Mantle cell lymphoma - historical

The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. As a general rule, this includes the inferior arm(s) of a randomized study, unless said regimens continue to be recommended by trustworthy sources such as the NCCN Guidelines. Is there a regimen missing from this list? See the main MCL page for current regimens.

9 regimens on this page 10 variants on this page

First-line therapy

CHOP

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CHOP: Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Nickenig et al. 2006 (GLSG '96)	1996-1998	Phase 3 (C)	MCP	Might have superior ORR
Lenz et al. 2005	2000-2002	Phase 3 (C)	R-CHOP	Inferior ORR

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
• Prednisone (Sterapred) 100 mg/m² PO once per day on days 1 to 5

21-day cycle for 6 to 8 cycles

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. GLSG '96: Nickenig C, Dreyling M, Hoster E, Pfreundschuh M, Trumper L, Reiser M, Wandt H, Lengfelder E, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. Combined cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) improves response rates but not survival and has lower hematologic toxicity compared with combined mitoxantrone, chlorambucil, and prednisone (MCP) in follicular and mantle cell lymphomas: results of a prospective randomized trial of the German Low-Grade Lymphoma Study Group. Cancer. 2006 Sep 1;107(5):1014-22. link to original article contains verified protocol PubMed

FC

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FC: Fludarabine, Cyclophosphamide

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rule et al. 2015 (CRUK-UCL-MCLIII)	2002-2010	Phase 3 (C)	FCR	Inferior OS

Chemotherapy

• Fludarabine (Fludara) 40 mg/m² PO once per day on days 1 to 3
  • Patients intolerant of the oral route received 25 mg/m² IV once per day on days 1 to 3
• Cyclophosphamide (Cytoxan) 250 mg/m² PO once per day on days 1 to 3
  • Patients intolerant of the oral route received 250 mg/m² IV once per day on days 1 to 3

Supportive medications

• PJP prophylaxis was mandatory

28-day cycle for up to 8 cycles

References

1. CRUK-UCL-MCLIII: Rule S, Smith P, Johnson PW, Bolam S, Follows G, Gambell J, Hillmen P, Jack A, Johnson S, Kirkwood AA, Kruger A, Pocock C, Seymour JF, Toncheva M, Walewski J, Linch D. The addition of rituximab to fludarabine and cyclophosphamide chemotherapy results in a significant improvement in overall survival in patients with newly diagnosed mantle cell lymphoma: results of a randomized UK National Cancer Research Institute trial. Haematologica. 2016 Feb;101(2):235-40. Epub 2015 Nov 26. link to original article contains verified protocol link to PMC article PubMed NCT00641095

FCR

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FCR: Fludarabine, Cyclophosphamide, Rituximab
R-FC: Rituximab, Fludarabine, Cyclophosphamide

Regimen variant #1, 30/250/375

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kluin-Nelemans et al. 2012 (MCLelderly)	2004-2010	Phase 3 (E-switch-ic)	R-CHOP	Inferior OS

Chemotherapy

• Fludarabine (Fludara) 30 mg/m² IV once per day on days 1 to 3
• Cyclophosphamide (Cytoxan) 250 mg/m² IV once per day on days 1 to 3

Targeted therapy

• Rituximab (Rituxan) 375 mg/m² (maximum dose of 750 mg) IV once on day 1

28-day cycle for 6 cycles

Subsequent treatment

• Responders: Rituximab versus interferon alfa maintenance

Regimen variant #2, 40/25/375

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rule et al. 2015 (CRUK-UCL-MCLIII)	2002-2010	Phase 3 (E-esc)	FC	Superior OS

Chemotherapy

• Fludarabine (Fludara) 40 mg/m² PO once per day on days 1 to 3
  • Patients intolerant of the oral route received 25 mg/m² IV once per day on days 1 to 3
• Cyclophosphamide (Cytoxan) 250 mg/m² PO once per day on days 1 to 3
  • Patients intolerant of the oral route received 250 mg/m² IV once per day on days 1 to 3

Targeted therapy

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

Supportive medications

• PJP prophylaxis was mandatory

28-day cycle for up to 8 cycles

References

1. 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 verified protocol 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
2. CRUK-UCL-MCLIII: Rule S, Smith P, Johnson PW, Bolam S, Follows G, Gambell J, Hillmen P, Jack A, Johnson S, Kirkwood AA, Kruger A, Pocock C, Seymour JF, Toncheva M, Walewski J, Linch D. The addition of rituximab to fludarabine and cyclophosphamide chemotherapy results in a significant improvement in overall survival in patients with newly diagnosed mantle cell lymphoma: results of a randomized UK National Cancer Research Institute trial. Haematologica. 2016 Feb;101(2):235-40. Epub 2015 Nov 26. link to original article contains verified protocol link to PMC article PubMed NCT00641095

MCP

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MCP: Mitoxantrone, Chlorambucil, Prednisone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Nickenig et al. 2006 (GLSG '96)	1996-1998	Phase 3 (E-switch-ic)	CHOP	Might have inferior ORR

Note: the chlorambucil dose is written in the reference as "3 x 3 mg/m²"; total dose per day is 9 mg/m².

Chemotherapy

• Mitoxantrone (Novantrone) 8 mg/m² IV once per day on days 1 & 2
• Chlorambucil (Leukeran) 3 mg/m² PO three times per day on days 1 to 5
• Prednisone (Sterapred) 25 mg/m² PO once per day on days 1 to 5

28-day cycle for 6 to 8 cycles

References

1. GLSG '96: Nickenig C, Dreyling M, Hoster E, Pfreundschuh M, Trumper L, Reiser M, Wandt H, Lengfelder E, Unterhalt M, Hiddemann W; German Low-Grade Lymphoma Study Group. Combined cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) improves response rates but not survival and has lower hematologic toxicity compared with combined mitoxantrone, chlorambucil, and prednisone (MCP) in follicular and mantle cell lymphomas: results of a prospective randomized trial of the German Low-Grade Lymphoma Study Group. Cancer. 2006 Sep 1;107(5):1014-22. link to original article contains verified protocol PubMed

VAD+C

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

Regimen

Study	Evidence
Gressin et al. 2010 (GOELAMS LM1996)	Phase 2

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)
• Dexamethasone (Decadron) 20 mg IV or PO twice per day on days 1 to 4
• Chlorambucil (Leukeran) 12 mg PO once per day on days 20 to 29

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 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 contains verified protocol link to PMC article PubMed NCT00285389

Relapsed or refractory

CHOP (Prednisolone)

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CHOP: 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 (C)	BCHOP	Inferior OS

Note: this regimen uses prednisolone.

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
• Prednisolone (Millipred) 100 mg PO once per day on days 1 to 5

21-day cycle for 6 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 verified protocol PubMed NCT00513955

FCM

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FCM: Fludarabine, Cyclophosphamide, Mitoxantrone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Forstpointner et al. 2004	1998-2001	Phase 3 (C)	R-FCM	Inferior OS

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 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 verified protocol PubMed content property of HemOnc.org
   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 verified protocol PubMed

Fludarabine & Rituximab (FR)

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FR: Fludarabine & Rituximab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Rummel et al. 2015 (StiL NHL 2-2003)	2003-2010	Phase 3 (C)	BR	Seems to have inferior OS

Chemotherapy

• Fludarabine (Fludara) 25 mg/m² (route not specified) once per day on days 1 to 3

Targeted therapy

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

28-day cycle for up to 6 cycles

References

1. 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 protocol PubMed NCT01456351