Staging page

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Guidelines

ESMO

• 2017: Dreyling et al. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Older

• 2014: Dreyling et al. Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PubMed

NCCN

• NCCN Guidelines - B-Cell Lymphomas

First-line therapy, pre-phase

CVP (Prednisolone)

CVP: Cyclophosphamide, Oncovin (Vincristine), Prednisolone

Regimen

Study	Years of enrollment	Evidence
Le Gouill et al. 2017 (LyMa)	2008-2012	Non-randomized portion of 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

• R-DHAC x 4 or R-DHAOx x 4 or R-DHAP x 4

References

1. 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 contains dosing details in supplement PubMed NCT00921414

First-line therapy, randomized data

Bendamustine & Rituximab (BR)

BR: Bendamustine, Rituximab
RB: Rituximab, Bendamustine

Regimen variant #1, 6 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rummel et al. 2013 (StiL NHL1)	2003-2008	Phase 3 (E-switch-ic)	R-CHOP	Superior PFS 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

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, depending on age and center

Regimen variant #2, 8 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Flinn et al. 2014 (BRIGHT)	2009-2012	Phase 3 (E-switch-ic)	1. R-CHOP 2. R-CVP	Superior PFS1 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

1. 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 contains dosing details in manuscript PubMed NCT00991211
   1. 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
2. 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 contains dosing details in manuscript link to PMC article PubMed NCT00877006
   1. 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 PubMed
3. 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 PubMed NCT01412879
   1. 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 PubMed
4. ACE-LY-308: NCT02972840
5. BGB-3111-306: NCT04002297

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kluin-Nelemans et al. 2012 (MCLelderly)	2004-2010	Phase 3 (C)	R-FC	Superior OS OS48: 62% vs 47% (HR 0.67, 95% CI 0.50-0.88)
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 up to 8 cycles

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Lenz et al. 2005	2000-2002	Phase 3 (E-esc)	CHOP	Superior ORR
Robak et al. 2015 (LYM-3002)	2008-2011	Phase 3 (C)	VR-CAP	Inferior OS1

¹Reported efficacy for LYM-3002 is based on the 2018 update.
Note the slight difference between the two protocols 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rummel et al. 2013 (StiL NHL1)	2003-2008	Phase 3 (C)	BR	Inferior 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 up to maximum of 6 cycles

Regimen variant #4, 3 cycles, rituximab in cycle 3 only

Study	Years of enrollment	Evidence
Delarue et al. 2012	2000-2003	Phase 2

Targeted therapy

• Rituximab (Rituxan) as follows:
  • Cycles 1 & 2: none
  • 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; patients who progress after first 2 cycles go directly to R-DHAP

Regimen variant #5, 4 cycles

Study	Years 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

1. 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 PubMed
2. 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 contains dosing details in manuscript PubMed
3. 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 contains dosing details in manuscript PubMed NCT00209209
   1. 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 PubMed
4. 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 contains dosing details in manuscript link to PMC article PubMed NCT00070447
   1. 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 PubMed
5. 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 contains dosing details in manuscript PubMed NCT00991211
   1. 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
6. 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 contains dosing details in manuscript link to PMC article PubMed NCT00877006
   1. 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 PubMed
7. 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 contains dosing details in manuscript PubMed NCT00722137
   1. 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 PubMed
8. 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 PubMed NCT00209222

R-CHOP (Prednisolone)

R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisolone

Example orders

• Example orders for R-CHOP in lymphoma

Regimen

Study	Years 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

• Patients with at least PR: R-HiDAC

References

1. 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 contains dosing details in manuscript PubMed

R-CHOP-14 (Prednisolone)

R-CHOP-14: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisolone every 14 days

Regimen

Study	Years of enrollment	Evidence
Le Gouill et al. 2017 (LyMa)	2008-2012	Non-randomized portion of 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

• 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

References

1. 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 contains dosing details in supplement PubMed NCT00921414

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)

Protocol

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hermine et al. 2016 (MCL Younger)	2004-2010	Phase 3 (E-esc)	See link	See link

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Chemotherapy, CHOP portion (Cycles 1, 3, 5)

• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1, 3, 5: 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) as follows:
  • Cycles 1, 3, 5: 50 mg/m² IV once on day 1
• Vincristine (Oncovin) as follows:
  • Cycles 1, 3, 5: 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1

Glucocorticoid therapy, CHOP portion (Cycles 1, 3, 5)

• Prednisone (Sterapred) as follows:
  • Cycles 1, 3, 5: 100 mg PO once per day on days 1 to 5

Glucocorticoid therapy, DHAP portion (Cycles 2, 4, 6)

• Dexamethasone (Decadron) as follows:
  • Cycles 2, 4, 6: 40 mg PO once per day on days 1 to 4

Chemotherapy, DHAP portion (Cycles 2, 4, 6)

• Cytarabine (Ara-C) as follows:
  • Cycles 2, 4, 6: 2000 mg/m² IV every 12 hours on day 2 (total dose per cycle: 4000 mg/m²)
• Cisplatin (Platinol) as follows:
  • Cycles 2, 4, 6: 100 mg/m² IV continuous infusion over 24 hours, started on day 1

21-day cycle for 6 cycles

Subsequent treatment

• Cytarabine, Melphalan, TBI with autologous hematopoietic stem cell transplant

References

1. 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 contains dosing details in manuscript PubMed NCT00209222
2. TRIANGLE: NCT02858258

R-CVP

R-CVP: Rituximab, Cyclophosphamide, Vincristine, Prednisone

Regimen

Study	Years 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

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00877006
   1. 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 PubMed

R-Hyper-CVAD/R-MA

R-Hyper-CVAD/R-MA: Rituximab, Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone alternating with Rituximab, Methotrexate, Ara-C (Cytarabine)

Protocol

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Romaguera et al. 2005	1999-2002	Phase 2
Wang et al. 2008	NR	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

• 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, Part A (cycles 1, 3, 5, 7)

• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1, 3, 5, 7: 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) as follows:
  • Cycles 1, 3, 5, 7: 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 (Cytoxan) on day 5
• Doxorubicin (Adriamycin) as follows:
  • Cycles 1, 3, 5, 7: 16.6 to 16.7 mg/m²/day IV continuous infusion over 72 hours, started on day 5 (total dose per cycle: 49.8 to 50.1 mg/m²)

Glucocorticoid therapy

• Dexamethasone (Decadron) as follows:
  • Cycles 1, 3, 5, 7: 40 mg IV or PO once per day on days 2 to 5, 12 to 15

Supportive therapy, Part A

• Mesna (Mesnex) as follows:
  • Cycles 1, 3, 5, 7: 600 mg/m²/day IV continuous infusion over 76 hours, started on day 2, 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan)
    • "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, Part B (cycles 2, 4, 6, 8)

• Methotrexate (MTX) as follows, by the following criteria:
  • Cycles 2, 4, 6, 8, patients with creatinine up to 1.5 mg/dL: 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)
  • Cycles 2, 4, 6, 8, patients with creatinine greater 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) as follows, by the following criteria:
  • Cycles 2, 4, 6, 8, standard patients: 3000 mg/m² IV over 2 hours every 12 hours on days 3 & 4 (total dose per cycle: 12,000 mg/m²)
  • Cycles 2, 4, 6, 8, patients older than 60 or with creatinine greater 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, Part B

• Folinic acid (Leucovorin) as follows:
  • Cycles 2, 4, 6, 8: 50 mg PO once on day 3, 12 hours after Methotrexate (MTX) 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 as follows:
  • Cycles 2, 4, 6, 8: 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 (Ara-C) infusion and was continued for 7 days to prevent chemical conjunctivitis.

Supportive therapy, all cycles

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)

References

1. 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 contains dosing details in manuscript PubMed
   1. 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 PubMed
   2. 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 PubMed
2. 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 contains dosing details in manuscript PubMed
3. 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 PubMed
4. 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 PubMed NCT00041132
5. 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 PubMed NCT01412879
   1. 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 PubMed

VR-CAP

VR-CAP: Velcade (Bortezomib), Rituximab, Cyclophosphamide, Adriamycin (Doxorubicin), Prednisone
VcR-CAP: Velcade (Bortezomib), Rituximab, Cyclophosphamide, Adriamycin (Doxorubicin), Prednisone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Robak et al. 2015 (LYM-3002)	2008-2011	Phase 3 (E-RT-esc)	R-CHOP	Superior OS1 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

1. 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 contains dosing details in manuscript PubMed NCT00722137
   1. 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 PubMed

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

Study	Years of enrollment	Evidence
Armand et al. 2016 (DFCI 12-168)	2012-2014	Phase 2

Chemotherapy, BR portion

• Bendamustine as follows:
  • Cycles 1 to 3: 90 mg/m² IV once per day on days 1 & 2

Chemotherapy, RC portion

• Cytarabine (Cytosar) by the following criteria:
  • Cycles 4 to 6, standard patients: 3000 mg/m² twice per day on days 1 & 2
  • Cycles 4 to 6, patients older than 60: 2000 mg/m² twice per day on days 1 & 2
  • Cycles 4 to 6, patients older than 60 with either renal dysfunction (Cr 1.3 to 2.0) or preexisting neurotoxicity: 1500 mg/m² twice per day on days 1 & 2
  • Cycles 4 to 6, patients older than 60 with both renal dysfunction (Cr 1.3 to 2.0) and preexisting neurotoxicity: 1000 mg/m² twice per day on days 1 & 2

Targeted therapy

• 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

Regimen variant #2

Study	Years 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

• Bendamustine as follows:
  • Cycles 1, 3, 5: 90 mg/m² IV once per day on days 1 & 2

Chemotherapy, RC portion

• Cytarabine (Cytosar) by the following criteria:
  • Cycles 2, 4, 6, standard patients: 3000 mg/m² twice per day on days 1 & 2
  • Cycles 2, 4, 6, patients older than 60 or with renal dysfunction (eGFR 40 to 59): 2000 mg/m² twice per day on days 1 & 2

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

28-day cycle, then 21-day cycle, then then 28-day cycle, then 21-day cycle, then 28-day cycle, then 21-day cycle

Subsequent treatment

• Auto HSCT

References

1. 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 contains dosing details in manuscript PubMed NCT01661881
   1. 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 contains dosing details in manuscript PubMed NCT01661881
2. 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 contains dosing details in manuscript PubMed NCT02728531

Chlorambucil & Rituximab (RClb)

Regimen

Study	Years of enrollment	Evidence
Sachanas et al. 2011	NR in abstract	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

• PR/CR: Rituximab maintenance

References

1. 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 contains dosing details in manuscript PubMed

Cladribine monotherapy

Regimen

Study	Years 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

1. 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 contains dosing details in manuscript link to PMC article PubMed

Cladribine & Rituximab

Regimen

Study	Years 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

1. 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 contains dosing details in manuscript link to PMC article PubMed

Lenalidomide & Rituximab (R²)

LR: Lenalidomide & Rituximab

Regimen

Study	Years of enrollment	Evidence
Ruan et al. 2015 (Cornell 1103011566)	2011-2014	Phase 2

Targeted therapy

• Lenalidomide (Revlimid) as follows:
  • Cycle 1: 20 mg PO once per day on days 1 to 21
  • Cycle 2 onwards (if no dose-limiting adverse events in cycle 1): 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

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT01472562
   1. 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 PubMed

Observation

Regimen

Study	Evidence
Martin et al. 2009	Retrospective

Also known as "watchful waiting".

References

1. 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. link to original article PubMed
2. 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 PubMed

R-BAC

R-BAC: Rituximab, Bendamustine, Ara-C (Cytarabine)

Regimen variant #1, 375/70/500 ("RBAC500")

Study	Years 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	Years 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
  • Cycle 2 onwards: 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

1. 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 contains dosing details in manuscript PubMed NCT00992134
2. 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 contains dosing details in abstract PubMed 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)

Protocol

Study	Years of enrollment	Evidence
Geisler et al. 2008 (NLG MCL2)	2000-2006	Phase 2

Note: This is 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

• Rituximab (Rituxan) as follows:
  • Cycles 3 & 5: 375 mg/m² IV once on day 1

Chemotherapy, maxi-R-CHOP portion

• 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

• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

21-day cycle for 3 cycles, alternating with R-HiDAC (6 cycles total)

Targeted therapy, R-HiDAC portion

• 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

• Cytarabine (Ara-C) by the following age-based criteria:
  • 60 and 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: 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

• 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 3 cycles, alternating with maxi-R-CHOP (6 cycles total)

Subsequent treatment

• BEAC with autologous HSCT or BEAM with autologous HSCT, 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

1. 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 PubMed ISRCTN87866680
   1. 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 PubMed
   2. 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 PubMed

R-DHAC

R-DHAC: Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Carboplatin

Regimen

Study	Years of enrollment	Evidence
Le Gouill et al. 2017 (LyMa)	2008-2012	Non-randomized portion of 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

• CR: R-BEAM with autologous HSCT
• PR: R-CHOP-14 x 4

References

1. 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 contains dosing details in supplement PubMed NCT00921414

R-DHAOx

R-DHAOx: Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Oxaliplatin

Regimen

Study	Years of enrollment	Evidence
Le Gouill et al. 2017 (LyMa)	2008-2012	Non-randomized portion of 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

• CR: R-BEAM with autologous HSCT
• PR: R-CHOP-14 x 4

References

1. 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 contains dosing details in supplement PubMed NCT00921414

R-DHAP

R-DHAP: Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin)

Regimen variant #1, 3 cycles

Study	Years 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 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

Regimen variant #2, 4 cycles

Study	Years of enrollment	Evidence
Le Gouill et al. 2017 (LyMa)	2008-2012	Non-randomized portion of 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

• CR: R-BEAM with autologous HSCT
• PR: R-CHOP-14 x 4

References

1. 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 PubMed
2. 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 contains dosing details in manuscript PubMed
3. 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 contains dosing details in supplement PubMed NCT00921414

R-HiDAC

R-HiDAC: Rituximab & High Dose Ara-C (Cytarabine)

Regimen

Study	Years of enrollment	Evidence
Van 't Veer et al. 2008 (HOVON 45)	2002-2005	Phase 2

Preceding treatment

• R-CHOP 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

References

1. 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 contains dosing details in manuscript PubMed

R-M-CHOP

R-M-CHOP: Rituximab, MTX (Methotrexate), Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin, Prednisone

Regimen

Study	Years 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 criteria:
  • Circulating mantle cells up to 10,000 cells/uL: 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

Supportive therapy

• Folinic acid (Leucovorin) 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/uL once or greater than 5000/uL twice
• Levofloxacin (Levaquin) 500 mg PO once per day, starting on day 6, to continue until ANC is greater than or equal to 1500/uL
• Fluconazole (Diflucan) 200 mg PO once per day, starting on day 6, to continue until ANC is greater than or equal to 1500/uL

2 cycles, with interval between cycle 1 & 2 based on count recovery

Subsequent treatment

• 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/uL, 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.
• Patients with bone marrow biopsy after treatment 2 has 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

CNS therapy

If cerebrospinal fluid (CSF) contained disease with CSF WBC count greater than or equal to 5 cells/uL:

• 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/uL:

• In addition to intrathecal chemotherapy above, patient also received 2 Gy x 12 fractions (total dose 24 Gy) cranial radiation

References

1. 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 contains dosing details in abstract link to PMC article PubMed NCT00020943

R-MACLO/R-IVAM

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

Protocol variant #1

Study	Years of enrollment	Evidence
Lossos et al. 2010 (UM-MCL1)	2004-2013	Phase 2

Targeted therapy, all cycles

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Chemotherapy, R-MACLO 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-MACLO portion (Cycles 1 & 3)

• Folinic acid (Leucovorin) 180 mg/m² IV once 12 hours after Methotrexate (MTX) 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/uL for two consecutive days

Next cycle to start after count recovery

Chemotherapy, R-IVAM 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-IVAM portion (Cycles 2 & 4)

• Mesna (Mesnex) 360 mg/m² IV every 3 hours on days 1 to 5, starting prior to Ifosfamide (Ifex) (total dose per cycle: 14,400 mg/m²)
• G-CSF starting on day 7, continued until ANC greater than 1500/uL for two consecutive days

Next cycle to start after count recovery + 2 weeks Total of 4 cycles

Subsequent treatment

• Patients achieving a CR: Thalidomide maintenance

Protocol variant #2

Study	Years of enrollment	Evidence
Lossos et al. 2010 (UM-MCL2)	2004-2013	Phase 2

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, all cycles

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Chemotherapy, R-MACLO 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-MACLO portion (Cycles 1 & 3)

• Folinic acid (Leucovorin) 180 mg/m² IV once 12 hours after Methotrexate (MTX) 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/uL for two consecutive days

Next cycle to start after count recovery

Chemotherapy, R-IVAM 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-IVAM portion (Cycles 2 & 4)

• Mesna (Mesnex) 360 mg/m² IV every 3 hours on days 1 to 5, starting prior to Ifosfamide (Ifex) (total dose per cycle: 14,400 mg/m²)
• G-CSF starting on day 7, continued until ANC greater than 1500/uL for two consecutive days

Next cycle to start after count recovery + 2 weeks Total of 4 cycles

Subsequent treatment

• Patients achieving a CR: Rituximab maintenance

References

1. 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 contains dosing details in manuscript PubMed NCT00450801
   1. 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 PubMed
2. 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 contains dosing details in manuscript PubMed NCT00878254
   1. 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 PubMed

RiPAD+C

RiPAD+C: Rituximab, PS-341 (Bortezomib), Adriamycin (Doxorubicin), Dexamethasone, Chlorambucil

Regimen

Study	Years 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
  • Cycle 2 onwards: 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

1. 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 contains dosing details in manuscript PubMed NCT00740415

R-VAD+C

R-VAD+C: Rituximab, Vincristine, Adriamycin (Doxorubicin), Dexamethasone, Chlorambucil

Regimen

Study	Years of enrollment	Evidence
Gressin et al. 2010 (GOELAMS LM2001)	2003-2005	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

• Transplant-eligible patients with more than partial response after 4 cycles: High-dose melphalan & TBI, then autologous HSCT 4 weeks after the 6th cycle

References

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00285389

VcR-CVAD

VcR-CVAD: Velcade (Bortezomib), Rituximab, Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone

Regimen

Study	Years of enrollment	Evidence
Chang et al. 2011	2005-2008	Phase 2
Chang et al. 2014 (ECOG E1405)	2007-NR	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/uL 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), patient choice

References

1. 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 contains dosing details in manuscript link to PMC article PubMed
2. 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 contains dosing details in manuscript link to PMC article PubMed NCT00433537

VR-CHOP

VR-CHOP: Velcade (Bortezomib), Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne

Regimen

Study	Years of enrollment	Evidence
Ruan et al. 2010 (Cornell 0309006313)	2004-2007	Phase 2
Till et al. 2015 (SWOG S0601)	2006-2008	Phase 2

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 (Rituxan)
• Diphenhydramine (Benadryl) (dose/route not specified) once on day 1, prior to Rituximab (Rituxan)

21-day cycle for 6 cycles

Subsequent treatment

• SWOG S0601: Bortezomib maintenance

References

1. 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 contains dosing details in manuscript PubMed NCT00151320
2. 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 contains dosing details in manuscript link to PMC article PubMed NCT00376961

Consolidation after first-line therapy

BEAC, then auto HSCT

BEAC: Rituximab, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Cyclophosphamide

Regimen

Study	Years of enrollment	Evidence
Geisler et al. 2008 (NLG MCL2)	2000-2006	Phase 2

Preceding treatment

• maxi-R-CHOP/R-HiDAC x 6 to 8

Autologous HSCT conditioning regimens Stem cells reinfused after chemotherapy, unclear exactly which day

References

1. 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 contains dosing details in manuscript PubMed ISRCTN87866680
   1. 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 PubMed
   2. 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 PubMed

BEAM, then auto HSCT

BEAM: Rituximab, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan

Regimen variant #1

Study	Years of enrollment	Evidence
Geisler et al. 2008 (NLG MCL2)	2000-2006	Phase 2

Preceding treatment

• maxi-R-CHOP/R-HiDAC x 6 to 8

Chemotherapy

• Carmustine (BCNU) 300 mg/m² IV once on day 1
• Etoposide (Vepesid) 100 mg/m² IV twice per day on days 2 to 5 (total dose: 800 mg/m²)
• Cytarabine (Ara-C) 400 mg/m² IV once per day on days 2 to 5
• Melphalan (Alkeran) 140 mg/m² IV once on day 6

Supportive therapy

• Autologous stem cells re-infused on unspecified day

One course

Stem cells re-infused after chemotherapy, unclear exactly which day

Regimen variant #2

Study	Years of enrollment	Evidence
Van 't Veer et al. 2008 (HOVON 45)	2002-2005	Phase 2

Preceding treatment

• R-CHOP x 3, then R-HiDAC x 1

Chemotherapy

• Carmustine (BCNU) 300 mg/m² IV once on day -7
• Etoposide (Vepesid) 100 mg/m² IV every 12 hours on days -6 to -3 (total dose: 800 mg/m²)
• Cytarabine (Ara-C) 100 mg/m² IV every 12 hours on days -6 to -3 (total dose: 800 mg/m²)
• Melphalan (Alkeran) 140 mg/m² IV once on day -2

Supportive therapy

• Autologous stem cells re-infused on day 0

One course

Stem cells re-infused on day 0

References

1. 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 contains dosing details in manuscript PubMed ISRCTN87866680
   1. 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 PubMed
   2. 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 PubMed
2. 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 contains dosing details in manuscript PubMed
3. 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 PubMed NCT01412879
   1. 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 PubMed

CBV, then auto HSCT

CBV: Cyclophosphamide, BiCNU (Carmustine), VP-16 (Etoposide)

Regimen

Study	Years 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 & stem cell mobilization

Autologous HSCT conditioning regimens

Subsequent treatment

• Rituximab (Rituxan) 375 mg/m² IV once per day on days +42 and +49

References

1. 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 contains dosing details in abstract link to PMC article PubMed NCT00020943
2. 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 PubMed NCT01412879
   1. 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 PubMed

Cyclophosphamide & TBI, then auto HSCT

CY/TBI: CYclophosphamide & Total Body Irradiation

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Dreyling et al. 2004	1996-2004	Phase 3 (E-esc)	Interferon alfa	Seems to have superior OS1 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 x 4 to 6, then Dexa-BEAM & G-CSF mobilization

Autologous HSCT conditioning regimens Stem cells re-infused on day 0

References

1. 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 contains dosing details in manuscript PubMed
   1. 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 PubMed

Ibritumomab tiuxetan protocol

Regimen

Study	Years of enrollment	Evidence
Smith et al. 2012 (ECOG E1499)	2003-2005	Phase 2

Preceding treatment

• R-CHOP 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 criteria:
  • Platelets at least 150 x 10⁹/L: 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day 8, given second
  • Platelets between 100 and 149 x 10⁹/L: 0.3 mCi/kg (maximum dose of 32 mCi) IV once on day 8, given second

8-day course

References

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00070447
   1. 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 PubMed

Melphalan & TBI, then auto HSCT

Melphalan & TBI: Melphalan & Total Body Irradiation

Regimen

Study	Years of enrollment	Evidence
Gressin et al. 2010 (GOELAMS LM1996)	1996-2000	Phase 2
Gressin et al. 2010 (GOELAMS LM2001)	2003-2005	Phase 2

Preceding treatment

• GOELAMS LM1996: VAD+C x 6
• GOELAMS LM2001: R-VAD+C x 6

Autologous HSCT conditioning regimens Stem cells reinfused after chemoradiotherapy, unclear exactly which day

References

1. 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 PubMed
2. 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 PubMed NCT00285389

R-BEAM, then auto HSCT

R-BEAM: Rituximab, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan

Regimen

Study	Years of enrollment	Evidence
Le Gouill et al. 2017 (LyMa)	2008-2012	Non-randomized portion of RCT

Preceding treatment

• CR: R-DHAC x 4 or R-DHAOx x 4 or R-DHAP x 4
• PR: R-DHAC x 4 or R-DHAOx x 4 or R-DHAP x 4, then R-CHOP-14 x 4

Autologous HSCT conditioning regimens Stem cells re-infused on day 0

Subsequent treatment

• Observation versus Rituximab maintenance

References

1. 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 contains dosing details in manuscript PubMed NCT00921414

TAM6, then auto HSCT

TAM: Total-body irradiation, Ara-C (Cytarabine), Melphalan

Regimen

Study	Years of enrollment	Evidence
Delarue et al. 2012	2000-2003	Phase 2

Preceding treatment

• R-DHAP x 3

Autologous HSCT conditioning regimens

References

1. 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 contains dosing details in manuscript PubMed

Maintenance after first-line therapy

Bortezomib monotherapy

Regimen

Study	Years of enrollment	Evidence
Till et al. 2015 (SWOG S0601)	2006-2008	Phase 2

Preceding treatment

• VR-CHOP 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

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00376961

Lenalidomide monotherapy

Regimen variant #1, 10 mg/day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ladetto et al. 2020 (MCL0208)	2010-2015	Phase 3 (E-esc)	Observation	Seems to have superior PFS PFS36: 80% vs 64% (HR 0.51, 95% CI 0.30-0.87)

Note: this dosing was intended for patients with platelet count between 60 and 100 x 10⁹/L.

Preceding treatment

• BEAM, then auto HSCT

Targeted therapy

• Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21

28-day cycle for 24 cycles

Regimen variant #2, 15 mg/day

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ladetto et al. 2020 (MCL0208)	2010-2015	Phase 3 (E-esc)	Observation	Seems to have superior PFS PFS36: 80% vs 64% (HR 0.51, 95% CI 0.30-0.87)

Note: this dosing was intended for patients with platelet count greater than 100 x 10⁹/L.

Preceding treatment

• BEAM, then auto HSCT

Targeted therapy

• Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21

28-day cycle for 24 cycles

References

1. 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 contains dosing details in abstract PubMed NCT02354313

Lenalidomide & Rituximab (R²)

Regimen

Study	Years 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
  • Even cycles: no treatment

28-day cycles

References

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT01472562
   1. 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 PubMed

Rituximab monotherapy

Regimen variant #1, 6 doses

Study	Years of enrollment	Evidence
Sachanas et al. 2011	NR in abstract	Phase 2

Preceding treatment

• Chlorambucil & Rituximab 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	Years of enrollment	Evidence
Räty et al. 2012	NR in abstract	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	Years of enrollment	Evidence
Chang et al. 2014 (ECOG E1405)	2007-NR	Phase 2

Preceding treatment

• VcR-CVAD 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Le Gouill et al. 2017 (LyMa)	2008-2012	Phase 3 (E-esc)	Observation	Seems to have superior OS OS48: 89% vs 80% (HR 0.50, 95% CI 0.26-0.99)

Preceding treatment

• R-BEAM with autologous HSCT

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	Years of enrollment	Evidence
Lossos et al. 2010 (UM-MCL2)	NR in abstract	Phase 2

Preceding treatment

• R-MACLO/R-IVAM 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kluin-Nelemans et al. 2012 (MCLelderly)	2004-2010	Phase 3 (E-switch-ooc)	Interferon alfa	Superior combined OS1

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 x 6

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

2-month cycles

References

1. 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 contains dosing details in manuscript PubMed NCT00878254
   1. 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 PubMed
2. 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 contains dosing details in manuscript PubMed
3. 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 contains dosing details in manuscript PubMed NCT00209209
   1. 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 PubMed
4. 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 contains dosing details in manuscript PubMed
   1. Update: Abstract: Riikka Räty, Tuomo Honkanen, Esa Jantunen, MD, PhD, Sirkku Jyrkkiö, Marja-Liisa Karjalainen-Lindsberg, MD, PhD, Outi Kuittinen, Minna Lehto, Maija Mikkola, Eira Poikonen, Auvo Rauhala, Johanna Rimpiläinen, Anu Räsänen, MD, Sanna Siitonen, Merja Suominen, MD, Mirja Vapaatalo and Erkki Elonen. Rituximab Maintenance Bimonthly for Two Years after Prolonged Immunochemotherapy in Elderly Patients with Mantle Cell Lymphoma (MCL) Results in Long Remissions: Update with Six-Year Follow-up of a Prospective Study By the Finnish Lymphoma Group. Blood 2014 124:1749. link to abstract
5. 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 contains dosing details in manuscript link to PMC article PubMed NCT00433537
6. 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 contains dosing details in manuscript PubMed NCT00921414
7. ECOG-ACRIN EA4151: NCT03267433

Relapsed or refractory, randomized data

Acalabrutinib monotherapy

Regimen

FDA-recommended dose

Study	Years 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

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

1. 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 contains dosing details in abstract link to PMC article PubMed NCT02213926
2. BRUIN MCL-321: NCT04662255

BCHOP

BCHOP: Bortezomib, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisolone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Furtado et al. 2014 (NCRN-Ply-26s)	2007-2011	Randomized Phase 2 (E-esc)	CHOP	Superior OS 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

1. 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 contains dosing details in manuscript PubMed NCT00513955

Bendamustine & Rituximab (BR)

BR: Bendamustine, Rituximab

Regimen variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Czuczman et al. 2015	NR	Phase 2
Rummel et al. 2015 (StiL NHL 2-2003)	2003-2010	Phase 3 (E-switch-ic)	FR	Seems to have superior OS

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 (Rituxan)

28-day cycle for 6 to 8 cycles

Regimen variant #2

Study	Years of enrollment	Evidence
Rummel et al. 2005	2000-2003	Phase 2, <20 pts in subgroup
Robinson et al. 2008 (SDX-105-01)	2004-2005	Phase 2, <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 (Rummel et al. 2005) or up to 6 cycles (SDX-105-01; see note)

References

1. 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 contains dosing details in manuscript PubMed
2. SDX-105-01: 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 contains dosing details in manuscript PubMed NCT00069758
3. 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 contains dosing details in manuscript PubMed
4. 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 contains dosing details in abstract PubMed NCT01456351

Cladribine monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Inwards et al. 2008 (NCCTG 95-80-53)	2003-2005	Phase 2, <20 pts
Hess et al. 2009 (OPTIMALMCL)	2005-2007	Phase 3 (C)	1. Temsirolimus; 175/25	Might have inferior PFS
			2. Temsirolimus; 175 -> 75	Inferior 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

1. 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 contains dosing details in manuscript link to PMC article PubMed
2. 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 contains dosing details in manuscript PubMed NCT00117598

Ibrutinib monotherapy

Regimen

FDA-recommended dose

Study	Years 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)	2012-2013	Phase 3 (E-switch-ic)	Temsirolimus	Might have superior OS1 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	TBD

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

Continued indefinitely

References

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT01236391
   1. 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 PubMed
2. 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 contains dosing details in manuscript PubMed NCT01646021
   1. 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 PubMed
   2. 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 PubMed
3. BRUIN MCL-321: NCT04662255

Lenalidomide monotherapy

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Wiernik et al. 2008 (CC-5013-NHL-002)	2005-2006	Phase 2, <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: 1. Chlorambucil 2. Cytarabine 3. Fludarabine 4. Gemcitabine 5. Rituximab	Superior PFS Median PFS: 8.7 vs 5.2 mo (HR 0.61, 95% CI 0.44-0.84)

Participants in EMERGE "were required to have had 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." Investigator's choice in the SPRINT trial was restricted to single-agent therapy with cytarabine, rituximab, gemcitabine, fludarabine, or chlorambucil.

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

1. 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 contains dosing details in manuscript PubMed NCT00179660
   1. 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 contains dosing details in manuscript PubMed
   2. 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 PubMed
2. 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 contains dosing details in manuscript PubMed NCT00413036
   1. 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 PubMed
   2. 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 PubMed
3. 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 contains dosing details in manuscript PubMed
4. 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 contains dosing details in manuscript link to PMC article PubMed NCT00737529
   1. 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 PubMed
   2. 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 PubMed
5. 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 PubMed NCT00875667

R-FCM

R-FCM: Rituximab, Fludarabine, Cyclophosphamide, Mitoxantrone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Forstpointner et al. 2004	1998-2001	Phase 3 (E-esc)	FCM	Superior OS

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

• PR/CR: Rituximab maintenance versus no further treatment

References

1. 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 contains dosing details in manuscript PubMed
   1. 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 contains dosing details in manuscript PubMed

Temsirolimus monotherapy

Regimen variant #1, 25 mg

Study	Years 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 (Torisel)

28-day cycle for up to 13 cycles, stopped at various timepoints (see paper for details)

Regimen variant #2, 175 -> 75

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Hess et al. 2009 (OPTIMALMCL)	2005-2007	Phase 3 (E-switch-ooc)	Investigator's choice: 1. Alemtuzumab 2. Chlorambucil 3. Cladribine 4. Etoposide 5. Fludarabine 6. Gemcitabine 7. Thalidomide 8. Vinblastine	Superior PFS Median PFS: 4.8 vs 1.9 mo (HR 0.44, 97.5% CI 0.25-0.78)
			9. Temsirolimus; 175/25	Not reported
Dreyling et al. 2015 (RAY)	2012-2013	Phase 3 (C)	Ibrutinib	Might have inferior OS1	Worse HRQoL

¹Reported efficacy is based on the 2018 update.
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 (Torisel)
• Corticosteroid use was not allowed in OPTIMAL.

21-day cycles

Regimen variant #3, 250 mg

Study	Years 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

1. 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 contains dosing details in manuscript PubMed
2. 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 contains dosing details in manuscript link to PMC article PubMed
3. 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 contains dosing details in manuscript PubMed NCT00117598
4. 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 contains dosing details in manuscript PubMed NCT01646021
   1. 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 PubMed
   2. 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 PubMed

Zanubrutinib monotherapy

Regimen

FDA-recommended dose

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Tam et al. 2019 (BGB-3111-AU-003)	2014-2018	Phase 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

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

28-day cycle for up to 39 cycles (3 years)

References

1. 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 PubMed NCT02343120
   1. 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 PubMed
2. 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 contains dosing details in manuscript PubMed NCT03206970
   1. 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 PubMed
3. BRUIN MCL-321: NCT04662255

Relapsed or refractory, non-randomized or retrospective data

Arsenic trioxide & Chlorambucil

Regimen

Study	Years 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

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 cycle for 1 cycle, then 28-day cycles

References

1. 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 contains dosing details in manuscript PubMed

BeRT

BeRT: Bendamustine, Rituximab, Temsirolimus

Regimen

Study	Years of enrollment	Evidence
Hess et al. 2015 (Mz-341)	2010-NR	Phase 1/2, <20 pts reported

The temsirolimus dose was the maximum dose used in the phase I 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

1. 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 contains dosing details in manuscript PubMed NCT01078142

BDR

BDR: Bortezomib, Dexamethasone, Rituximab
BORID: BOrtezomib, RItuximab, Dexamethasone

Regimen

Study	Years of enrollment	Evidence
Lamm et al. 2011 (MCL 03)	2005-NR	Phase 2, <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

• Responding patients: Rituximab consolidation

References

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00261612

Bortezomib monotherapy

Regimen variant #1, 1.3 mg/m²

Study	Years of enrollment	Evidence
Fisher et al. 2006 (PINNACLE)	2003-NR	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	Years of enrollment	Evidence
O'Connor et al. 2005	2001-2003	Phase 2, <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

1. 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 contains dosing details in manuscript PubMed
2. 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 contains dosing details in manuscript PubMed
   1. 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 contains dosing details in abstract link to PMC article PubMed

Brexucabtagene autoleucel monotherapy

Regimen

Study	Years of enrollment	Evidence
Wang et al. 2020 (ZUMA-2)	2016-2019	Phase 2 (RT)

Preceding treatment

• FC conditioning

Immunotherapy

• Brexucabtagene autoleucel (Tecartus) 2 x 10⁶ CAR T cells/kg IV once on day 0

References

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT02601313

Everolimus monotherapy

Regimen

Study	Years of enrollment	Evidence
Renner et al. 2012 (SAKK 36/06)	2007-2010	Phase 2
Wang et al. 2014 (PILLAR-1)	2008-2011	Phase 2

Note: to be taken in a fasting state or with a light fat-free meal.

Targeted therapy

• Everolimus (Afinitor) 10 mg PO once per day

28-day cycles

References

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00516412
2. 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 contains dosing details in manuscript PubMed NCT00702052

Ibrutinib & Rituximab

Regimen

Study	Years 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) 560 mg PO once per day
• Rituximab (Rituxan) as follows:
  • Cycle 1: 375 mg/m² IV once per day on days 1, 8, 15, 22
  • Cycle 2: no rituximab
  • Cycles 3 to 7: 375 mg/m² IV once on day 1
  • Cycle 8 onwards: 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

1. 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 contains dosing details in manuscript PubMed NCT01880567

Ibrutinib & Venetoclax

Regimen

Study	Years 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
• Venetoclax (Venclexta) as follows:
  • Week 5: 50 mg PO once per day
  • Week 6: 100 mg PO once per day
  • Week 7: 200 mg PO once per day
  • Weeks 8 to 15: 400 mg PO once per day
  • Week 16 onwards:
    • CR achieved: 400 mg PO once per day
    • CR not achieved: 800 mg PO once per day

Continued indefinitely

References

1. 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 contains dosing details in manuscript PubMed NCT02471391

Lenalidomide & Rituximab (R²)

Regimen variant #1, 10/375

Study	Years of enrollment	Evidence
Chong et al. 2015 (UPCC 02408)	2008-2012	Phase 2, <20 pts in subgroup

Targeted therapy

• Lenalidomide (Revlimid) 10 mg PO once per day
• Rituximab (Rituxan) as follows:
  • Cycle 3 only: 375 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycles

Regimen variant #2, 25/375

Study	Years of enrollment	Evidence
Wang et al. 2012 (MDACC 2005-0461)	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 only: 375 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycles

References

1. MDACC 2005-0461: 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 contains dosing details in abstract PubMed NCT00294632
2. UPCC 02408: 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 contains dosing details in manuscript PubMed NCT00783367

Obinutuzumab monotherapy

Regimen

Study	Years 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 (Gazyva)
• An antihistamine once per infusion, 30 minutes prior to Obinutuzumab (Gazyva)
  • 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

1. 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 PubMed NCT00517530
   1. 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 contains dosing details in manuscript PubMed
   2. 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 contains dosing details in manuscript PubMed
   3. 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 contains dosing details in manuscript PubMed

PEP-C

PEP-C: Prednisone, Etoposide, Procarbazine, Cyclophosphamide

Protocol

Study	Evidence
Coleman et al. 2008MCL	Retrospective

Glucocorticoid therapy, induction phase

• Prednisone (Sterapred) 20 mg PO once per day after breakfast

Chemotherapy, induction phase

• Etoposide (Vepesid) 50 mg PO once per day after dinner
• Procarbazine (Matulane) 50 mg PO once per day at bedtime
• Cyclophosphamide (Cytoxan) 50 mg PO once per day after lunch

Supportive therapy

• Ondansetron (Zofran) (dose not specified) with each Procarbazine (Matulane) 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)

Chemotherapy, maintenance phase

• Same medications and doses given per day as used 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.

References

1. 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 contains dosing details in manuscript PubMed

R-BL

R-BL: Rituximab, Bendamustine, Lenalidomide
R2B: Revlimid (Lenalidomide), Rituximab, Bendamustine

Regimen

Study	Years 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

• Patients with PR/CR: Lenalidomide & rituximab consolidation

References

1. 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 contains dosing details in manuscript PubMed

RT-PEPC

RT-PEPC: Rituximab, Thalidomide, Prednisone, Etoposide, Procarbazine, Cyclophosphamide

Protocol

Study	Years of enrollment	Evidence
Ruan et al. 2010a	NR	Non-randomized

Targeted therapy, induction phase

• 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, induction phase

• Prednisone (Sterapred) 20 mg PO once per day after breakfast

Chemotherapy, induction phase

• Etoposide (Vepesid) 50 mg PO once per day after dinner
• Procarbazine (Matulane) 50 mg PO once per day at bedtime
• Cyclophosphamide (Cytoxan) 50 mg PO once per day after lunch

Supportive therapy, induction phase

• Aspirin 81 mg PO once per day "after 2 episodes of DVT occurred."

3-month course, followed by:

Targeted therapy, maintenance phase

• Rituximab (Rituxan) (dose not specified) IV once per day on days 1, 8, 15, 22
• Thalidomide (Thalomid) 100 mg PO once per day

Chemotherapy, maintenance phase

• PEPC: Same medications and doses given per day as used in the induction phase, but titrated to maintain ANC of at least 2000/uL.

Supportive therapy, maintenance phase

• Aspirin 81 mg PO once per day "after 2 episodes of DVT occurred."

4-month cycles

References

1. 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 contains dosing details in manuscript link to PMC article PubMed

Temsirolimus & Rituximab

Regimen

Study	Years 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 up to 12 cycles

References

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00109967

Bortezomib & Rituximab (VR)

VR: Velcade (Bortezomib), Rituximab

Regimen

Study	Years of enrollment	Evidence
Baiocchi et al. 2011 (OSU-0430)	2005-2009	Phase 2, <20 pts

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

• SD or better: Optional VR maintenance

References

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00201877

Consolidation after second-line therapy

BFR, then allo HSCT

BFR: Bendamustine, Fludarabine, Rituximab

Regimen

Study	Years of enrollment	Evidence
Khouri et al. 2014 (MDACC 2008-0246)	2009-2013	Phase 2, <20 pts in this subgroup

Chemotherapy

• Bendamustine 130 mg/m² IV once per day on days -5 to -3
• Fludarabine (Fludara) 30 mg/m² IV over 30 minutes once per day on days -5 to -3

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once per day on days -13, -6, +1, +8

Immunotherapy

• Allogeneic stem cells transfused on day 0

GVHD prophylaxis

• See article for GVHD prophylaxis information

One course

Immunotherapy

• Allogeneic stem cells

Stem cells transfused on day 0

References

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00880815

FluBuCy, then allo HSCT

FluBuCy: Fludarabine, Busulfan, Cyclophosphamide

Regimen

Study	Years of enrollment	Evidence
Glass et al. 2014 (DSHNHL R3)	2004-2009	Phase 2

Chemotherapy

• Fludarabine (Fludara) 25 mg/m²/day IV on days -8 to -4
• Busulfan (Myleran) 4 mg/kg/day PO on days -6 to -4
• Cyclophosphamide (Cytoxan) 60 mg/kg/day IV on days -3 and -2

Immunotherapy

• Allogeneic stem cells transfused on day 0

GVHD prophylaxis

• Antithymocyte globulin, rabbit ATG (Thymoglobulin) 2 mg/kg IV from day -3 to -1 (unclear if this is a total dose or a daily dose)
  • Option also to use ATG-Fresenius S at a higher dose of 10 mg/kg
• Tacrolimus (Prograf) 8 to 12 mcg/L (route/frequency not specified) starting on day -1, tapered from day +100 in absence of GVHD
• Mycophenolate mofetil (CellCept) 1000 mg (route not specified) twice per day from day +1 to +28

One course

Immunotherapy

• Allogeneic stem cells

Stem cells transfused on day 0

References

1. 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 link to original protocol (in German) contains dosing details in manuscript PubMed NCT00785330

Lenalidomide & Rituximab (R²)

Regimen

Study	Years of enrollment	Evidence
Zaja et al. 2017	2012-2013	Phase 2

Preceding treatment

• R2B 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

• Patients with a continued PR/CR: Lenalidomide maintenance

References

1. 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 contains dosing details in manuscript PubMed

Maintenance after second-line therapy

Lenalidomide monotherapy

Regimen variant #1, 15 mg 21/28, 18 months

Study	Years of enrollment	Evidence
Zaja et al. 2017	2012-2013	Phase 2

Preceding treatment

• Lenalidomide & Rituximab 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	Years of enrollment	Evidence
Eve et al. 2012	2008-2010	Phase 2

Preceding treatment

• Lenalidomide x 6

Targeted therapy

• Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21

28-day cycles

References

1. 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 contains dosing details in manuscript PubMed
2. 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 contains dosing details in manuscript PubMed

Rituximab monotherapy

Regimen variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Forstpointner et al. 2004	1998-2001	Phase 3 (E-esc)	Observation	Seems to have superior response duration

Preceding treatment

• 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	Years of enrollment	Evidence
Lamm et al. 2011 (MCL 03)	2005-NR	Phase 2, <20 pts

Preceding treatment

• BORID x 6

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1

8-week cycle for 4 cycles

References

1. 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 contains dosing details in manuscript PubMed
   1. 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 contains dosing details in manuscript PubMed
2. 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 contains dosing details in manuscript link to PMC article PubMed NCT00261612

Bortezomib & Rituximab (VR)

VR: Velcade (Bortezomib), Rituximab

Regimen

Study	Years of enrollment	Evidence
Baiocchi et al. 2011 (OSU-0430)	2005-2009	Phase 2, <20 pts

Preceding treatment

• 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

1. 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 contains dosing details in manuscript link to PMC article PubMed NCT00201877

Investigational agents

These are drugs under study with at least some promising results for this disease.

• Abexinostat (PCI-24781)
• Alisertib (MLN8237)

Prognosis

Mantle cell lymphoma international prognostic index (MIPI)

Calculation generally require a calculator. The MIPI is calculated using the following formula: [0.03535 × age (in years)] + 0.6978 (if ECOG PS greater than 1) + [1.367 × log₁₀(LDH/ULN)] + [0.9393 × 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

References

1. 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 PubMed
2. 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 PubMed

Response criteria

• Lugano Classification criteria (2014) link to PMC article PubMed
• NCI Sponsored International Working Group criteria (1999) PubMed