (CALGB 59909)	2001-2004 	Phase 2
Note: this is the transplant portion ("Treatment 4") of CALGB 59909.
====Preceding treatment====
*EAR with stem cell mobilization
====Subsequent treatment====
*Rituximab (Rituxan) consolidation: 375 mg/m2 IV once per day on days +42 and +49
===References===
# CALGB 59909: Damon LE, Johnson JL, Niedzwiecki D, Cheson BD, Hurd DD, Bartlett NL, Lacasce AS, Blum KA, Byrd JC, Kelly M, Stock W, Linker CA, Canellos GP. Immunochemotherapy and autologous stem-cell transplantation for untreated patients with mantle-cell lymphoma: CALGB 59909. J Clin Oncol. 2009 Dec 20;27(36):6101-8. Epub 2009 Nov 16. link to original article dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC NCT00020943
# SWOG S1106: Chen RW, Li H, Bernstein SH, Kahwash S, Rimsza LM, Forman SJ, Constine L, Shea TC, Cashen AF, Blum KA, Fenske TS, Barr PM, Phillips T, Leblanc M, Fisher RI, Cheson BD, Smith SM, Faham M, Wilkins J, Leonard JP, Kahl BS, Friedberg JW. RB but not R-HCVAD is a feasible induction regimen prior to auto-HCT in frontline MCL: results of SWOG Study S1106. Br J Haematol. 2017 Mar;176(5):759-769. Epub 2016 Dec 19. link to original article link to PMC article does not contain dosing details EuroPMC NCT01412879
## Update: Kamdar M, Li H, Chen RW, Rimsza LM, Leblanc ML, Fenske TS, Shea TC, Barr PM, Phillips TJ, Leonard JP, Kahl BS, Friedberg JW, Smith SM. Five-year outcomes of the S1106 study of R-hyper-CVAD vs R-bendamustine in transplant-eligible patients with mantle cell lymphoma. Blood Adv. 2019 Oct 22;3(20):3132-3135. link to original article link to PMC article EuroPMC
==Cyclophosphamide & TBI, then auto HSCT==
CY/TBI: CYclophosphamide & Total Body Irradiation
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Dreyling et al. 2004	1996-2004 	Phase 3 (E-esc)	Interferon alfa	Seems to have longer PFS (primary endpoint)Seems to have longer OS1 (secondary endpoint)Median OS: 7.5 vs 4.8 yrs(HR 0.66, 95% CI 0.46-0.95)
1Reported efficacy is based on the 2021 update; note that this study was conducted in the pre-rituximab era.
====Preceding treatment====
*CHOP-like chemotherapy induction x 4 to 6, then Dexa-BEAM & G-CSF mobilization
===References===
# Dreyling M, Lenz G, Hoster E, Van Hoof A, Gisselbrecht C, Schmits R, Metzner B, Truemper L, Reiser M, Steinhauer H, Boiron JM, Boogaerts MA, Aldaoud A, Silingardi V, Kluin-Nelemans HC, Hasford J, Parwaresch R, Unterhalt M, Hiddemann W. Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL Network. Blood. 2005 Apr 1;105(7):2677-84. Epub 2004 Dec 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Zoellner AK, Unterhalt M, Stilgenbauer S, Hübel K, Thieblemont C, Metzner B, Topp M, Truemper L, Schmidt C, Bouabdallah K, Krauter J, Lenz G, Dürig J, Vergote V, Schäfer-Eckart K, André M, Kluin-Nelemans HC, van Hoof A, Klapper W, Hiddemann W, Dreyling M, Hoster E; European Mantle Cell Lymphoma Network. Long-term survival of patients with mantle cell lymphoma after autologous haematopoietic stem-cell transplantation in first remission: a post-hoc analysis of an open-label, multicentre, randomised, phase 3 trial. Lancet Haematol. 2021 Sep;8(9):e648-e657. link to original article EuroPMC
==Ibritumomab tiuxetan protocol==
===Regimen===
Study 	Dates of enrollment	Evidence
Smith et al. 2012 (ECOG E1499)	2003-2005 	Phase 2
====Preceding treatment====
*R-CHOP induction x 4
====Targeted therapy====
*Rituximab (Rituxan) 250 mg/m2 IV once per day on days 1 & 8, given first on day 8
====Radioconjugate therapy====
*Ibritumomab tiuxetan & Yttrium-90 (Zevalin) by the following laboratory-based criteria:
**Platelet count 150 x 109/L or more: 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day 8, given second
**Platelet count 100 to 149 x 109/L: 0.3 mCi/kg (maximum dose of 32 mCi) IV once on day 8, given second
8-day course
===References===
# ECOG E1499: Smith MR, Li H, Gordon L, Gascoyne RD, Paietta E, Forero-Torres A, Kahl BS, Advani R, Hong F, Horning SJ. Phase II study of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy followed by yttrium-90-ibritumomab tiuxetan in untreated mantle-cell lymphoma: Eastern Cooperative Oncology Group Study E1499. J Clin Oncol. 2012 Sep 1;30(25):3119-26. Epub 2012 Jul 30. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00070447
## Update: Smith MR, Hong F, Li H, Gordon LI, Gascoyne RD, Paietta EM, Advani RH, Forero-Torres A, Horning SJ, Kahl BS. Mantle cell lymphoma initial therapy with abbreviated R-CHOP followed by (90)Y-ibritumomab tiuxetan: 10-year follow-up of the phase 2 ECOG-ACRIN study E1499. Leukemia. 2017 Feb;31(2):517-519. Epub 2016 Oct 26. link to original article link to PMC article EuroPMC
==Melphalan & TBI, then auto HSCT==
Melphalan & TBI: Melphalan & Total Body Irradiation
===Regimen===
Study 	Dates of enrollment	Evidence
Gressin et al. 2010 (GOELAMS LM1996)	1996-09 to 2000-12 	Phase 2
Gressin et al. 2010 (GOELAMS LM2001)	2003-09 to 2005-12 	Phase 2
====Preceding treatment====
*GOELAMS LM1996: Induction VAD+C x 6
*GOELAMS LM2001: Induction R-VAD+C x 6
===References===
# GOELAMS LM1996: Gressin R, Caulet-Maugendre S, Deconinck E, Tournilhac O, Gyan E, Moles MP, El Yamani A, Cornillon J, Rossi JF, Le Gouill S, Lepeu G, Damaj G, Celigny PS, Maisonneuve H, Corront B, Vilque JP, Casassus P, Lamy T, Colonna M, Colombat P; GOELAMS. Evaluation of the (R)VAD+C regimen for the treatment of newly diagnosed mantle cell lymphoma: combined results of two prospective phase II trials from the French GOELAMS Group. Haematologica. 2010 Aug;95(8):1350-7. Epub 2010 Mar 10. link to original article link to PMC article contains partial protocol EuroPMC
# GOELAMS LM2001: Gressin R, Caulet-Maugendre S, Deconinck E, Tournilhac O, Gyan E, Moles MP, El Yamani A, Cornillon J, Rossi JF, Le Gouill S, Lepeu G, Damaj G, Celigny PS, Maisonneuve H, Corront B, Vilque JP, Casassus P, Lamy T, Colonna M, Colombat P; GOELAMS. Evaluation of the (R)VAD+C regimen for the treatment of newly diagnosed mantle cell lymphoma: combined results of two prospective phase II trials from the French GOELAMS Group. Haematologica. 2010 Aug;95(8):1350-7. Epub 2010 Mar 10. link to original article link to PMC article contains partial protocol EuroPMC NCT00285389
==R-BEAM, then auto HSCT==
R-BEAM: Rituximab, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan
===Regimen===
Study 	Dates of enrollment	Evidence
Le Gouill et al. 2017 (LyMa)	2008-2012 	Non-randomized part of phase 3 RCT
====Preceding treatment====
*LyMa, CR: Induction R-DHAC x 4 or R-DHAOx x 4 or R-DHAP x 4
*LyMa, PR: Induction R-DHAC x 4 or R-DHAOx x 4 or R-DHAP x 4, then salvage R-CHOP-14 x 4
====Subsequent treatment====
*Observation versus rituximab maintenance
===References===
# LyMa: Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, Damaj G, Gastinne T, Ribrag V, Feugier P, Casasnovas O, Zerazhi H, Haioun C, Maisonneuve H, Houot R, Jardin F, Van Den Neste E, Tournilhac O, Le Dû K, Morschhauser F, Cartron G, Fornecker LM, Canioni D, Callanan M, Béné MC, Salles G, Tilly H, Lamy T, Gressin R, Hermine O; LYSA. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017 Sep 28;377(13):1250-1260. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00921414
==TAM6, then auto HSCT==
TAM: Total-body irradiation, Ara-C (Cytarabine), Melphalan
===Regimen===
Study 	Dates of enrollment	Evidence
Delarue et al. 2012	2000-2003 	Phase 2
====Preceding treatment====
*R-DHAP induction x 3
===References===
# Delarue R, Haioun C, Ribrag V, Brice P, Delmer A, Tilly H, Salles G, Van Hoof A, Casasnovas O, Brousse N, Lefrere F, Hermine O; Groupe d'Etude des Lymphomes de l'Adulte. CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d'Etude des Lymphomes de l'Adulte. Blood. 2013 Jan 3;121(1):48-53. Epub 2012 Jun 20. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=Maintenance after first-line therapy=
==Bortezomib monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Till et al. 2015 (SWOG S0601)	2006-2008 	Phase 2
====Preceding treatment====
*VR-CHOP induction x 6
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
3-month cycle for 8 cycles (2 years) 
===References===
# SWOG S0601: Till BG, Li H, Bernstein SH, Fisher RI, Burack WR, Rimsza LM, Floyd JD, DaSilva MA, Moore DF Jr, Pozdnyakova O, Smith SM, LeBlanc M, Friedberg JW. Phase II trial of R-CHOP plus bortezomib induction therapy followed by bortezomib maintenance for newly diagnosed mantle cell lymphoma: SWOG S0601. Br J Haematol. 2016 Jan;172(2):208-18. Epub 2015 Oct 22. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00376961
==Lenalidomide monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Ladetto et al. 2020 (MCL0208)	2010-2015 	Phase 3 (E-esc)	Observation	Longer PFS (primary endpoint)PFS36: 80% vs 64%(HR 0.51, 95% CI 0.30-0.87)
====Preceding treatment====
*BEAM, then auto HSCT consolidation
====Targeted therapy====
*Lenalidomide (Revlimid) by the following laboratory-based criteria:
**Platelet count 60 to 100 x 109/L: 10 mg PO once per day on days 1 to 21
**Platelet count more than 100 x 109/L: 15 mg PO once per day on days 1 to 21
28-day cycle for 26 cycles (2 years)
===References===
#MCL0208: Ladetto M, Cortelazzo S, Ferrero S, Evangelista A, Mian M, Tavarozzi R, Zanni M, Cavallo F, Di Rocco A, Stefoni V, Pagani C, Re A, Chiappella A, Balzarotti M, Zilioli VR, Gomes da Silva M, Arcaini L, Molinari AL, Ballerini F, Ferreri AJM, Puccini B, Benedetti F, Stefani PM, Narni F, Casaroli I, Stelitano C, Ciccone G, Vitolo U, Martelli M; Fondazione Italiana Linfomi. Lenalidomide maintenance after autologous haematopoietic stem-cell transplantation in mantle cell lymphoma: results of a Fondazione Italiana Linfomi (FIL) multicentre, randomised, phase 3 trial. Lancet Haematol. 2021 Jan;8(1):e34-e44. Epub 2020 Dec 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02354313
==Lenalidomide & Rituximab (R2)==
===Regimen===
Study 	Dates of enrollment	Evidence
Ruan et al. 2015 (Cornell 1103011566)	2011-2014 	Phase 2
====Preceding treatment====
*Lenalidomide & Rituximab induction
====Targeted therapy====
*Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21 
*Rituximab (Rituxan) as follows:
**Odd cycles: 375 mg/m2 IV once on day 1
28-day cycles
===References===
# Cornell 1103011566: Ruan J, Martin P, Shah B, Schuster SJ, Smith SM, Furman RR, Christos P, Rodriguez A, Svoboda J, Lewis J, Katz O, Coleman M, Leonard JP. Lenalidomide plus rituximab as initial treatment for mantle-cell lymphoma. N Engl J Med. 2015 Nov 5;373(19):1835-44. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01472562
## Update: Ruan J, Martin P, Christos P, Cerchietti L, Tam W, Shah B, Schuster SJ, Rodriguez A, Hyman D, Calvo-Vidal MN, Smith SM, Svoboda J, Furman RR, Coleman M, Leonard JP. Five-year follow-up of lenalidomide plus rituximab as initial treatment of mantle cell lymphoma. Blood. 2018 Nov 8;132(19):2016-2025. Epub 2018 Sep 4. link to original article link to PMC article EuroPMC
==Rituximab monotherapy==
===Regimen variant #1, 6 doses===
Study 	Dates of enrollment	Evidence
Sachanas et al. 2011	2004-06 to 2008-08 	Phase 2
====Preceding treatment====
*Chlorambucil & Rituximab induction x 12
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
2-month cycle for 6 cycles (1 year)
===Regimen variant #2, 12 doses===
Study 	Dates of enrollment	Evidence
Räty et al. 2012	2004-12 to 2010-08 	Phase 2
====Preceding treatment====
*Induction chemotherapy x 10, with CR/PR
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
2-month cycle for 12 cycles (2 years)
===Regimen variant #3, 16 doses===
Study 	Dates of enrollment 	Evidence
Chang et al. 2014 (ECOG E1405)	2007 to not reported	Phase 2
====Preceding treatment====
*VcR-CVAD induction x 6
====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)
===Regimen variant #4, 18 doses===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Le Gouill et al. 2017 (LyMa)	2008-2012 	Phase 3 (E-esc)	Observation	Longer EFS1 (primary endpoint)Median EFS: 5.8 vs NYR years(HR 0.39, 95% CI 0.52-0.60)Did not meet secondary endpoint of OS1OS84: 83.2% vs 72.2%(HR 0.63, 95% CI 0.37-1.08)
1Reported efficacy is based on the 2024 update.
====Preceding treatment====
*R-BEAM with autologous HSCT consolidation
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
2-month cycle for 18 cycles (3 years)
===Regimen variant #5, 24 doses===
Study 	Dates of enrollment	Evidence
Lossos et al. 2010 (UM-MCL2)	2004-2013 	Phase 2
====Preceding treatment====
*R-MACLO/R-IVAM induction x 4
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
6-month cycle for 6 cycles (3 years)
===Regimen variant #6, indefinite===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Kluin-Nelemans et al. 2012 (MCLelderly)	2004-2010 	Phase 3 (E-switch-ooc)	Interferon alfa	Longer combined OS1 (secondary endpoint)
1Superiority was only demonstrated in the group of patients who got R-CHOP first; overall, there was no statistically significant survival difference between the two maintenance groups.
====Preceding treatment====
*R-CHOP x 8 versus R-FC induction x 6
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
2-month cycles
===References===
# UM-MCL2: Lossos IS, Hosein PJ, Morgensztern D, Coleman F, Escalón MP, Byrne GE Jr, Rosenblatt JD, Walker GR. High rate and prolonged duration of complete remissions induced by rituximab, methotrexate, doxorubicin, cyclophosphamide, vincristine, ifosfamide, etoposide, cytarabine, and thalidomide (R-MACLO-IVAM-T), a modification of the National Cancer Institute 89-C-41 regimen, in patients with newly diagnosed mantle cell lymphoma. Leuk Lymphoma. 2010 Mar;51(3):406-14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00878254
## Update: Hosein PJ, Sandoval-Sus JD, Goodman D, Arteaga AG, Reis I, Hoffman J, Stefanovic A, Rosenblatt JD, Lossos IS. Updated survival analysis of two sequential prospective trials of R-MACLO-IVAM followed by maintenance for newly diagnosed mantle cell lymphoma. Am J Hematol. 2015 Jun;90(6):E111-6. Epub 2015 Apr 2. link to original article link to PMC article EuroPMC
# Sachanas S, Pangalis GA, Vassilakopoulos TP, Korkolopoulou P, Kontopidou FN, Athanasoulia M, Yiakoumis X, Kalpadakis C, Georgiou G, Masouridis S, Moschogiannis M, Tsirkinidis P, Pappis V, Kokoris SI, Siakantaris MP, Panayiotidis P, Angelopoulou MK. Combination of rituximab with chlorambucil as first line treatment in patients with mantle cell lymphoma: a highly effective regimen. Leuk Lymphoma. 2011 Mar;52(3):387-93. Epub 2010 Dec 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# MCLelderly: Kluin-Nelemans HC, Hoster E, Hermine O, Walewski J, Trneny M, Geisler CH, Stilgenbauer S, Thieblemont C, Vehling-Kaiser U, Doorduijn JK, Coiffier B, Forstpointner R, Tilly H, Kanz L, Feugier P, Szymczyk M, Hallek M, Kremers S, Lepeu G, Sanhes L, Zijlstra JM, Bouabdallah R, Lugtenburg PJ, Macro M, Pfreundschuh M, Procházka V, Di Raimondo F, Ribrag V, Uppenkamp M, André M, Klapper W, Hiddemann W, Unterhalt M, Dreyling MH. Treatment of older patients with mantle-cell lymphoma. N Engl J Med. 2012 Aug 9;367(6):520-31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00209209
## Update: Kluin-Nelemans HC, Hoster E, Hermine O, Walewski J, Geisler CH, Trneny M, Stilgenbauer S, Kaiser F, Doorduijn JK, Salles G, Szymczyk M, Tilly H, Kanz L, Schmidt C, Feugier P, Thieblemont C, Zijlstra JM, Ribrag V, Klapper W, Pott C, Unterhalt M, Dreyling MH. Treatment of Older Patients With Mantle Cell Lymphoma (MCL): Long-Term Follow-Up of the Randomized European MCL Elderly Trial. J Clin Oncol. 2020 Jan 20;38(3):248-256. Epub 2019 Dec 5. link to original article EuroPMC
# Räty R, Honkanen T, Jantunen E, Jyrkkiö S, Karjalainen-Lindsberg ML, Kuittinen O, Lehto M, Mikkola M, Poikonen E, Rauhala A, Rimpiläinen J, Räsänen A, Siitonen S, Suominen M, Vapaatalo M, Elonen E; Finnish Lymphoma Group. Prolonged immunochemotherapy with rituximab, cytarabine and fludarabine added to cyclophosphamide, doxorubicin, vincristine and prednisolone and followed by rituximab maintenance in untreated elderly patients with mantle cell lymphoma: a prospective study by the Finnish Lymphoma Group. Leuk Lymphoma. 2012 Oct;53(10):1920-8. Epub 2012 Apr 23. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# ECOG E1405: Chang JE, Li H, Smith MR, Gascoyne RD, Paietta EM, Yang DT, Advani RH, Horning SJ, Kahl BS. Phase 2 study of VcR-CVAD with maintenance rituximab for untreated mantle cell lymphoma: an Eastern Cooperative Oncology Group study (E1405). Blood. 2014 Mar 13;123(11):1665-73. Epub 2014 Jan 23. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00433537
# LyMa: Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, Damaj G, Gastinne T, Ribrag V, Feugier P, Casasnovas O, Zerazhi H, Haioun C, Maisonneuve H, Houot R, Jardin F, Van Den Neste E, Tournilhac O, Le Dû K, Morschhauser F, Cartron G, Fornecker LM, Canioni D, Callanan M, Béné MC, Salles G, Tilly H, Lamy T, Gressin R, Hermine O; LYSA. Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma. N Engl J Med. 2017 Sep 28;377(13):1250-1260. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00921414
##Update: Sarkozy C, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Damaj G, Gastinne T, Tessoulin B, Ribrag V, Casasnovas O, Haioun C, Houot R, Jardin F, Van Den Neste E, Cheminant M, Morschhauser F, Callanan M, Safar V, Gressin R, Hermine O, Le Gouill S. Long-Term Follow-Up of Rituximab Maintenance in Young Patients With Mantle-Cell Lymphoma Included in the LYMA Trial: A LYSA Study. J Clin Oncol. 2024 Mar 1;42(7):769-773. Epub 2023 Dec 18. link to original article EuroPMC
#ECOG-ACRIN EA4151: NCT03267433
=Relapsed or refractory, randomized data=
==Acalabrutinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Wang et al. 2017 (ACE-LY-004) 	2015-2016 	Phase 2 (RT)	 	ORR: 81% (95% CI: 73-87)
Awaiting publication (BRUIN MCL-321)	2021-2025 	Phase 3 (C) 	Pirtobrutinib	TBD if different primary endpoint of PFS
====Prior treatment criteria====
*BRUIN MCL-321: 1 or more lines of therapy and are BTK inhibitor naïve
====Targeted therapy====
*Acalabrutinib (Calquence) 100 mg PO twice per day
Continued indefinitely
===References===
# ACE-LY-004: Wang M, Rule S, Zinzani PL, Goy A, Casasnovas O, Smith SD, Damaj G, Doorduijn J, Lamy T, Morschhauser F, Panizo C, Shah B, Davies A, Eek R, Dupuis J, Jacobsen E, Kater AP, Le Gouill S, Oberic L, Robak T, Covey T, Dua R, Hamdy A, Huang X, Izumi R, Patel P, Rothbaum W, Slatter JG, Jurczak W. Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, multicentre, phase 2 trial. Lancet. 2018 Feb 17;391(10121):659-667. Epub 2017 Dec 11. link to original article dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC NCT02213926
# BRUIN MCL-321: NCT04662255
==BCHOP==
BCHOP: Bortezomib, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisolone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Furtado et al. 2014 (NCRN-Ply-26s)	2007-2011 	Randomized Phase 2 (E-esc)	CHOP 	Longer OS (secondary endpoint)Median OS: 35.6 vs 11.8 mo(HR 0.37, 95% CI 0.16-0.83)
====Targeted therapy====
*Bortezomib (Velcade) 1.6 mg/m2 IV once per day on days 1 & 8
====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
====Supportive therapy====
*Acyclovir (Zovirax) 400 mg PO twice per day
21-day cycle for up to 8 cycles
===References===
# NCRN-Ply-26s: Furtado M, Johnson R, Kruger A, Turner D, Rule S. Addition of bortezomib to standard dose chop chemotherapy improves response and survival in relapsed mantle cell lymphoma. Br J Haematol. 2015 Jan;168(1):55-62. Epub 2014 Aug 22. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00513955
==Bendamustine & Rituximab (BR)==
BR: Bendamustine, Rituximab
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Czuczman et al. 2015 	Not reported 	Phase 2 	 	
Rummel et al. 2015 (StiL NHL 2-2003)	2003-2010 	Phase 3 (E-switch-ic)	FR 	Seems to have longer OS (secondary endpoint)
====Chemotherapy====
*Bendamustine 90 mg/m2 IV once per day on days 1 & 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
====Supportive therapy====
*Analgesics and antipyretics prior to each dose of rituximab
28-day cycle for up to 6 cycles
===Regimen variant #2, 4 cycles===
Study 	Dates of enrollment	Evidence
Rummel et al. 2005 	2000-07 to 2003-07 	Phase 2, fewer than 20 pts in subgroup
Robinson et al. 2008 (SDX-105-01 part 1)	2004-2005 	Phase 2, fewer than 20 pts in subgroup
Note: Robinson et al. 2008 said that patients "could receive up to six cycles if disease regression was evident between the second and fourth cycles".
====Chemotherapy====
*Bendamustine 90 mg/m2 IV once per day on days 2 & 3
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**One week prior to start of cycle 1: 375 mg/m2 IV once
**Cycles 1 to 4: 375 mg/m2 IV once on day 1
**4 weeks after cycle 4: 375 mg/m2 IV once
28-day cycle for 4 cycles (see note)
===References===
# Rummel MJ, Al-Batran SE, Kim SZ, Welslau M, Hecker R, Kofahl-Krause D, Josten KM, Dürk H, Rost A, Neise M, von Grünhagen U, Chow KU, Hansmann ML, Hoelzer D, Mitrou PS. Bendamustine plus rituximab is effective and has a favorable toxicity profile in the treatment of mantle cell and low-grade non-Hodgkin's lymphoma. J Clin Oncol. 2005 May 20;23(15):3383-9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# SDX-105-01 part 1: Robinson KS, Williams ME, van der Jagt RH, Cohen P, Herst JA, Tulpule A, Schwartzberg LS, Lemieux B, Cheson BD. Phase II multicenter study of bendamustine plus rituximab in patients with relapsed indolent B-cell and mantle cell non-Hodgkin's lymphoma. J Clin Oncol. 2008 Sep 20;26(27):4473-9. Epub 2008 Jul 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00069758
# Czuczman MS, Goy A, Lamonica D, Graf DA, Munteanu MC, van der Jagt RH. Phase II study of bendamustine combined with rituximab in relapsed/refractory mantle cell lymphoma: efficacy, tolerability, and safety findings. Ann Hematol. 2015 Dec;94(12):2025-32. Epub 2015 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# StiL NHL 2-2003: Rummel M, Kaiser U, Balser C, Stauch M, Brugger W, Welslau M, Niederle N, Losem C, Boeck HP, Weidmann E, von Gruenhagen U, Mueller L, Sandherr M, Hahn L, Vereshchagina J, Kauff F, Blau W, Hinke A, Barth J; StiL. Bendamustine plus rituximab versus fludarabine plus rituximab for patients with relapsed indolent and mantle-cell lymphomas: a multicentre, randomised, open-label, non-inferiority phase 3 trial. Lancet Oncol. 2016 Jan;17(1):57-66. Epub 2015 Dec 5. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT01456351
==Chlorambucil monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Trněný et al. 2016 (SPRINT)	2009-2013 	Randomized Phase 2 (C)	Lenalidomide	Shorter PFSMedian PFS: 5.2 vs 8.7 mo(HR 1.64, 95% CI 1.19-2.27)
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. The reference stated that the total monthly dose of 40 mg/m2 could be divided over 3 to 10 days; 10 days is shown here.
====Chemotherapy====
*Chlorambucil (Leukeran) 4 mg/m2 PO once per day on days 1 to 10
1-month cycles
===References===
# SPRINT: Trněný M, Lamy T, Walewski J, Belada D, Mayer J, Radford J, Jurczak W, Morschhauser F, Alexeeva J, Rule S, Afanasyev B, Kaplanov K, Thyss A, Kuzmin A, Voloshin S, Kuliczkowski K, Giza A, Milpied N, Stelitano C, Marks R, Trümper L, Biyukov T, Patturajan M, Bravo MC, Arcaini L; SPRINT trial investigators and in collaboration with the European Mantle Cell Lymphoma Network. Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial. Lancet Oncol. 2016 Mar;17(3):319-31. Epub 2016 Feb 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00875667
==Cladribine monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Inwards et al. 2008 (NCCTG 95-80-53)	2003-2005 	Phase 2, fewer than 20 pts	 	
Hess et al. 2009 (OPTIMALMCL) 	2005-2007 	Phase 3 (C) 	1. Temsirolimus; 175/25 	Might have shorter PFS
Hess et al. 2009 (OPTIMALMCL) 	2005-2007 	Phase 3 (C) 	2. Temsirolimus; 175 -> 75	Shorter PFS
====Chemotherapy====
*Cladribine (Leustatin) 5 mg/m2 IV over 2 hours once per day on days 1 to 5 
28-day cycle for up to 6 cycles
===References===
# NCCTG 95-80-53: Inwards DJ, Fishkin PA, Hillman DW, Brown DW, Ansell SM, Kurtin PJ, Fonseca R, Morton RF, Veeder MH, Witzig TE. Long-term results of the treatment of patients with mantle cell lymphoma with cladribine (2-CDA) alone (95-80-53) or 2-CDA and rituximab (N0189) in the North Central Cancer Treatment Group. Cancer. 2008 Jul 1;113(1):108-16. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# OPTIMAL: Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M, Gisselbrecht C, Laurell A, Offner F, Strahs A, Berkenblit A, Hanushevsky O, Clancy J, Hewes B, Moore L, Coiffier B. Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009 Aug 10;27(23):3822-9. Epub 2009 Jul 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00117598
==High-dose Cytarabine monotherapy (HiDAC)==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Trněný et al. 2016 (SPRINT)	2009-2013 	Randomized Phase 2 (C)	Lenalidomide	Shorter PFSMedian PFS: 5.2 vs 8.7 mo(HR 1.64, 95% CI 1.19-2.27)
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. SPRINT gave a range of cytarabine doses; this is the upper end of the range.
====Chemotherapy====
*Cytarabine (Ara-C) 2000 mg/m2 IV every 12 hours on days 1 & 2 (4 total doses)
28-day cycle for up to 6 cycles
===References===
# SPRINT: Trněný M, Lamy T, Walewski J, Belada D, Mayer J, Radford J, Jurczak W, Morschhauser F, Alexeeva J, Rule S, Afanasyev B, Kaplanov K, Thyss A, Kuzmin A, Voloshin S, Kuliczkowski K, Giza A, Milpied N, Stelitano C, Marks R, Trümper L, Biyukov T, Patturajan M, Bravo MC, Arcaini L; SPRINT trial investigators and in collaboration with the European Mantle Cell Lymphoma Network. Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial. Lancet Oncol. 2016 Mar;17(3):319-31. Epub 2016 Feb 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00875667
==Intermediate-dose Cytarabine monotherapy (IDAC)==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Trněný et al. 2016 (SPRINT)	2009-2013 	Randomized Phase 2 (C)	Lenalidomide	Shorter PFSMedian PFS: 5.2 vs 8.7 mo(HR 1.64, 95% CI 1.19-2.27)
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. SPRINT gave a range of cytarabine doses; this is the lower end of the range.
====Chemotherapy====
*Cytarabine (Ara-C) 1000 mg/m2 IV once per day on days 1 & 2
28-day cycle for up to 6 cycles
===References===
# SPRINT: Trněný M, Lamy T, Walewski J, Belada D, Mayer J, Radford J, Jurczak W, Morschhauser F, Alexeeva J, Rule S, Afanasyev B, Kaplanov K, Thyss A, Kuzmin A, Voloshin S, Kuliczkowski K, Giza A, Milpied N, Stelitano C, Marks R, Trümper L, Biyukov T, Patturajan M, Bravo MC, Arcaini L; SPRINT trial investigators and in collaboration with the European Mantle Cell Lymphoma Network. Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial. Lancet Oncol. 2016 Mar;17(3):319-31. Epub 2016 Feb 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00875667
==Fludarabine monotherapy==
===Regimen variant #1, IV===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hess et al. 2009 (OPTIMALMCL)	2005-2007 	Phase 3 (C) 	1. Temsirolimus; 175/75	Shorter PFS
Hess et al. 2009 (OPTIMALMCL)	2005-2007 	Phase 3 (C) 	2. Temsirolimus; 175/25	Might have shorter PFS
Trněný et al. 2016 (SPRINT) 	2009-2013 	Randomized Phase 2 (C)	Lenalidomide 	Shorter PFSMedian PFS: 5.2 vs 8.7 mo(HR 1.64, 95% CI 1.19-2.27)
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====
*Fludarabine (Fludara) 25 mg/m2 IV once per day on days 1 to 5
28-day cycle for varying durations: 6 cycles (SPRINT); indefinitely (OPTIMALMCL)
===Regimen variant #2, oral===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hess et al. 2009 (OPTIMALMCL)	2005-2007 	Phase 3 (C) 	1. Temsirolimus; 175/75	Shorter PFS
Hess et al. 2009 (OPTIMALMCL)	2005-2007 	Phase 3 (C) 	2. Temsirolimus; 175/25	Might have shorter PFS
Trněný et al. 2016 (SPRINT) 	2009-2013 	Randomized Phase 2 (C)	Lenalidomide 	Shorter PFSMedian PFS: 5.2 vs 8.7 mo(HR 1.64, 95% CI 1.19-2.27)
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====
*Fludarabine (Fludara) 40 mg/m2 PO once per day on days 1 to 5
28-day cycle for varying durations: 6 cycles (SPRINT); indefinitely (OPTIMALMCL)
===References===
# OPTIMALMCL: Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M, Gisselbrecht C, Laurell A, Offner F, Strahs A, Berkenblit A, Hanushevsky O, Clancy J, Hewes B, Moore L, Coiffier B. Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009 Aug 10;27(23):3822-9. Epub 2009 Jul 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00117598
# SPRINT: Trněný M, Lamy T, Walewski J, Belada D, Mayer J, Radford J, Jurczak W, Morschhauser F, Alexeeva J, Rule S, Afanasyev B, Kaplanov K, Thyss A, Kuzmin A, Voloshin S, Kuliczkowski K, Giza A, Milpied N, Stelitano C, Marks R, Trümper L, Biyukov T, Patturajan M, Bravo MC, Arcaini L; SPRINT trial investigators and in collaboration with the European Mantle Cell Lymphoma Network. Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial. Lancet Oncol. 2016 Mar;17(3):319-31. Epub 2016 Feb 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00875667
==Gemcitabine monotherapy==
===Regimen variant #1, 3 out of 4 weeks===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hess et al. 2009 (OPTIMALMCL)	2005-2007 	Phase 3 (C) 	1. Temsirolimus; 175/75	Shorter PFS
Hess et al. 2009 (OPTIMALMCL)	2005-2007 	Phase 3 (C) 	2. Temsirolimus; 175/25	Might have shorter PFS
Trněný et al. 2016 (SPRINT) 	2009-2013 	Randomized Phase 2 (C)	Lenalidomide 	Shorter PFSMedian PFS: 5.2 vs 8.7 mo(HR 1.64, 95% CI 1.19-2.27)
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 over 30 minutes once per day on days 1, 8, 15
28-day cycle for up to 6 cycles (SPRINT) or indefinitely (OPTIMALMCL)
===Regimen variant #2, 2 out of 3 weeks===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hess et al. 2009 (OPTIMALMCL)	2005-2007 	Phase 3 (C)	1. Temsirolimus; 175/75	Shorter PFS
Hess et al. 2009 (OPTIMALMCL)	2005-2007 	Phase 3 (C)	2. Temsirolimus; 175/25	Might have shorter PFS
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 over 30 minutes once per day on days 1 & 8
28-day cycles
===References===
# OPTIMALMCL: Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M, Gisselbrecht C, Laurell A, Offner F, Strahs A, Berkenblit A, Hanushevsky O, Clancy J, Hewes B, Moore L, Coiffier B. Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009 Aug 10;27(23):3822-9. Epub 2009 Jul 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00117598
# SPRINT: Trněný M, Lamy T, Walewski J, Belada D, Mayer J, Radford J, Jurczak W, Morschhauser F, Alexeeva J, Rule S, Afanasyev B, Kaplanov K, Thyss A, Kuzmin A, Voloshin S, Kuliczkowski K, Giza A, Milpied N, Stelitano C, Marks R, Trümper L, Biyukov T, Patturajan M, Bravo MC, Arcaini L; SPRINT trial investigators and in collaboration with the European Mantle Cell Lymphoma Network. Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial. Lancet Oncol. 2016 Mar;17(3):319-31. Epub 2016 Feb 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00875667
==Ibrutinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Wang et al. 2013 (PCYC-1104-CA) 	2011-2012 	Phase 2 (RT) 	 	 	
Dreyling et al. 2015 (RAY) 	2012-12-10 to 2013-11-26	Phase 3 (E-switch-ic)	Temsirolimus 	Might have longer OS1 (secondary endpoint)Median OS: 30.3 vs 23.5 mo(HR 0.74, 95% CI 0.54-1.02)	Improved HRQoL
Awaiting publication (BRUIN MCL-321)	2021-2025 	Phase 3 (C) 	Pirtobrutinib	TBD if different primary endpoint of PFS 	
1Reported efficacy is based on the 2018 update.
====Prior treatment criteria====
*BRUIN MCL-321: 1 or more lines of therapy and are BTK inhibitor naïve
====Targeted therapy====
*Ibrutinib (Imbruvica) 560 mg PO once per day on days 1 to 28
28-day cycles
===References===
# PCYC-1104-CA: Wang ML, Rule S, Martin P, Goy A, Auer R, Kahl BS, Jurczak W, Advani RH, Romaguera JE, Williams ME, Barrientos JC, Chmielowska E, Radford J, Stilgenbauer S, Dreyling M, Jedrzejczak WW, Johnson P, Spurgeon SE, Li L, Zhang L, Newberry K, Ou Z, Cheng N, Fang B, McGreivy J, Clow F, Buggy JJ, Chang BY, Beaupre DM, Kunkel LA, Blum KA. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med. 2013 Aug 8;369(6):507-16. Epub 2013 Jun 19. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT01236391
## Update: Wang ML, Blum KA, Martin P, Goy A, Auer R, Kahl BS, Jurczak W, Advani RH, Romaguera JE, Williams ME, Barrientos JC, Chmielowska E, Radford J, Stilgenbauer S, Dreyling M, Jedrzejczak WW, Johnson P, Spurgeon SE, Zhang L, Baher L, Cheng M, Lee D, Beaupre DM, Rule S. Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results. Blood. 2015 Aug 6;126(6):739-45. Epub 2015 Jun 9. link to original article link to PMC article EuroPMC
# RAY: Dreyling M, Jurczak W, Jerkeman M, Silva RS, Rusconi C, Trneny M, Offner F, Caballero D, Joao C, Witzens-Harig M, Hess G, Bence-Bruckler I, Cho SG, Bothos J, Goldberg JD, Enny C, Traina S, Balasubramanian S, Bandyopadhyay N, Sun S, Vermeulen J, Rizo A, Rule S. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet. 2016 Feb 20;387(10020):770-8. Epub 2015 Dec 4. Erratum in: Lancet. 2016 Feb 20;387(10020):750.link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01646021
## HRQoL analysis: Hess G, Rule S, Jurczak W, Jerkeman M, Santucci Silva R, Rusconi C, Caballero D, Joao C, Witzens-Harig M, Bence-Bruckler I, Cho SG, Zhou W, Goldberg JD, Trambitas C, Enny C, Vermeulen J, Traina S, Chiou CF, Diels J, Dreyling M. Health-related quality of life data from a phase 3, international, randomized, open-label, multicenter study in patients with previously treated mantle cell lymphoma treated with ibrutinib versus temsirolimus. Leuk Lymphoma. 2017 Dec;58(12):2824-2832. Epub 2017 May 30. link to original article EuroPMC
## Update: Rule S, Jurczak W, Jerkeman M, Rusconi C, Trneny M, Offner F, Caballero D, Joao C, Witzens-Harig M, Hess G, Bence-Bruckler I, Cho SG, Thieblemont C, Zhou W, Henninger T, Goldberg J, Vermeulen J, Dreyling M. Ibrutinib versus temsirolimus: 3-year follow-up of patients with previously treated mantle cell lymphoma from the phase 3, international, randomized, open-label RAY study. Leukemia. 2018 Aug;32(8):1799-1803. Epub 2018 Feb 2. link to original article link to PMC article EuroPMC
# BRUIN MCL-321: NCT04662255
==Lenalidomide monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Wiernik et al. 2008 (CC-5013-NHL-002)	2005-2006 	Phase 2, fewer than 20 pts in subgroup	 	
Witzig et al. 2011 (NHL-003) 	2006-2008 	Phase 2 	 	
Eve et al. 2012 	2008-2010 	Phase 2 	 	
Goy et al. 2013 (EMERGE) 	2009-2012 	Phase 2 (RT) 	 	
Trněný et al. 2016 (SPRINT) 	2009-2013 	Randomized Phase 2 (E-switch-ooc) 	Investigator's choice of:1a. Chlorambucil1b. IDAC1c. HiDAC1d. Fludarabine1e. Gemcitabine1f. Rituximab	Longer PFS (primary endpoint)Median PFS: 8.7 vs 5.2 mo(HR 0.61, 95% CI 0.44-0.84)
====Prior treatment criteria====
*EMERGE: prior treatment with rituximab, cyclophosphamide and anthracycline (or mitoxantrone), and to have relapsed or progressed (less than 12 months) after or were refractory to bortezomib.
====Targeted therapy====
*Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycles
====Subsequent treatment====
*Eve et al. 2012: Lenalidomide maintenance after 6 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
## Update: Habermann TM, Lossos IS, Justice G, Vose JM, Wiernik PH, McBride K, Wride K, Ervin-Haynes A, Takeshita K, Pietronigro D, Zeldis JB, Tuscano JM. Lenalidomide oral monotherapy produces a high response rate in patients with relapsed or refractory mantle cell lymphoma. Br J Haematol. 2009 May;145(3):344-9. Epub 2009 Feb 24. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Pooled update: Witzig TE, Zinzani PL, Habermann TM, Tuscano JM, Drach J, Ramchandren R, Kalayoglu Besisik S, Takeshita K, Casadebaig Bravo ML, Zhang L, Fu T, Goy A. Long-term analysis of phase II studies of single-agent lenalidomide in relapsed/refractory mantle cell lymphoma. Am J Hematol. 2017 Oct;92(10):E575-E583. Epub 2017 Aug 28. link to original article link to PMC article EuroPMC
# 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
## Update: Zinzani PL, Vose JM, Czuczman MS, Reeder CB, Haioun C, Polikoff J, Tilly H, Zhang L, Prandi K, Li J, Witzig TE. Long-term follow-up of lenalidomide in relapsed/refractory mantle cell lymphoma: subset analysis of the NHL-003 study. Ann Oncol. 2013 Nov;24(11):2892-7. Epub 2013 Sep 12. link to original article link to PMC article EuroPMC
## Pooled update: Witzig TE, Zinzani PL, Habermann TM, Tuscano JM, Drach J, Ramchandren R, Kalayoglu Besisik S, Takeshita K, Casadebaig Bravo ML, Zhang L, Fu T, Goy A. Long-term analysis of phase II studies of single-agent lenalidomide in relapsed/refractory mantle cell lymphoma. Am J Hematol. 2017 Oct;92(10):E575-E583. Epub 2017 Aug 28. link to original article link to PMC article EuroPMC
# Eve HE, Carey S, Richardson SJ, Heise CC, Mamidipudi V, Shi T, Radford JA, Auer RL, Bullard SH, Rule SA. Single-agent lenalidomide in relapsed/refractory mantle cell lymphoma: results from a UK phase II study suggest activity and possible gender differences. Br J Haematol. 2012 Oct;159(2):154-63. Epub 2012 Aug 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# EMERGE: Goy A, Sinha R, Williams ME, Kalayoglu Besisik S, Drach J, Ramchandren R, Zhang L, Cicero S, Fu T, Witzig TE. Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: Phase II MCL-001 (EMERGE) study. J Clin Oncol. 2013 Oct 10;31(29):3688-95. Epub 2013 Sep 3. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00737529
## Update: Goy A, Kalayoglu Besisik S, Drach J, Ramchandren R, Robertson MJ, Avivi I, Rowe JM, Herbrecht R, Van Hoof A, Zhang L, Cicero S, Fu T, Witzig T. Longer-term follow-up and outcome by tumour cell proliferation rate (Ki-67) in patients with relapsed/refractory mantle cell lymphoma treated with lenalidomide on MCL-001(EMERGE) pivotal trial. Br J Haematol. 2015 Aug;170(4):496-503. Epub 2015 Apr 28. link to original article link to PMC article EuroPMC
## Pooled update: Witzig TE, Zinzani PL, Habermann TM, Tuscano JM, Drach J, Ramchandren R, Kalayoglu Besisik S, Takeshita K, Casadebaig Bravo ML, Zhang L, Fu T, Goy A. Long-term analysis of phase II studies of single-agent lenalidomide in relapsed/refractory mantle cell lymphoma. Am J Hematol. 2017 Oct;92(10):E575-E583. Epub 2017 Aug 28. link to original article link to PMC article EuroPMC
# SPRINT: Trněný M, Lamy T, Walewski J, Belada D, Mayer J, Radford J, Jurczak W, Morschhauser F, Alexeeva J, Rule S, Afanasyev B, Kaplanov K, Thyss A, Kuzmin A, Voloshin S, Kuliczkowski K, Giza A, Milpied N, Stelitano C, Marks R, Trümper L, Biyukov T, Patturajan M, Bravo MC, Arcaini L; SPRINT trial investigators and in collaboration with the European Mantle Cell Lymphoma Network. Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial. Lancet Oncol. 2016 Mar;17(3):319-31. Epub 2016 Feb 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00875667
==R-FCM==
R-FCM: Rituximab, Fludarabine, Cyclophosphamide, Mitoxantrone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Forstpointner et al. 2004	1998-2001 	Phase 3 (E-esc)	FCM 	Longer OS (secondary endpoint)
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day -1
====Chemotherapy====
*Fludarabine (Fludara) 25 mg/m2 IV over 30 minutes once per day on days 1 to 3
*Cyclophosphamide (Cytoxan) 200 mg/m2 IV over 4 hours once per day on days 1 to 3
*Mitoxantrone (Novantrone) 8 mg/m2 IV over 30 minutes once on day 1
28-day cycle for 4 cycles
====Subsequent treatment====
*Forstpointner et al. 2004, PR/CR: Rituximab maintenance versus no further treatment
===References===
# Forstpointner R, Dreyling M, Repp R, Hermann S, Hänel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Böck HP, Wandt H, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 15;104(10):3064-71. Epub 2004 Jul 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Forstpointner R, Unterhalt M, Dreyling M, Böck HP, Repp R, Wandt H, Pott C, Seymour JF, Metzner B, Hänel A, Lehmann T, Hartmann F, Einsele H, Hiddemann W; German Low Grade Lymphoma Study Group. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006 Dec 15;108(13):4003-8. Epub 2006 Aug 31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==R-HAD==
R-HAD: Rituximab, High-dose Ara-C (Cytarabine), Dexamethasone
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Fischer et al. 2024 (MCL2005-01)	2012-05 to 2016-12 	Phase 3 (C)	R-HAD+B 	Might have shorter TTF (primary endpoint)Median TTF: 2.6 vs 12 mo(MIPI-adjusted HR 1.45, 95% CI 0.98-2.13)
====Targeted therapy====
*Rituximab (Rituxan) 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) by the following criteria:
**65 years old and younger and no prior ASCT: 2000 mg/m2 IV once per day on days 2 & 3
**Older than 65 years old or prior ASCT: 1000 mg/m2 IV once per day on days 2 & 3
21-day cycle for 4 cycles
===References===
#MCL2005-01: Fischer L, Jiang L, Dürig J, Schmidt C, Stilgenbauer S, Bouabdallah K, Solal-Celigny P, Scholz CW, Feugier P, de Wit M, Trappe RU, Hallek M, Graeven U, Hänel M, Hoffmann M, Delwail V, Macro M, Greiner J, Giagounidis AAN, Dargel B, Durot E, Foussard C, Silkenstedt E, Weigert O, Pott C, Klapper W, Hiddemann W, Unterhalt M, Hoster E, Ribrag V, Dreyling M. The addition of bortezomib to rituximab, high-dose cytarabine and dexamethasone in relapsed or refractory mantle cell lymphoma-a randomized, open-label phase III trial of the European mantle cell lymphoma network. Leukemia. 2024 Jun;38(6):1307-1314. Epub 2024 Apr 27. link to original article link to PMC article EuroPMC NCT01449344
==Rituximab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Trněný et al. 2016 (SPRINT)	2009-2013 	Randomized Phase 2 (C)	Lenalidomide	Shorter PFSMedian PFS: 5.2 vs 8.7 mo(HR 1.64, 95% CI 1.19-2.27)
====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
12-week course, then 8-week cycles
===References===
# SPRINT: Trněný M, Lamy T, Walewski J, Belada D, Mayer J, Radford J, Jurczak W, Morschhauser F, Alexeeva J, Rule S, Afanasyev B, Kaplanov K, Thyss A, Kuzmin A, Voloshin S, Kuliczkowski K, Giza A, Milpied N, Stelitano C, Marks R, Trümper L, Biyukov T, Patturajan M, Bravo MC, Arcaini L; SPRINT trial investigators and in collaboration with the European Mantle Cell Lymphoma Network. Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial. Lancet Oncol. 2016 Mar;17(3):319-31. Epub 2016 Feb 15. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00875667
==Temsirolimus monotherapy==
===Regimen variant #1, 25 mg===
Study 	Dates of enrollment	Evidence
Ansell et al. 2008	2004-2005 	Phase 2
====Targeted therapy====
*Temsirolimus (Torisel) 25 mg IV over 30 minutes once per day on days 1, 8, 15, 22
====Supportive therapy====
*Diphenhydramine (Benadryl) 25 to 50 mg IV once per day on days 1, 8, 15, 22, given prior to temsirolimus
28-day cycle for up to 13 cycles, stopped at various timepoints (see paper for details)
===Regimen variant #2, 175 -> 75===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy 	Comparative Toxicity
Hess et al. 2009 (OPTIMALMCL)	2005-2007 	Phase 3 (E-switch-ooc)	Investigator's choice of:1a. Alemtuzumab1b. Chlorambucil1c. Cladribine1d. Etoposide1e. Fludarabine1f. Gemcitabine1g. Thalidomide1h. Vinblastine	Longer PFS (primary endpoint)Median PFS: 4.8 vs 1.9 mo(HR 0.44, 97.5% CI 0.25-0.78)	
Hess et al. 2009 (OPTIMALMCL)	2005-2007 	Phase 3 (E-switch-ooc)	2. Temsirolimus; 175/25 	Not reported 	
Dreyling et al. 2015 (RAY) 	2012-12-10 to 2013-11-26	Phase 3 (C) 	Ibrutinib 	Might have shorter OS1Median OS: 23.5 vs 30.3 mo(HR 1.35, 95% CI 0.98-1.85) 	Worse HRQoL
1Reported efficacy is based on the 2018 update.
Note: The most commonly compared regimens in OPTIMAL were single agent gemcitabine and single agent fludarabine. Note that OPTIMAL should not be confused with the trial by the same name in NSCLC.
====Targeted therapy====
*Temsirolimus (Torisel) as follows:
**Cycle 1: 175 mg IV over 30 to 60 minutes once per day on days 1, 8, 15
**Cycle 2 onwards: 75 mg IV over 30 to 60 minutes once per day on days 1, 8, 15
====Supportive therapy====
*Antihistamine once per day on days 1, 8, 15; 30 minutes prior to temsirolimus
*Corticosteroid use was not allowed in OPTIMAL.
21-day cycles
===Regimen variant #3, 250 mg===
Study 	Dates of enrollment	Evidence
Witzig et al. 2005	2002-2003 	Phase 2
====Targeted therapy====
*Temsirolimus (Torisel) 250 mg IV over 30 minutes once per day on days 1, 8, 15, 22
====Supportive therapy====
*Use of white blood cell growth factors at physician discretion if neutropenia occurred.
*Use of erythropoietin for anemia was allowed.
28-day cycle for up to 13 cycles or 2 cycles past CR
===References===
# Witzig TE, Geyer SM, Ghobrial I, Inwards DJ, Fonseca R, Kurtin P, Ansell SM, Luyun R, Flynn PJ, Morton RF, Dakhil SR, Gross H, Kaufmann SH. Phase II trial of single-agent temsirolimus (CCI-779) for relapsed mantle cell lymphoma. J Clin Oncol. 2005 Aug 10;23(23):5347-56. Epub 2005 Jun 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Ansell SM, Inwards DJ, Rowland KM Jr, Flynn PJ, Morton RF, Moore DF Jr, Kaufmann SH, Ghobrial I, Kurtin PJ, Maurer M, Allmer C, Witzig TE; North Central Cancer Treatment Group. Low-dose, single-agent temsirolimus for relapsed mantle cell lymphoma: a phase 2 trial in the North Central Cancer Treatment Group. Cancer. 2008 Aug 1;113(3):508-14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# OPTIMALMCL: Hess G, Herbrecht R, Romaguera J, Verhoef G, Crump M, Gisselbrecht C, Laurell A, Offner F, Strahs A, Berkenblit A, Hanushevsky O, Clancy J, Hewes B, Moore L, Coiffier B. Phase III study to evaluate temsirolimus compared with investigator's choice therapy for the treatment of relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2009 Aug 10;27(23):3822-9. Epub 2009 Jul 6. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00117598
# RAY: Dreyling M, Jurczak W, Jerkeman M, Silva RS, Rusconi C, Trneny M, Offner F, Caballero D, Joao C, Witzens-Harig M, Hess G, Bence-Bruckler I, Cho SG, Bothos J, Goldberg JD, Enny C, Traina S, Balasubramanian S, Bandyopadhyay N, Sun S, Vermeulen J, Rizo A, Rule S. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet. 2016 Feb 20;387(10020):770-8. Epub 2015 Dec 4. Erratum in: Lancet. 2016 Feb 20;387(10020):750.link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01646021
## HRQoL analysis: Hess G, Rule S, Jurczak W, Jerkeman M, Santucci Silva R, Rusconi C, Caballero D, Joao C, Witzens-Harig M, Bence-Bruckler I, Cho SG, Zhou W, Goldberg JD, Trambitas C, Enny C, Vermeulen J, Traina S, Chiou CF, Diels J, Dreyling M. Health-related quality of life data from a phase 3, international, randomized, open-label, multicenter study in patients with previously treated mantle cell lymphoma treated with ibrutinib versus temsirolimus. Leuk Lymphoma. 2017 Dec;58(12):2824-2832. Epub 2017 May 30. link to original article EuroPMC
## Update: Rule S, Jurczak W, Jerkeman M, Rusconi C, Trneny M, Offner F, Caballero D, Joao C, Witzens-Harig M, Hess G, Bence-Bruckler I, Cho SG, Thieblemont C, Zhou W, Henninger T, Goldberg J, Vermeulen J, Dreyling M. Ibrutinib versus temsirolimus: 3-year follow-up of patients with previously treated mantle cell lymphoma from the phase 3, international, randomized, open-label RAY study. Leukemia. 2018 Aug;32(8):1799-1803. Epub 2018 Feb 2. link to original article link to PMC article EuroPMC
==Zanubrutinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Tam et al. 2019 (BGB-3111-AU-003) 	2014-2018 	Phase 1/2 (RT)	 	
Song et al. 2020 (BGB-3111-206) 	2017 	Phase 2 (RT) 	 	
Awaiting publication (BRUIN MCL-321)	2021-2025 	Phase 3 (C) 	Pirtobrutinib	TBD if different primary endpoint of PFS
Note: this was the RP2D in BGB-3111-AU-003.
====Prior treatment criteria====
*BRUIN MCL-321: 1 or more lines of therapy and are BTK inhibitor naïve
====Targeted therapy====
*Zanubrutinib (Brukinsa) 160 mg PO twice per day on days 1 to 28
28-day cycle for up to 39 cycles (3 years)
===References===
# BGB-3111-AU-003: Tam CS, Trotman J, Opat S, Burger JA, Cull G, Gottlieb D, Harrup R, Johnston PB, Marlton P, Munoz J, Seymour JF, Simpson D, Tedeschi A, Elstrom R, Yu Y, Tang Z, Han L, Huang J, Novotny W, Wang L, Roberts AW. Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL. Blood. 2019 Sep 12;134(11):851-859. Epub 2019 Jul 24. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02343120
## Update: Tam CS, Opat S, Simpson D, Cull G, Munoz J, Phillips TJ, Kim WS, Rule S, Atwal SK, Wei R, Novotny W, Huang J, Wang M, Trotman J. Zanubrutinib for the treatment of relapsed or refractory mantle cell lymphoma. Blood Adv. 2021 Jun 22;5(12):2577-2585. link to original article link to PMC article EuroPMC
# BGB-3111-206: Song Y, Zhou K, Zou D, Zhou J, Hu J, Yang H, Zhang H, Ji J, Xu W, Jin J, Lv F, Feng R, Gao S, Guo H, Zhou L, Elstrom R, Huang J, Novotny W, Wei R, Zhu J. Treatment of Patients with Relapsed or Refractory Mantle-Cell Lymphoma with Zanubrutinib, a Selective Inhibitor of Bruton's Tyrosine Kinase. Clin Cancer Res. 2020 Aug 15;26(16):4216-4224. Epub 2020 May 27. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT03206970
## Update: Song Y, Zhou K, Zou D, Zhou J, Hu J, Yang H, Zhang H, Ji J, Xu W, Jin J, Lv F, Feng R, Gao S, Guo H, Zhou L, Huang J, Novotny W, Kim P, Yu Y, Wu B, Zhu J. Zanubrutinib in relapsed/refractory mantle cell lymphoma: long-term efficacy and safety results from a phase 2 study. Blood. 2022 May 26;139(21):3148-3158. link to original article link to PMC article EuroPMC
# BRUIN MCL-321: NCT04662255
=Relapsed or refractory, non-randomized or retrospective data=
==Arsenic trioxide & Chlorambucil==
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Gill et al. 2014	2003-2011 	Phase 2 	ORR: 49%
Note: patients with SD or better after cycle 1 proceed onwards.
====Targeted therapy====
*Arsenic trioxide (Trisenox) as follows:
**Cycle 1: 10 mg PO once per day on days 1 to 28, then 5 mg PO once per day on days 29 to 42
**Cycle 2 onwards: 3 mg PO once per day
====Chemotherapy====
*Chlorambucil (Leukeran) as follows:
**Cycle 1: 4 mg PO once per day, increased to 8 mg PO once per day if leukocyte count allowed
**Cycle 2 onwards: 2 mg PO once per day on days 1 to 28
====Supportive therapy====
*Ascorbic acid (Vitamin C) as follows:
**Cycle 1: 1000 mg PO once per day
**Cycle 2 onwards: 300 mg PO once per day
42-day course, then 28-day cycles
===References===
# Gill H, Au WY, Cheung WW, Lee EY, Kwong YL. Oral arsenic trioxide-based regimen as salvage treatment for relapsed or refractory mantle cell lymphoma. Ann Oncol. 2014 Jul;25(7):1391-7. Epub 2014 Apr 12. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==BeRT==
BeRT: Bendamustine, Rituximab, Temsirolimus
===Regimen===
Study 	Dates of enrollment 	Evidence
Hess et al. 2015 (Mz-341)	2010 to not reported	Phase 1/2, fewer than 20 pts reported
Note: The temsirolimus dose was the maximum dose used in the phase 1 portion of the trial; no DLT were observed.
====Chemotherapy====
*Bendamustine 90 mg/m2 IV once per day on days 1 & 2
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
*Temsirolimus (Torisel) 75 mg IV once per day on days 1, 8, 15
28-day cycle for up to 4 cycles
===References===
# Mz-341: Hess G, Keller U, Scholz CW, Witzens-Harig M, Atta J, Buske C, Kirschey S, Ruckes C, Medler C, van Oordt C, Klapper W, Theobald M, Dreyling M. Safety and efficacy of Temsirolimus in combination with Bendamustine and Rituximab in relapsed mantle cell and follicular lymphoma. Leukemia. 2015 Aug;29(8):1695-701. Epub 2015 Mar 13. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01078142
==BDR==
BDR: Bortezomib, Dexamethasone, Rituximab
BORID: BOrtezomib, RItuximab, Dexamethasone
===Regimen===
Study 	Dates of enrollment 	Evidence
Lamm et al. 2011 (MCL 03)	2005 to not reported	Phase 2, fewer than 20 pts reported
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV over 3 to 5 seconds once per day on days 1, 4, 8, 11
*Rituximab (Rituxan) 375 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 6 cycles
====Subsequent treatment====
*MCL 03, responding patients: Rituximab consolidation
===References===
# MCL 03: Lamm W, Kaufmann H, Raderer M, Hoffmann M, Chott A, Zielinski C, Drach J. Bortezomib combined with rituximab and dexamethasone is an active regimen for patients with relapsed and chemotherapy-refractory mantle cell lymphoma. Haematologica. 2011 Jul;96(7):1008-14. Epub 2011 Apr 12. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00261612
==Bortezomib monotherapy==
===Regimen variant #1, 1.3 mg/m2===
Study 	Dates of enrollment 	Evidence
Fisher et al. 2006 (PINNACLE)	2003 to not reported	Phase 2 (RT)
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
21-day cycles "up to 17 cycles or four cycles beyond initial reporting of CR/CRu, discontinuing for progressive disease (PD) or unacceptable toxicity, or by patient/investigator decision."
===Regimen variant #2, 1.5 mg/m2===
Study 	Dates of enrollment	Evidence
O'Connor et al. 2005	2001-2003 	Phase 2, fewer than 20 pts reported
====Targeted therapy====
*Bortezomib (Velcade) 1.5 mg/m2 IV once per day on days 1, 4, 8, 11
====Supportive therapy====
*"Use of antiemetics, erythropoietin, and Filgrastim (Neupogen) was allowed if deemed necessary by the treating physician."
21-day cycles 
===References===
# O'Connor OA, Wright J, Moskowitz C, Muzzy J, MacGregor-Cortelli B, Stubblefield M, Straus D, Portlock C, Hamlin P, Choi E, Dumetrescu O, Esseltine D, Trehu E, Adams J, Schenkein D, Zelenetz AD. Phase II clinical experience with the novel proteasome inhibitor bortezomib in patients with indolent non-Hodgkin's lymphoma and mantle cell lymphoma. J Clin Oncol. 2005 Feb 1;23(4):676-84. Epub 2004 Dec 21. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# PINNACLE: Fisher RI, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, Epner E, Krishnan A, Leonard JP, Lonial S, Stadtmauer EA, O'Connor OA, Shi H, Boral AL, Goy A. Multicenter phase II study of bortezomib in patients with relapsed or refractory mantle cell lymphoma. J Clin Oncol. 2006 Oct 20;24(30):4867-74. Epub 2006 Sep 25. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 
## Update: Goy A, Bernstein SH, Kahl BS, Djulbegovic B, Robertson MJ, de Vos S, Epner E, Krishnan A, Leonard JP, Lonial S, Nasta S, O'Connor OA, Shi H, Boral AL, Fisher RI. Bortezomib in patients with relapsed or refractory mantle cell lymphoma: updated time-to-event analyses of the multicenter phase 2 PINNACLE study. Ann Oncol. 2009 Mar;20(3):520-5. Epub 2008 Dec 12. link to original article dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC
==Brexucabtagene autoleucel monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Wang et al. 2020 (ZUMA-2)	2016-2019 	Phase 2 (RT)
====Preceding treatment====
*FC lymphodepletion
====Immunotherapy====
*Brexucabtagene autoleucel (Tecartus) 2 x 106 CAR T cells/kg IV once on day 0
One course
===References===
#ZUMA-2: Wang M, Munoz J, Goy A, Locke FL, Jacobson CA, Hill BT, Timmerman JM, Holmes H, Jaglowski S, Flinn IW, McSweeney PA, Miklos DB, Pagel JM, Kersten MJ, Milpied N, Fung H, Topp MS, Houot R, Beitinjaneh A, Peng W, Zheng L, Rossi JM, Jain RK, Rao AV, Reagan PM. KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. N Engl J Med. 2020 Apr 2;382(14):1331-1342. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT02601313
##Update: Wang M, Munoz J, Goy A, Locke FL, Jacobson CA, Hill BT, Timmerman JM, Holmes H, Jaglowski S, Flinn IW, McSweeney PA, Miklos DB, Pagel JM, Kersten MJ, Bouabdallah K, Khanal R, Topp MS, Houot R, Beitinjaneh A, Peng W, Fang X, Shen RR, Siddiqi R, Kloos I, Reagan PM. Three-Year Follow-Up of KTE-X19 in Patients With Relapsed/Refractory Mantle Cell Lymphoma, Including High-Risk Subgroups, in the ZUMA-2 Study. J Clin Oncol. 2023 Jan 20;41(3):555-567. Epub 2022 Jun 4. link to original article link to PMC article EuroPMC
==Everolimus monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Renner et al. 2012 (SAKK 36/06)	2007-2010 	Phase 2
Wang et al. 2014 (PILLAR-1) 	2008-2011 	Phase 2
====Targeted therapy====
*Everolimus (Afinitor) 10 mg PO once per day on days 1 to 28, taken in a fasting state or with a light fat-free meal
28-day cycles
===References===
# SAKK 36/06: Renner C, Zinzani PL, Gressin R, Klingbiel D, Dietrich PY, Hitz F, Bargetzi M, Mingrone W, Martinelli G, Trojan A, Bouabdallah K, Lohri A, Gyan E, Biaggi C, Cogliatti S, Bertoni F, Ghielmini M, Brauchli P, Ketterer N; SAKK; GOELAMS; European Mantle Cell Lymphoma Network. A multicenter phase II trial (SAKK 36/06) of single-agent everolimus (RAD001) in patients with relapsed or refractory mantle cell lymphoma. Haematologica. 2012 Jul;97(7):1085-91. Epub 2012 Feb 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00516412
# PILLAR-1: Wang M, Popplewell LL, Collins RH Jr, Winter JN, Goy A, Kaminski MS, Bartlett NL, Johnston PB, Lister J, Fanning SR, Tuscano JM, Beck JT, Kaya H, Robeva A, Fan J, Klimovsky J, Cheung W, Cherfi A, O'Connor OA. Everolimus for patients with mantle cell lymphoma refractory to or intolerant of bortezomib: multicentre, single-arm, phase 2 study. Br J Haematol. 2014 May;165(4):510-8. Epub 2014 Mar 2. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00702052
==Ibrutinib & Rituximab==
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Wang et al. 2015 (MDACC 2013-0090)	2013-2014 	Phase 2 	ORR: 88% (95% CI 76-95.5)
====Targeted therapy====
*Ibrutinib (Imbruvica) as follows:
**Cycles 1 to 7: 560 mg PO once per day on days 1 to 28
**Cycle 8 onwards: 560 mg PO once per day on days 1 to 56
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
**Cycles 3 to 7: 375 mg/m2 IV once on day 1
**Cycles 8 up to 20: 375 mg/m2 IV once on day 1
28-day cycle for 7 cycles, then 8-week cycles (up to 2 years for rituximab)
===References===
# MDACC 2013-0090: Wang ML, Lee H, Chuang H, Wagner-Bartak N, Hagemeister F, Westin J, Fayad L, Samaniego F, Turturro F, Oki Y, Chen W, Badillo M, Nomie K, DeLa Rosa M, Zhao D, Lam L, Addison A, Zhang H, Young KH, Li S, Santos D, Medeiros LJ, Champlin R, Romaguera J, Zhang L. Ibrutinib in combination with rituximab in relapsed or refractory mantle cell lymphoma: a single-centre, open-label, phase 2 trial. Lancet Oncol. 2016 Jan;17(1):48-56. Epub 2015 Nov 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01880567
==Ibrutinib & Venetoclax==
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Tam et al. 2018 (AIM)	2015-2016 	Phase 2 	ORR: 71% (95% CI 49-87)
Note: the venetoclax dosing is based on a mid-protocol amendment.
====Targeted therapy====
*Ibrutinib (Imbruvica) 560 mg PO once per day on days 1 to 28
*Venetoclax (Venclexta) as follows:
**Cycle 2: 50 mg PO once per day on days 1 to 7, then 100 mg once per day on days 8 to 14, then 200 mg PO once per day on days 15 to 21, then 400 mg PO once per day on days 22 to 28
**Cycle 3 onwards: 400 mg PO once per day on days 1 to 28
28-day cycles
====Dose and schedule modifications====
*If CR is not achieved by week 16, venetoclax dose is increased to 800 mg PO once per day
===References===
# AIM: Tam CS, Anderson MA, Pott C, Agarwal R, Handunnetti S, Hicks RJ, Burbury K, Turner G, Di Iulio J, Bressel M, Westerman D, Lade S, Dreyling M, Dawson SJ, Dawson MA, Seymour JF, Roberts AW. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018 Mar 29;378(13):1211-1223. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02471391
##Update: Handunnetti SM, Anderson MA, Burbury K, Thompson PA, Burke G, Bressel M, Di Iulio J, Hicks RJ, Westerman D, Lade S, Pott C, Agarwal R, Koldej R, Ritchie D, Dreyling M, Dawson MA, Dawson SJ, Seymour JF, Roberts AW, Tam CS. Seven-year outcomes of venetoclax-ibrutinib therapy in mantle cell lymphoma: durable responses and treatment-free remissions. Blood. 2024 Aug 22;144(8):867-872. link to original article EuroPMC
==Lenalidomide & Rituximab (R2)==
===Regimen variant #1, 10/375===
Study 	Dates of enrollment	Evidence
Chong et al. 2015 (UPCC 02408 R2)	2008-2012 	Phase 2, fewer than 20 pts in subgroup
====Targeted therapy====
*Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 28
*Rituximab (Rituxan) as follows:
**Cycle 3: 375 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycles
===Regimen variant #2, 25/375===
Study 	Dates of enrollment	Evidence
Wang et al. 2012 (MDACC 2005-0461MCL)	2006-2009 	Phase 1/2
====Targeted therapy====
*Lenalidomide (Revlimid) 25 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
===References===
# MDACC 2005-0461MCL: Wang M, Fayad L, Wagner-Bartak N, Zhang L, Hagemeister F, Neelapu SS, Samaniego F, McLaughlin P, Fanale M, Younes A, Cabanillas F, Fowler N, Newberry KJ, Sun L, Young KH, Champlin R, Kwak L, Feng L, Badillo M, Bejarano M, Hartig K, Chen W, Chen Y, Byrne C, Bell N, Zeldis J, Romaguera J. Lenalidomide in combination with rituximab for patients with relapsed or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol. 2012 Jul;13(7):716-23. Epub 2012 Jun 6. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00294632
# UPCC 02408 R2: Chong EA, Ahmadi T, Aqui NA, Svoboda J, Nasta SD, Mato AR, Walsh KM, Schuster SJ. Combination of lenalidomide and rituximab overcomes rituximab resistance in patients with indolent B-cell and mantle cell lymphomas. Clin Cancer Res. 2015 Apr 15;21(8):1835-42. Epub 2015 Jan 28. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00783367
==Lisocabtagene maraleucel monotherapy==
===Regimen===
Study 	Dates of enrollment 	Evidence
Wang et al. 2023 (TRANSCEND-MCL)	2016-03-28 to 2022-02-10	Phase 1 (RT)
Note: This was the recommended dose/dose-level 2.
====Immunotherapy====
*Lisocabtagene maraleucel (Breyanzi) 100 x 106 CAR T cells/kg IV once on day 0
One course
===References===
#TRANSCEND-MCL: Wang M, Siddiqi T, Gordon LI, Kamdar M, Lunning M, Hirayama AV, Abramson JS, Arnason J, Ghosh N, Mehta A, Andreadis C, Solomon SR, Kostic A, Dehner C, Espinola R, Peng L, Ogasawara K, Chattin A, Eliason L, Palomba ML. Lisocabtagene Maraleucel in Relapsed/Refractory Mantle Cell Lymphoma: Primary Analysis of the Mantle Cell Lymphoma Cohort From TRANSCEND NHL 001, a Phase I Multicenter Seamless Design Study. J Clin Oncol. 2024 Apr 1;42(10):1146-1157. Epub 2023 Dec 10. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02631044
==Obinutuzumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence
Salles et al. 2012 (GAUGUIN)	2008-2009 	Phase 1/2
Note: this is the phase 2 dosing used in the subgroup analysis by 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
==PEP-C==
PEP-C: Prednisone, Etoposide, Procarbazine, Cyclophosphamide
===Regimen===
Study 	Dates of enrollment	Evidence
Coleman et al. 2008	Not reported 	Retrospective
Note: the dosing below is for the induction phase. Once WBC count is at goal, the same medications and doses are used as in the induction phase, but the number of days per week they are used is titrated to maintain a WBC count of at least 3; for example, 5 out of 7 days, every other day, once per week, etc.
====Glucocorticoid therapy====
*Prednisone (Sterapred) 20 mg PO once per day, taken after breakfast
====Chemotherapy====
*Etoposide (Vepesid) 50 mg PO once per day, taken after dinner
*Procarbazine (Matulane) 50 mg PO once per day, taken at bedtime
*Cyclophosphamide (Cytoxan) 50 mg PO once per day, taken after lunch
====Supportive therapy====
*Ondansetron (Zofran) (dose not specified) with each procarbazine dose
Continue until WBC count less than 3 x 109/L, hold until WBC count recovery, then titrate in maintenance phase per paper (see publication for details)
===References===
# Retrospective: Coleman M, Martin P, Ruan J, Furman R, Niesvizky R, Elstrom R, George P, Leonard J, Kaufmann T. Low-dose metronomic, multidrug therapy with the PEP-C oral combination chemotherapy regimen for mantle cell lymphoma. Leuk Lymphoma. 2008 Mar;49(3):447-50. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Pirtobrutinib monotherapy==
===Regimen===
FDA-recommended dose
Study 	Dates of enrollment 	Evidence
Mato et al. 2021 (BRUINMCL)	2019-03-21 to 2020-09-27	Phase 1/2 (RT)
Note: this is the phase 2 dosing.
====Targeted therapy====
*Pirtobrutinib (Jaypirca) 200 mg PO once per day
Continued indefinitely
===References===
#BRUINMCL: Mato AR, Shah NN, Jurczak W, Cheah CY, Pagel JM, Woyach JA, Fakhri B, Eyre TA, Lamanna N, Patel MR, Alencar A, Lech-Maranda E, Wierda WG, Coombs CC, Gerson JN, Ghia P, Le Gouill S, Lewis DJ, Sundaram S, Cohen JB, Flinn IW, Tam CS, Barve MA, Kuss B, Taylor J, Abdel-Wahab O, Schuster SJ, Palomba ML, Lewis KL, Roeker LE, Davids MS, Tan XN, Fenske TS, Wallin J, Tsai DE, Ku NC, Zhu E, Chen J, Yin M, Nair B, Ebata K, Marella N, Brown JR, Wang M. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021 Mar 6;397(10277):892-901. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT03740529
==R-BL==
R-BL: Rituximab, Bendamustine, Lenalidomide
R2B: Revlimid (Lenalidomide), Rituximab, Bendamustine
===Regimen===
Study 	Dates of enrollment	Evidence
Zaja et al. 2017	2012-2013 	Phase 2
====Targeted therapy====
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once on day 8
**Cycles 2 to 4: 375 mg/m2 IV once on day 1
*Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 14
====Chemotherapy====
*Bendamustine 70 mg/m2 IV once per day on days 2 & 3
28-day cycle for 4 cycles
====Subsequent treatment====
*Zaja et al. 2017, patients with PR/CR: Lenalidomide & rituximab consolidation
===References===
# Zaja F, Ferrero S, Stelitano C, Ferrari A, Salvi F, Arcari A, Musuraca G, Botto B, Spina M, Cellini C, Patti C, Liberati AM, Minotto C, Pileri SA, Ceccarelli M, Volpetti S, Ferranti A, Drandi D, Montechiarello E, Ladetto M, Carmichael J, Fanin R. Second-line rituximab, lenalidomide, and bendamustine in mantle cell lymphoma: a phase II clinical trial of the Fondazione Italiana Linfomi. Haematologica. 2017 May;102(5):e203-e206. Epub 2017 Jan 12. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
==RT-PEPC==
RT-PEPC: Rituximab, Thalidomide, Prednisone, Etoposide, Procarbazine, Cyclophosphamide
Study 	Dates of enrollment	Evidence
Ruan et al. 2010a	Not reported 	Non-randomized
===Induction===
====Targeted therapy====
*Rituximab (Rituxan) (dose not specified) IV once per day on days 1, 8, 15, 22
*Thalidomide (Thalomid) 50 mg PO once per day during months 1 & 2, then 100 mg PO once per day for month 3
====Glucocorticoid therapy====
*Prednisone (Sterapred) 20 mg PO once per day, taken after breakfast
====Chemotherapy====
*Etoposide (Vepesid) 50 mg PO once per day, taken after dinner
*Procarbazine (Matulane) 50 mg PO once per day, taken at bedtime
*Cyclophosphamide (Cytoxan) 50 mg PO once per day, taken after lunch
====Supportive therapy====
*Aspirin 81 mg PO once per day "after 2 episodes of DVT occurred."
3-month course, followed by:
===Maintenance===
====Targeted therapy====
*Rituximab (Rituxan) (dose not specified) IV once per day on days 1, 8, 15, 22
*Thalidomide (Thalomid) 100 mg PO once per day
====Chemotherapy====
*PEPC: Same medications and doses given per day as used in the induction phase, but titrated to maintain ANC of at least 2000/μL.
====Supportive therapy====
*Aspirin 81 mg PO once per day "after 2 episodes of DVT occurred."
4-month cycles
===References===
# Ruan J, Martin P, Coleman M, Furman RR, Cheung K, Faye A, Elstrom R, Lachs M, Hajjar KA, Leonard JP. Durable responses with the metronomic rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide regimen in elderly patients with recurrent mantle cell lymphoma. Cancer. 2010 Jun 1;116(11):2655-64. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==Temsirolimus & Rituximab==
===Regimen===
Study 	Dates of enrollment	Evidence
Ansell et al. 2011 (NCCTG N038H)	2005-2009 	Phase 2
====Targeted therapy====
*Temsirolimus (Torisel) 25 mg IV once per day on days 1, 8, 15, 22
*Rituximab (Rituxan) as follows:
**Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
**Cycles 3, 5, 7, 9, 11: 375 mg/m2 IV once on day 1
28-day cycle for up to 12 cycles
===References===
# NCCTG N038H: Ansell SM, Tang H, Kurtin PJ, Koenig PA, Inwards DJ, Shah K, Ziesmer SC, Feldman AL, Rao R, Gupta M, Erlichman C, Witzig TE. Temsirolimus and rituximab in patients with relapsed or refractory mantle cell lymphoma: a phase 2 study. Lancet Oncol. 2011 Apr;12(4):361-8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00109967
==Bortezomib & Rituximab (VR)==
VR: Velcade (Bortezomib), Rituximab
===Regimen===
Study 	Dates of enrollment	Evidence
Baiocchi et al. 2011 (OSU-0430)	2005-2009 	Phase 2, fewer than 20 pts
Note: Bortezomib dose was initially 1.5 mg/m2 but was reduced due to excess grade 3 neurotoxicity.
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1, 4, 8, 11
*Rituximab (Rituxan) as follows:
**Cycles 2 to 5: 375 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 5 cycles
====Subsequent treatment====
*OSU-0430, SD or better: Optional VR maintenance
===References===
# OSU-0430: Baiocchi RA, Alinari L, Lustberg ME, Lin TS, Porcu P, Li X, Johnston JS, Byrd JC, Blum KA. Phase 2 trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma. Cancer. 2011 Jun 1;117(11):2442-51. Epub 2010 Dec 14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00201877
=Consolidation after second-line therapy=
==BFR, then allo HSCT==
BFR: Bendamustine, Fludarabine, Rituximab
===Regimen===
Study 	Dates of enrollment	Evidence
Khouri et al. 2014 (MDACC 2008-0246)	2009-04 to 2013-02 	Phase 2, fewer than 20 pts in this subgroup
===References===
# MDACC 2008-0246: Khouri IF, Wei W, Korbling M, Turturro F, Ahmed S, Alousi A, Anderlini P, Ciurea S, Jabbour E, Oran B, Popat UR, Rondon G, Bassett RL Jr, Gulbis A. BFR (bendamustine, fludarabine, and rituximab) allogeneic conditioning for chronic lymphocytic leukemia/lymphoma: reduced myelosuppression and GVHD. Blood. 2014 Oct 2;124(14):2306-12. Epub 2014 Aug 21. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00880815
==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
==Lenalidomide & Rituximab (R2)==
===Regimen===
Study 	Dates of enrollment	Evidence
Zaja et al. 2017	2012-2013 	Phase 2
====Preceding treatment====
*R2B salvage x 4
====Targeted therapy====
*Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycle for 2 cycles
====Subsequent treatment====
*Zaja et al. 2017, patients with a continued PR/CR: Lenalidomide maintenance
===References===
# Zaja F, Ferrero S, Stelitano C, Ferrari A, Salvi F, Arcari A, Musuraca G, Botto B, Spina M, Cellini C, Patti C, Liberati AM, Minotto C, Pileri SA, Ceccarelli M, Volpetti S, Ferranti A, Drandi D, Montechiarello E, Ladetto M, Carmichael J, Fanin R. Second-line rituximab, lenalidomide, and bendamustine in mantle cell lymphoma: a phase II clinical trial of the Fondazione Italiana Linfomi. Haematologica. 2017 May;102(5):e203-e206. Epub 2017 Jan 12. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
==V-BEAM, then auto HSCT==
V-BEAM: Velcade (Bortezomib), BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan
===Regimen===
Study 	Dates of enrollment 	Evidence
William et al. 2014	Not reported to 2009-08-14	Phase 1/2
===References===
# William BM, Allen MS, Loberiza FR Jr, Bociek RG, Bierman PJ, Armitage JO, Vose JM. Phase I/II study of bortezomib-BEAM and autologous hematopoietic stem cell transplantation for relapsed indolent non-Hodgkin lymphoma, transformed, or mantle cell lymphoma. Biol Blood Marrow Transplant. 2014 Apr;20(4):536-42. Epub 2014 Jan 14. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=Maintenance after second-line therapy=
==Lenalidomide monotherapy==
===Regimen variant #1, 15 mg 21/28, 18 months===
Study 	Dates of enrollment	Evidence
Zaja et al. 2017	2012-2013 	Phase 2
====Preceding treatment====
*Lenalidomide & Rituximab salvage x 2
====Targeted therapy====
*Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
28-day cycle for up to 20 cycles (18 months)
===Regimen variant #2, 15 mg 21/28, indefinite===
Study 	Dates of enrollment	Evidence
Eve et al. 2012	2008-2010 	Phase 2
====Preceding treatment====
*Lenalidomide salvage x 6
====Targeted therapy====
*Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21 
28-day cycles
===References===
# Eve HE, Carey S, Richardson SJ, Heise CC, Mamidipudi V, Shi T, Radford JA, Auer RL, Bullard SH, Rule SA. Single-agent lenalidomide in relapsed/refractory mantle cell lymphoma: results from a UK phase II study suggest activity and possible gender differences. Br J Haematol. 2012 Oct;159(2):154-63. Epub 2012 Aug 9. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# Zaja F, Ferrero S, Stelitano C, Ferrari A, Salvi F, Arcari A, Musuraca G, Botto B, Spina M, Cellini C, Patti C, Liberati AM, Minotto C, Pileri SA, Ceccarelli M, Volpetti S, Ferranti A, Drandi D, Montechiarello E, Ladetto M, Carmichael J, Fanin R. Second-line rituximab, lenalidomide, and bendamustine in mantle cell lymphoma: a phase II clinical trial of the Fondazione Italiana Linfomi. Haematologica. 2017 May;102(5):e203-e206. Epub 2017 Jan 12. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
==Rituximab monotherapy==
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Forstpointner et al. 2004	1998-2001 	Phase 3 (E-esc)	Observation	Seems to have longer response duration (secondary endpoint)
====Preceding treatment====
*Salvage FCM x 4 versus R-FCM x 4, followed in 3 months by:
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
3-month cycle for 2 cycles
===Regimen variant #2===
Study 	Dates of enrollment 	Evidence
Lamm et al. 2011 (MCL 03)	2005 to not reported	Phase 2, fewer than 20 pts
====Preceding treatment====
*Salvage BORID x 6
====Targeted therapy====
*Rituximab (Rituxan) 375 mg/m2 IV once on day 1
8-week cycle for 4 cycles
===References===
# Forstpointner R, Dreyling M, Repp R, Hermann S, Hänel A, Metzner B, Pott C, Hartmann F, Rothmann F, Rohrberg R, Böck HP, Wandt H, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival as compared with FCM alone in patients with relapsed and refractory follicular and mantle cell lymphomas: results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood. 2004 Nov 15;104(10):3064-71. Epub 2004 Jul 29. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## Update: Forstpointner R, Unterhalt M, Dreyling M, Böck HP, Repp R, Wandt H, Pott C, Seymour JF, Metzner B, Hänel A, Lehmann T, Hartmann F, Einsele H, Hiddemann W; German Low Grade Lymphoma Study Group. Maintenance therapy with rituximab leads to a significant prolongation of response duration after salvage therapy with a combination of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) in patients with recurring and refractory follicular and mantle cell lymphomas: Results of a prospective randomized study of the German Low Grade Lymphoma Study Group (GLSG). Blood. 2006 Dec 15;108(13):4003-8. Epub 2006 Aug 31. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# MCL 03: Lamm W, Kaufmann H, Raderer M, Hoffmann M, Chott A, Zielinski C, Drach J. Bortezomib combined with rituximab and dexamethasone is an active regimen for patients with relapsed and chemotherapy-refractory mantle cell lymphoma. Haematologica. 2011 Jul;96(7):1008-14. Epub 2011 Apr 12. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00261612
==Bortezomib & Rituximab (VR)==
VR: Velcade (Bortezomib), Rituximab
===Regimen===
Study 	Dates of enrollment	Evidence
Baiocchi et al. 2011 (OSU-0430)	2005-2009 	Phase 2, fewer than 20 pts
====Preceding treatment====
*Salvage VR x 5
====Targeted therapy====
*Bortezomib (Velcade) 1.3 mg/m2 IV once per day on days 1 & 8
*Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1 & 8
6-month cycle for up to 4 cycles (2 years)
===References===
# OSU-0430: Baiocchi RA, Alinari L, Lustberg ME, Lin TS, Porcu P, Li X, Johnston JS, Byrd JC, Blum KA. Phase 2 trial of rituximab and bortezomib in patients with relapsed or refractory mantle cell and follicular lymphoma. Cancer. 2011 Jun 1;117(11):2442-51. Epub 2010 Dec 14. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC NCT00201877
=Prognosis=
==Mantle cell lymphoma international prognostic index (MIPI)==
Calculation generally require a calculator. The MIPI is calculated using the following formula: [0.03535 x age (in years)] + 0.6978 (if ECOG PS greater than 1) + [1.367 x log10(LDH/ULN)] + [0.9393 x log10(white cells per uL blood)]. Risk factors include:
*Age
*ECOG Performance Status
*Serum LDH level (note that reference ranges can vary widely!)
*Number of nodal sites
*WBC count
Risk stratification:
*Less than 5.7 points: Low risk
*5.7 to less than 6.2 points: Intermediate risk
*Greater than or equal to 6.2 points: High risk
</div>
===References===
# Hoster E, Dreyling M, Klapper W, Gisselbrecht C, van Hoof A, Kluin-Nelemans HC, Pfreundschuh M, Reiser M, Metzner B, Einsele H, Peter N, Jung W, Wörmann B, Ludwig WD, Dührsen U, Eimermacher H, Wandt H, Hasford J, Hiddemann W, Unterhalt M; German Low Grade Lymphoma Study Group; European Mantle Cell Lymphoma Network. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008 Jan 15;111(2):558-65. Epub 2007 Oct 25. Erratum in: Blood. 2008 Jun 15;111(12):5761. link to original article EuroPMC
# Hoster E, Klapper W, Hermine O, Kluin-Nelemans HC, Walewski J, van Hoof A, Trneny M, Geisler CH, Di Raimondo F, Szymczyk M, Stilgenbauer S, Thieblemont C, Hallek M, Forstpointner R, Pott C, Ribrag V, Doorduijn J, Hiddemann W, Dreyling MH, Unterhalt M. Confirmation of the mantle-cell lymphoma International Prognostic Index in randomized trials of the European Mantle-Cell Lymphoma Network. J Clin Oncol. 2014 May 1;32(13):1338-46. Epub 2014 Mar 31. link to original article EuroPMC
</div>
=Response criteria=
*Lugano Classification criteria (2014) link to PMC article EuroPMC
*NCI Sponsored International Working Group criteria (1999) EuroPMC
Category:Mantle cell lymphoma regimens
Category:Disease-specific pages
Category:Aggressive non-Hodgkin lymphomas
Category:B-cell lymphomas