Mantle cell lymphoma

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81 regimens on this page 105 variants on this page

Untreated, randomized data

BR

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BR: Bendamustine, Rituximab

Regimen

Study	Evidence	Comparator	Efficacy
Rummel et al. 2013 (StiL NHL1)	Phase III	R-CHOP	Superior PFS
Flinn et al. 2014 (BRIGHT)	Phase III	R-CHOP R-CVP	Seems non-inferior

Chemotherapy

Note: the bendamustine infusion instructions are for the Treanda formulation, which was discontinued on 3/31/2016.

• Bendamustine 90 mg/m² IV over 30 to 60 minutes once per day on days 1 & 2
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Supportive medications

• 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 (StiL NHL1) or 8 cycles (BRIGHT)

References

1. 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; on behalf of the Study group indolent Lymphomas (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 verified protocol PubMed
   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. 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 verified protocol PubMed

CHOP

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

Regimen

Study	Evidence	Comparator	Efficacy
Lenz et al. 2005	Phase III	R-CHOP	Inferior ORR
Nickenig et al. 2006	Phase III	MCP	Might have superior 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 per cycle) 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. 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. 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	Evidence	Comparator	Efficacy
Rule et al. 2015 (CRUK-UCL-MCLIII)	Phase III	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. 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 PubMed

FCR

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

Regimen #1

Study	Evidence	Comparator	Efficacy
Rule et al. 2015 (CRUK-UCL-MCLIII)	Phase III	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
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Supportive medications

• PJP prophylaxis was mandatory

28-day cycle for up to 8 cycles

Regimen #2, "R-FC"

Study	Evidence	Comparator	Efficacy
Kluin-Nelemans et al. 2012	Phase III	R-CHOP	Inferior OS

Chemotherapy

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

28-day cycle for 6 cycles

Responding patients were randomized to receive rituximab maintenance versus interferon alfa maintenance.

References

1. 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
2. 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 PubMed

MCP

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MCP: Mitoxantrone, Chlorambucil, Prednisolone

Regimen

Study	Evidence	Comparator	Efficacy
Nickenig et al. 2006	Phase III	CHOP	Might have inferior ORR

Chemotherapy

• Mitoxantrone (Novantrone) 8 mg/m² IV once per day on days 1 & 2
• Chlorambucil (Leukeran) 3 mg/m² PO TID (written in the reference as "3 x 3"; total daily dose is 9 mg/m²) 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. 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

R-CHOP

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

Synonyms: R-CHOP-21, CHOP-R

Structured Concept: C9760 (NCI-T), C0393023 (NCI-MT/UMLS)

Example orders

• Example orders for R-CHOP in lymphoma

Regimen #1

Study	Evidence	Comparator	Efficacy
Lenz et al. 2005	Phase III	CHOP	Superior ORR
Robak et al. 2015 (LYM-3002)	Phase III	VR-CAP	Inferior PFS

Note the slight differences between the two regimens.

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once on day -1 (Lenz et al. 2005) or day 1 (LYM-3002)
• 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 2mg per cycle) IV once on day 1
• 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 #2

Study	Evidence	Comparator	Efficacy
Kluin-Nelemans et al. 2012	Phase III	R-FC	Superior OS
Flinn et al. 2014 (BRIGHT)	Phase III	BR	Seems non-inferior

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• 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 per cycle) IV once on day 1
• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

Supportive medications

• 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

Patients responding after 8 cycles in Kluin-Nelemans et al. 2012 were randomized to receive rituximab maintenance versus interferon alfa maintenance.

Regimen #3

Study	Evidence	Comparator	Efficacy
Rummel et al. 2013 (StiL NHL1)	Phase III	BR	Inferior PFS

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• 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
• Prednisone (Sterapred) 100 mg once per day on days 1 to 5

21-day cycle up to maximum of 6 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. 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. 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
3. 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; on behalf of the Study group indolent Lymphomas (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 verified protocol PubMed
   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
4. 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 verified protocol PubMed
5. 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 verified protocol PubMed
6. 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

R-CHOP/R-DHAP

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R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone
R-DHAP: Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin)

Regimen

Study	Evidence	Comparator	Efficacy
Hermine et al. 2016 (MCL Younger)	Phase III	R-CHOP	Seems to have superior TTTF

Note: dosing details were not available in the abstract. The doses here are similar to the regimen of R-CHOP followed by R-DHAP by Delarue et al. 2012; please see original paper for actual dosing details.

Chemotherapy, R-CHOP portion

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• 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
• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 5

21-day cycle for up to 3 cycles, alternating with R-DHAP

Chemotherapy, R-DHAP portion

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• Dexamethasone (Decadron) 40 mg once per day on days 1 to 4
• Cytarabine (Cytosar) 2000 mg/m² IV Q12H x 2 doses on day 2 (total dose is 4000 mg/m²)
• Cisplatin (Platinol) 100 mg/m² IV continuous infusion over 24 hours on day 1

21-day cycle for 3 cycles, alternating with R-CHOP

Treatment followed by high-dose therapy with autologous hematopoietic cell transplant.

References

1. 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

R-CVP

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R-CVP: Rituximab, Cyclophosphamide, Vincristine, Prednisone

Regimen

Study	Evidence	Comparator	Efficacy
Flinn et al. 2014 (BRIGHT)	Phase III	BR	Seems non-inferior

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• 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 per cycle) IV once on day 1
• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

Supportive medications

• 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. 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 verified protocol PubMed

VR-CAP

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

Regimen

Study	Evidence	Comparator	Efficacy
Robak et al. 2015 (LYM-3002)	Phase III	R-CHOP	Superior PFS

Chemotherapy

• 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
• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Prednisone (Sterapred) 100 mg/m² PO once per day on days 1 to 5

21-day cycle for up to 8 cycles

References

1. 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 verified protocol PubMed

Untreated, non-randomized or retrospective data

CALGB 59909 Regimen (R-M-CHOP, EAR, CBV auto SCT, Rituximab)

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Regimen

Study	Evidence
Damon et al. 2009	Phase II

Treatments 1-2, R-M-CHOP

• Rituximab (Rituxan) 375 mg/m² IV once on day 1 (rituximab withheld if circulating mantle cells are >10,000 cells/uL)
• 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) 1.4 mg/m² (maximum dose of 2 mg for patients >40 years old) IV once on day 3
• Prednisone (Sterapred) 100 mg/m² PO once per day on days 3 to 7

Supportive medications

• Folinic acid (Leucovorin) 50 mg/m² IV every 6 hours x 3 doses, starting 24 hours after completion of Methotrexate (MTX), then 10 mg/m² IV/PO every 6 hours until serum methotrexate level <0.05 uM
• Filgrastim (Neupogen) 5 mcg/kg SC once per day starting on day 4, to continue until ANC >10000 once or >5000 twice
• Levofloxacin (Levaquin) 500 mg PO once per day, starting on day 6, to continue until ANC =1500
• Fluconazole (Diflucan) 200 mg PO once per day, starting on day 6, to continue until ANC =1500

Interval between treatment 1 & 2 based on count recovery. Median days between treatment 1 & 2 was 23 days, with a range of 16 to 41 days observed.

Patients with =15% involvement by disease in bone marrow biopsy after treatment 2 proceed to treatment 3. If bone marrow biopsy after treatment 2 has >15% involvement by disease, repeat treatment 2 (identified as "treatment 2.5"). Patients with >15% bone marrow involvement by disease after treatment 2.5 were removed from protocol.

Treatment 3, "EAR"

EAR: Etoposide, Ara-C, Rituximab
Treatment 3 begins 4 weeks after treatment 2, if ANC =1000, platelets =100,000/uL, Cr <2 mg/dL, total bilirubin <2x upper limit of normal, and AST <3x upper limit of normal.

• Etoposide (Vepesid) 10 mg/kg/day (40 mg/kg total dose) IV continuous infusion over 96 hours on days 1 to 4
• Cytarabine (Cytosar) 2000 mg/m² IV over 2 hours BID on days 1 to 4 (8 total doses)
• Rituximab (Rituxan) 375 mg/m² IV once per day on days 6 & 13
• Daily leukapheresis to start when WBC =5000/uL

Supportive medications

• Filgrastim (Neupogen) 10 mcg/kg SC once per day starting on day 14, to continue until peripheral blood stem cell collection is complete
• Levofloxacin (Levaquin) 500 mg PO once per day, starting on day 7, to continue until ANC =500
• Fluconazole (Diflucan) 200 mg PO once per day, starting on day 6, to continue until ANC =500
• Acyclovir (Zovirax) 200 mg PO TID, starting on day 6, to continue until 1 year after autologous stem cell transplant (ASCT)
• Note: Text specified that Trimethoprim/Sulfamethoxazole (Bactrim DS) prophylaxis started during treatment 3 (see dose/schedule in treatment 4)--although table 1 did not list it--to continue until 3 months after ASCT.

Treatment 4, CBV with autologous stem cell transplant

CBV: Cyclophosphamide, BiCNU, VP-16

See details of regimen at Transplant conditioning regimens#CBV

Treatment 5, Rituximab

• Rituximab (Rituxan) 375 mg/m² IV once per week x 2 doses, during the sixth and seventh weeks after ASCT

Additional considerations

If cerebrospinal fluid (CSF) contained disease with CSF WBC =5 cells/uL:

• Methotrexate (MTX) 12 mg intrathecal x 10 total doses during treatments 1 to 3; not given concurrently with intrathecal methotrexate or cytarabine

If CSF contained >5 cells/uL:

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

If any patient appeared to be experiencing carmustine-induced pneumonitis:

• Prednisone (Sterapred) 0.5 mg/kg PO BID x 2 weeks, then tapered over 4 weeks

References

1. 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 protocol PubMed

Chlorambucil & Rituximab

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Regimen

Study	Evidence
Sachanas et al. 2011	Phase II

Chemotherapy

• Chlorambucil (Leukeran) 10 mg PO once per day on days 2 to 11 of cycles 1 to 8, then once per day on days 1 to 10 of cycles 9 to 12
• Rituximab (Rituxan) 375 mg/m² IV once on day 1 of cycles 1 to 8

28-day cycle for 12 cycles

Patients in PR/CR received maintenance rituximab.

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 verified protocol PubMed

Cladribine (Leustatin)

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Regimen

Study	Evidence
Inwards et al. 2008 (NCCTG 95-80-53)	Phase II

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. 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 verified protocol PubMed

Cladribine & Rituximab

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Regimen

Study	Evidence
Inwards et al. 2008 (NCCTG N0189)	Phase II

Chemotherapy

• Cladribine (Leustatin) 5 mg/m² IV over 2 hours once per day on days 1 to 5
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Supportive medications

• 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. 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 verified protocol PubMed

Lenalidomide & Rituximab

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Regimen

Study	Evidence
Ruan et al. 2015	Phase II

Chemotherapy

• 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) 375 mg/m² IV once per week on weeks 1 to 4, 13, 21, 29, 37, 45 (total of 9 doses)

Supportive medications

• Thromboprophylaxis with Aspirin or low molecular weight heparin unless on treatment for known thrombosis

28-day cycle for 12 cycles

Induction followed by maintenance lenalidomide & rituximab.

References

1. 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 verified protocol PubMed

Nordic Regimen (maxi-CHOP, HiDAC, Rituximab)

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CHOP: Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone
HiDAC: High Dose Ara-C

Regimen

Study	Evidence
Geisler et al. 2008	Phase II

Protocol originally started rituximab during cycle 4, but the protocol was amended to start it on cycle 2.
Cycle 1 uses maxi-CHOP, cycle 2 uses HiDAC, cycle 3 uses maxi-CHOP, etc.

• Rituximab (Rituxan) as follows:
  • Cycles 2 to 5: 375 mg/m² IV once on day 1
  • Cycle 6: 375 mg/m² IV once per day on days 1 & 9

maxi-CHOP

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

21-day cycles, alternating with high-dose cytarabine, for a total of 3 cycles of maxi-CHOP and 3 cycles of high-dose cytarabine

HiDAC/HDAC, high-dose Cytarabine (Cytosar)

• Cytarabine (Cytosar) as follows:
  • Patients ≤60 years old: 3000 mg/m² IV over 3 hours Q12H on days 1 & 2 (4 total doses)
  • Patients >60 years old: 2000 mg/m² IV over 3 hours Q12H on days 1 & 2 (4 total doses)

Supportive medications

• Filgrastim (Neupogen) given during cycle 6 as part of stem cell mobilization, with at least 2 million CD34+ cells/kg harvested

21-day cycles, alternating with maxi-CHOP, for a total of 3 cycles of maxi-CHOP and 3 cycles of high-dose cytarabine

Followed in 1 to 2 weeks with autologous stem cell transplant. If transplant was delayed, an additional 1 to 2 cycles of chemotherapy with maxi-CHOP or HiDAC could be given.

References

1. 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 PubMed

Observation

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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; RB/RC

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

Regimen #1, RB/RC

Study	Evidence
Armand et al. 2016	Phase II

Chemotherapy

Note: the bendamustine infusion instructions are for the Treanda formulation, which was discontinued on 3/31/2016.

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• Bendamustine as follows:
  • Cycles 1 to 3: (dose not specified) IV over 30 to 60 minutes once per day on days 1 & 2
• Cytarabine (Cytosar) as follows:
  • Cycles 4 to 6: (dose not specified) IV q12h on days 1 & 2

28-day cycle for 6 cycles

Regimen #2, R-BAC

Study	Evidence
Visco et al. 2013	Phase II

Chemotherapy

Note: the bendamustine infusion instructions are for the Treanda formulation, which was discontinued on 3/31/2016.

• 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
• Bendamustine 70 mg/m² IV over 30 to 60 minutes once per day on days 2 & 3
• Cytarabine (Cytosar) 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 cycles (up to 6 for newly diagnosed patients under the age of 80, tolerated treatment, or had regression of disease between cycles 2 and 4)

References

1. 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 verified protocol PubMed
2. 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 PubMed

R-CHOP

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

Synonyms: R-CHOP-21, CHOP-R

Structured Concept: C9760 (NCI-T), C0393023 (NCI-MT/UMLS)

Example orders

• Example orders for R-CHOP in lymphoma

Regimen

Study	Evidence
Smith et al. 2012 (ECOG E1499)	Phase II

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• 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 per cycle) IV once on day 1
• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

3-week cycle for 4 cycles

Followed in 4 to 8 weeks by ibritumomab tiuxetan consolidation.

References

1. 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 verified protocol PubMed

R-CHOP -> HiDAC-R

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R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone
HiDAC-R: High Dose Ara-C (Cytarabine) and Rituximab

Regimen

Study	Evidence
Van't Veer et al. 2008 (HOVON 45)	Phase II

R-CHOP portion

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• 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
• Prednisolone (Millipred) 100 mg PO once per day on days 1 to 5

3-week cycle for 3 cycles

Patients with at least a partial response proceeded to received HiDAC-R:

HiDAC-R portion

• Cytarabine (Cytosar) 2000 mg/m² IV q12h on days 1 to 4 (8 total doses)
• Rituximab (Rituxan) 375 mg/m² IV once on day 11

One course

Stem cells were collected after this cycle with G-CSF given to "enhance" collection. Patients then proceeded to BEAM autologous stem cell transplant.

References

1. 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 verified protocol PubMed

R-CHOP -> R-DHAP

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R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone
R-DHAP: Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin)

Regimen

Study	Evidence
Delarue et al. 2012	Phase II

Chemotherapy, R-CHOP portion

• Rituximab (Rituxan) as follows:
  • Cycles 1 & 2: none
  • Cycle 3: 375 mg/m² IV once on day 1
• 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
• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 5

21-day cycle for up to 3 cycles, +/- intrathecal therapy below; patients who progress after first 2 cycles go directly to R-DHAP

Chemotherapy, R-DHAP portion

Note: Delarue et al. 2013 did not clearly specify the total dose/schedule of cytarabine in this part of the regimen, but this is believed to be correct based on other documented DHAP protocols.

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• Dexamethasone (Decadron) 40 mg once per day on days 1 to 4
• Cytarabine (Cytosar) 2000 mg/m² IV Q12H x 2 doses on day 2 (total dose is 4000 mg/m²)
• Cisplatin (Platinol) 100 mg/m² IV continuous infusion over 24 hours on day 1

21-day cycle for 3 cycles, +/- intrathecal therapy below, then proceed with stem cell collection and intensified therapy

Intrathecal therapy

Intrathecal prophylaxis with the following was given per physician discretion; no timeframe or total number of doses is described in Delarue et al. 2013:

• Methotrexate (MTX) 15 mg IT
• Cytarabine (Cytosar) 40 mg IT
• Corticosteroids

Treatment followed by TAM6 or BEAM regimen (see Transplant 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; for the Groupe d'Etude des Lymphomes de l'Adulte (GELA). 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 verified protocol PubMed

R-DHAP

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

Regimen

Study	Evidence
de Guibert et al. 2006	Non-randomized, <20 pts
Le Gouill et al. 2014 (LyMa)	Non-randomized

Neither reference contains details about the R-DHAP dosing. The below is the dosing used in the NCIC-CTG LY.12 trial.

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
• Cytarabine (Cytosar) 2000 mg/m² IV over 3 hours Q12H x 2 doses on day 2 (total of 2 doses)
• Cisplatin (Platinol) 100 mg/m² IV continuous infusion over 24 hours on day 1

4 to 6 cycles

Responding patients in de Guibert et al. 2006 received BEAM autologous transplant if older than 60, or TBI-based autologous transplant if younger than 60. Patients in LyMa who did not achieve at least a PR could go on to receive R-CHOP x4; all others proceeded to R-BEAM autologous stem cell transplant.

References

1. 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 protocol PubMed
2. Abstract: Steven Le Gouill, MD, PhD, Catherine Thieblemont, MD, PhD, Lucie Oberic, Krimo Bouabdallah, MD, Emmanuel Gyan, MD, PhD, Gandhi Damaj, MD, Vincent Ribrag, MD, Serge Bologna, MD, Remy Gressin, MD, Olivier Casasnovas, MD, Corinne Haioun, MD, PhD, Philippe Solal-Celigny, MD, Herve Maisonneuve, MD, Eric Van Den Neste, MD, PhD, Anne Moreau, MD, Marie C Bene, Gilles Salles, MD PhD, Hervé Tilly, MD, PhD, Thierry Lamy, MD, PhD and Olivier Hermine, MD, PhD. Rituximab Maintenance Versus Wait and Watch after Four Courses of R-DHAP Followed By Autologous Stem Cell transplantation in Previously Untreated Young Patients with Mantle Cell Lymphoma: First Interim Analysis of the Phase III Prospective Lyma Trial, a Lysa Study. Blood 2014 124:146. link to abstract

R-HyperCVAD/R-MA

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R-HyperCVAD: Rituximab, Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone
R-MA: Rituximab, Methotrexate, Ara-C (Cytarabine)
R-MTX-Ara-C: Rituximab, MTX (Methotrexate), Ara-C (Cytarabine)

Regimen

Study	Evidence
Romaguera et al. 2005	Phase II
Wang et al. 2008	Phase II
Bernstein et al. 2013 (SWOG 0213)	Phase II

Bernstein et al. 2013 use the original protocol as specified in Romaguera et al. 2005.

Part A (cycles 1, 3, 5, 7)

• 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
• Cyclophosphamide (Cytoxan) 300 mg/m² IV over 3 hours Q12H x 6 doses on days 2 to 4, given second
• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once per day on days 5 & 12; day 5 dose is given 12 hours after the last dose of Cyclophosphamide (Cytoxan)
• Doxorubicin (Adriamycin) 16.6 to 16.7 (note: Romaguera et al. 2005 had slightly different dosages in the text vs. table 1) mg/m²/day IV continuous infusion over 72 hours on days 5 to 7 (total dose per cycle: 49.8 to 50.1 mg/m²)
• Dexamethasone (Decadron) 40 mg PO/IV once per day on days 2 to 5, 12 to 15

Supportive medications

• Mesna (Mesnex) 600 mg/m²/day IV continuous infusion over 76 hours on days 2 to 4, starting 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.

All growth factors and antibiotics given for 10 days, starting 24 to 36 hours after doxorubicin infusion is complete

• 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
• Levofloxacin (Levaquin) 500 mg PO once per day or Ciprofloxacin (Cipro) 500 mg PO BID
• Erythropoietin was permitted throughout therapy

21-day cycles, alternating every 21 days with Part B, for a total of 4 cycles of Part A and 4 cycles of Part B

Part B (cycles 2, 4, 6, 8)

• Rituximab (Rituxan) 375 mg/m² IV once on day 1, given first
• Methotrexate (MTX) 200 mg/m² IV over 2 hours, then 800 mg/m² IV over 22 hours once on day 2, given second
  • Urine alkalinized to pH of 6.8 or more prior to the start of methotrexate and kept within that range until methotrexate is cleared
  • Patients with a Cr >1.5 mg/dL received a 50% reduced dose of methotrexate
• Cytarabine (Cytosar) 3000 mg/m² IV over 2 hours Q12H on days 3 & 4 (4 doses total)
  • Dose reduced to 1000 mg/m² for patients >60 years old or with Cr >1.5

Supportive medications

• Folinic acid (Leucovorin) 50 mg PO x1 12 hours after Methotrexate (MTX) is complete, then 15 mg PO Q6H x 8 doses. If serum methotrexate level at 24 hours is >1 umol/L or at 48 hours is >0.1 umol/L, dose of folinic acid is increased to 100 mg IV Q3H.
• Prednisolone 1% ophthalmic solution 2 drops in each eye 4 times per day on days 3 to 9 was started on the day of the start of Cytarabine (Cytosar) infusion and was continued for 7 days to prevent chemical conjunctivitis.

The starting day of the following medications was not specified. All medications are given for 10 days.

• 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
• Levofloxacin (Levaquin) 500 mg PO once per day or Ciprofloxacin (Cipro) 500 mg PO BID
• Erythropoietin was permitted throughout therapy

21-day cycles, alternating every 21 days with Part A, for a total of 4 cycles of Part A and 4 cycles of Part B

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 verified protocol 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 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 verified protocol PubMed
3. 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 PubMed

R-MACLO/R-IVAM

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R-MACLO: Rituximab, MTX (Methotrexate), Adriamycin (Doxorubicin), Cyclophosphamide, Leucovorin (Folinic acid), Oncovin (Vincristine)
R-IVAM: Rituximab, VP-16 (Etoposide), Ara-C (Cytarabine), Mesna

Regimen #1

Study	Evidence
Lossos et al. 2010 (UM-MCL1)	Phase II

R-MACLO (Cycles 1 & 3)

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• 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 1 hour, then 5520 mg/m² IV over 23 hours on day 10

Supportive medications

• Folinic acid (Leucovorin) 180 mg/m² IV once 12 hours after Methotrexate (MTX) is complete, then 12 mg/m² IV Q6H for at least 10 doses or until serum methotrexate level is <0.05 umol/L
• G-CSF given starting on day 13, continued until ANC >1.5 x 10^9 for two consecutive days

Next cycle to start after count recovery

R-IVAM (Cycles 2 & 4)

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• Cytarabine (Cytosar) 2000 mg/m² IV Q12H on days 1 & 2 (4 doses total)
• Etoposide (Vepesid) 60 mg/m² IV once per day on days 1 to 5
• Ifosfamide (Ifex) 1500 mg/m² IV onc per day on days 1 to 5

Supportive medications

• Mesna (Mesnex) 360 mg/m² IV starting "prior to Ifosfamide (Ifex)" and given Q3H through day 5 (total of 40 doses)
• G-CSF given starting on day 7, continued until ANC >1.5 x 10^9 for two consecutive days

Next cycle to start after count recovery + 2 weeks

Total of 4 cycles

Patients achieving a CR proceeded to thalidomide maintenance.

Regimen #2

Study	Evidence
Hosein et al. 2015 (UM-MCL2)	Phase II

The only difference between this regimen and regimen #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.

R-MACLO (Cycles 1 & 3)

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• 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 1 hour, then 3000 mg/m² IV over 23 hours on day 10

Supportive medications

• Folinic acid (Leucovorin) 180 mg/m² IV once 12 hours after Methotrexate (MTX) is complete, then 12 mg/m² IV Q6H for at least 10 doses or until serum methotrexate level is <0.05 umol/L
• G-CSF given starting on day 13, continued until ANC >1.5 x 10^9 for two consecutive days

Next cycle to start after count recovery

R-IVAM (Cycles 2 & 4)

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• Cytarabine (Cytosar) 2000 mg/m² IV Q12H on days 1 & 2 (4 doses total)
• Etoposide (Vepesid) 60 mg/m² IV once per day on days 1 to 5
• Ifosfamide (Ifex) 1500 mg/m² IV onc per day on days 1 to 5

Supportive medications

• Mesna (Mesnex) 360 mg/m² IV starting "prior to Ifosfamide (Ifex)" and given Q3H through day 5 (total of 40 doses)
• G-CSF given starting on day 7, continued until ANC >1.5 x 10^9 for two consecutive days

Next cycle to start after count recovery + 2 weeks

Total of 4 cycles

Patients achieving a CR proceeded to rituximab maintenance.

References

1. 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 verified protocol PubMed
   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 PubMed

RiPAD+C

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

Regimen

Study	Evidence
Houot et al. 2011	Phase II

Chemotherapy

• 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
• Doxorubicin (Adriamycin) 9 mg/m²/day IV continuous infusion on days 1 to 4 (total dose = 36 mg/m²)
• Dexamethasone (Decadron) 20 mg (route not specified) BID on days 1 to 4
• Chlorambucil (Leukeran) 12 mg PO once per day on days 20 to 29

35-day cycle for up to 6 cycles

References

1. 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; French GOELAMS group. 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 verified protocol PubMed

(R)VAD+C

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

Regimen

Study	Evidence
Gressin et al. 2010 (GOELAMS LM1996, Lm2001)	Phase II

LM1996 did not incorporate rituximab, but these trials were pooled in the publication.

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• Vincristine (Oncovin) 0.4 mg/m²/day IV continuous infusion on days 1 to 4 (total dose = 1.6 mg/m²)
• Doxorubicin (Adriamycin) 9 mg/m²/day IV continuous infusion on days 1 to 4 (total dose = 36 mg/m²)
• Dexamethasone (Decadron) 20 mg PO/IV BID on days 1 to 4
• Chlorambucil (Leukeran) 12 mg PO once per day on days 20 to 29

5-week cycle for 4 to 8 cycles

Transplant-eligible patients with more than partial response after 4 cycles proceed to high-dose melphalan & TBI -> autologous transplant 4 weeks after the 6th cycle.

References

1. 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; French GOELAMS Group. 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 PMC article link to original article contains verified protocol PubMed

VcR-CVAD

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

Regimen

Study	Evidence
Chang et al. 2011	Phase II
Chang et al. 2014 (E1405)	Phase II

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per day on days 1 & 4
• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 300 mg/m² IV over 3 hours Q12H x 6 doses 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 IV continuous infusion over 48 hours on days 1 & 2 (total dose per cycle: 100 mg/m²)
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

Supportive medications

• Mesna (Mesnex) dose not specified Chang et al. 2011; not mentioned in Chang et al. 2014
• Filgrastim (Neupogen) 5 mcg/kg SC once per day or Pegfilgrastim (Neulasta) on day 5 or 6 of each cycle

21-day cycle for 6 cycles

Patients in E1405 with at least a PR proceeded to receive maintenance rituximab or autologous stem cell transplant, 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. 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 verified protocol PubMed
2. 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 verified protocol PubMed

VR-CHOP

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VR-CHOP: Velcade (Bortezomib), Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone

Regimen

Study	Evidence
Ruan et al. 2010	Phase II
Till et al. 2015 (SWOG S0601)	Phase II

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

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² (route not specified) once per day on days 1 & 4 (day 1 given prior to R-CHOP)
• Rituximab (Rituxan) 375 mg/m² IV once on day 1
• 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 per cycle) IV once on day 1
• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5

Supportive medications

• "Standard" Acetaminophen (Tylenol) and Diphenhydramine (Benadryl) prior to Rituximab (Rituxan)

21-day cycle for 6 cycles

Patients in SWOG S0601 proceeded to receive bortezomib maintenance.

References

1. 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 verified protocol PubMed
2. 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 protocol PubMed

Consolidation and/or maintenance after upfront therapy

Autologous stem cell transplant

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To be completed. See details about preparative regimens.

Regimen #1, BEAM

Study	Evidence
Van't Veer et al. 2008 (HOVON 45)	Phase II

Treatment preceded by R-CHOP -> HiDAC-R.

Preparative regimen

• Carmustine (BiCNU) 300 mg/m² IV once on day -7
• Etoposide (Vepesid) 100 mg/m² IV Q12H on days -6 to -3
• Cytarabine (Cytosar) 100 mg/m² IV Q12H on days -6 to -3
• Melphalan (Alkeran) 140 mg/m² IV once on day -2

Stem cells re-infused on day 0

Regimen #2

Study	Evidence
Geisler et al. 2008	Phase II

Treatment preceded by Nordic regimen.

High-dose chemotherapy with BEAM or BEAC

References

1. 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 PubMed
2. 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 verified protocol PubMed
3. 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; French GOELAMS Group. 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 PubMed
4. 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 PubMed

Bortezomib (Velcade)

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Regimen

Study	Evidence
Till et al. 2015 (SWOG S0601)	Phase II

Treatment preceded by VR-CHOP x 6.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² (route not specified) once per day on days 1, 4, 8, 11

3-month cycle for 2 years

References

1. 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 protocol PubMed

Ibritumomab tiuxetan (Zevalin)

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Regimen

Study	Evidence
Smith et al. 2012 (ECOG E1499)	Phase II

Treatment preceded by R-CHOP x 4.

Chemotherapy

• Rituximab (Rituxan) 250 mg/m² IV once on day 1, then another single dose on day 8
• Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (maximum dose of 32 mCi) IV once, given after second dose of Rituximab (Rituxan)
  • Dose-reduced to 0.3 mCi/kg if platelet count between 100,000/µL and 149,000/µL

One course

References

1. 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 verified protocol PubMed

Lenalidomide & Rituximab

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Regimen

Study	Evidence
Ruan et al. 2015	Phase II

Treatment preceded by lenalidomide & rituximab induction.

Chemotherapy

• Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 21
• Rituximab (Rituxan) 375 mg/m² IV once on day 1 every other cycle (every 8 weeks)

28-day cycles until progression of disease.

References

1. 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 verified protocol PubMed

Observation

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Regimen

Study	Evidence	Comparator	Efficacy
Le Gouill et al. 2014 (LyMa)	Phase III	Rituximab	Seems to have inferior PFS

Preceded by R-DHAP x4 and R-BEAM autologous stem cell transplant. This arm received no further treatment.

References

1. Abstract: Steven Le Gouill, MD, PhD, Catherine Thieblemont, MD, PhD, Lucie Oberic, Krimo Bouabdallah, MD, Emmanuel Gyan, MD, PhD, Gandhi Damaj, MD, Vincent Ribrag, MD, Serge Bologna, MD, Remy Gressin, MD, Olivier Casasnovas, MD, Corinne Haioun, MD, PhD, Philippe Solal-Celigny, MD, Herve Maisonneuve, MD, Eric Van Den Neste, MD, PhD, Anne Moreau, MD, Marie C Bene, Gilles Salles, MD PhD, Hervé Tilly, MD, PhD, Thierry Lamy, MD, PhD and Olivier Hermine, MD, PhD. Rituximab Maintenance Versus Wait and Watch after Four Courses of R-DHAP Followed By Autologous Stem Cell transplantation in Previously Untreated Young Patients with Mantle Cell Lymphoma: First Interim Analysis of the Phase III Prospective Lyma Trial, a Lysa Study. Blood 2014 124:146. link to abstract

Rituximab (Rituxan)

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Regimen #1

Study	Evidence	Comparator	Efficacy
Le Gouill et al. 2014 (LyMa)	Phase III	Observation	Seems to have superior PFS

Treatment preceded by R-DHAP x4 and R-BEAM autologous stem cell transplant.

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once every 3 months

3-year course (12 total doses)

Regimen #2

Study	Evidence	Comparator	Efficacy
Kluin-Nelemans et al. 2012	Phase III	Interferon alfa	Seeems to have superior combined PFS/OS

Treatment preceded by R-CHOP x 8 versus R-FC x 6.

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once every 2 months

Continued until progression

Regimen #3, Räty et al. 2012

To be completed

Regimen #4

Study	Evidence
Hosein et al. 2015 (UM-MCL2)	Phase II

Treatment preceded by R-MACLO/R-IVAM.

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once per week for four weeks

Course repeats every 6 months for 3 years (24 total doses)

Regimen #5

Study	Evidence
Chang et al. 2014 (ECOG E1405)	Phase II

Treatment preceded by VcR-CVAD.

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once per week for four weeks

Course repeats every 6 months for 2 years (16 total doses)

Regimen #6

Study	Evidence
Sachanas et al. 2011	Phase II

Treatment preceded by chlorambucil & rituximab.

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once every 2 months

12-month course (6 total doses)

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 verified protocol PubMed
2. 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
3. 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. 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. 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
4. 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 verified protocol PubMed
5. Abstract: Steven Le Gouill, MD, PhD, Catherine Thieblemont, MD, PhD, Lucie Oberic, Krimo Bouabdallah, MD, Emmanuel Gyan, MD, PhD, Gandhi Damaj, MD, Vincent Ribrag, MD, Serge Bologna, MD, Remy Gressin, MD, Olivier Casasnovas, MD, Corinne Haioun, MD, PhD, Philippe Solal-Celigny, MD, Herve Maisonneuve, MD, Eric Van Den Neste, MD, PhD, Anne Moreau, MD, Marie C Bene, Gilles Salles, MD PhD, Hervé Tilly, MD, PhD, Thierry Lamy, MD, PhD and Olivier Hermine, MD, PhD. Rituximab Maintenance Versus Wait and Watch after Four Courses of R-DHAP Followed By Autologous Stem Cell transplantation in Previously Untreated Young Patients with Mantle Cell Lymphoma: First Interim Analysis of the Phase III Prospective Lyma Trial, a Lysa Study. Blood 2014 124:146. link to abstract
6. 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 PubMed

Relapsed/refractory, randomized data

BCHOP

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

Regimen

Study	Evidence	Comparator	Efficacy
Furtado et al. 2014	Randomized Phase II	CHOP	Seems to have superior OS

Chemotherapy

• Bortezomib (Velcade) 1.6 mg/m² (route not specified) once per day on days 1 & 8
• 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 per cycle) IV once on day 1
• Prednisolone (Millipred) 100 mg PO once per day on days 1 to 5

Supportive medications

• Acyclovir (Zovirax) 400 mg PO BID

21-day cycle for up to 8 cycles

References

1. 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

BR

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BR: Bendamustine, Rituximab

Regimen

Study	Evidence	Comparator	Efficacy
Czuczman et al. 2015	Phase II
Rummel et al. 2015 (StiL NHL 2-2003)	Phase III	FR	Seems to have superior OS

Chemotherapy

• Bendamustine 90 mg/m² IV once per day on days 1 & 2
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

Supportive medications

• Analgesics and antipyretics prior to each dose of Rituximab (Rituxan)

28-day cycle for 6 to 8 cycles

References

1. 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 verified protocol PubMed
2. 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; Study group indolent Lymphomas (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

CHOP

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

Regimen

Study	Evidence	Comparator	Efficacy
Furtado et al. 2014	Randomized Phase II	BCHOP	Seems to have inferior OS

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. 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

FCM

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FCM: Fludarabine, Cyclophosphamide, Mitoxantrone

Regimen

Study	Evidence	Comparator	Efficacy
Forstpointner et al. 2004	Phase III	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

Responders (PR or CR) were randomized to maintenance Rituximab (Rituxan) 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 (GLSG). 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

FR

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FR: Fludarabine, Rituximab

Regimen

Study	Evidence	Comparator	Efficacy
Rummel et al. 2015 (StiL NHL 2-2003)	Phase III	BR	Seems to have inferior OS

Chemotherapy

• Fludarabine (Fludara) 25 mg/m² (route not specified) once per day on days 1 to 3
• Rituximab (Rituxan) 375 mg/m² IV once on day 1

28-day cycle for up to 6 cycles

References

1. 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; Study group indolent Lymphomas (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

Ibrutinib (Imbruvica)

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Regimen

Study	Evidence	Comparator	Efficacy
Wang et al. 2013 (PCYC-1104-CA)	Phase II
Dreyling et al. 2015	Phase III	Temsirolimus	Superior PFS

Chemotherapy

• Ibrutinib (Imbruvica) 560 mg PO once per day

Given until progression of disease or unacceptable toxicity

References

1. 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 verified protocol PubMed
   1. Update: Abstract: Michael Wang, MD, Simon Rule, MD, Peter Martin, MD, Andre Goy, MD, Rebecca Auer, MD, PhD, Brad S. Kahl, MD, Wojciech Jurczak, Ranjana Advani, MD, Jorge E. Romaguera, MD, Michael E. Williams, MD, Jacqueline C. Barrientos, M.D., Ewa Chmielowska, MD, John Radford, Stephan Stilgenbauer, MD, Martin Dreyling, Wieslaw Wiktor Jedrzejczak, MD, Peter W Johnson, MD, Stephen E. Spurgeon, MD, Liang Zhang, MD, PhD, Linda Baher, Mei Cheng, PhD, Darrin M. Beaupre, MD and Kristie A. Blum, MD. Single-Agent Ibrutinib Demonstrates Safety and Durability of Response at 2 Years Follow-up in Patients with Relapsed or Refractory Mantle Cell Lymphoma: Updated Results of an International, Multicenter, Open-Label Phase 2 Study. Blood 2014 124:4453. link to abstract
   2. 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 PubMed
2. 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. link to original article contains verified protocol PubMed

Lenalidomide (Revlimid)

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Regimen

Study	Evidence	Comparator	Efficacy
Wiernik et al. 2008 (NHL-002)	Phase II, <20 pts in subgroup
Habermann et al. 2009	Phase II, <20 pts in subgroup
Witzig et al. 2011 (NHL-003)	Phase II
Eve et al. 2012	Phase II
Goy et al. 2013 (MCL-001, EMERGE)	Phase II
Trněný et al. 2016 (MCL-002, SPRINT)	Randomized Phase II	Investigator's choice	Superior PFS

Participants in EMERGE "were required to have had prior treatment with rituximab, cyclophosphamide and anthracycline (or mitoxantrone), and to have relapsed or progressed (<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.

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

28-day cycles, given until progression of disease, unacceptable toxicity, or voluntary withdrawal

Patients in Eve et al. 2012 proceeded to receive maintenance lenalidomide after 6 cycles.

References

1. 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 verified protocol PubMed
2. 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 verified protocol PubMed
3. 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 verified protocol PubMed
   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 PubMed
4. 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 verified protocol PubMed
5. 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 verified protocol PubMed
   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 PubMed
6. 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

R-FCM

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R-FCM: Rituximab, Fludarabine, Cyclophosphamide, Mitoxantrone

Regimen

Study	Evidence	Comparator	Efficacy
Forstpointner et al. 2004	Phase III	FCM	Superior OS

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once on day -1 (the day before FCM)
• 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

Responders (PR or CR) were randomized to 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
   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 (GLSG). 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

Temsirolimus (Torisel)

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Regimen

Study	Evidence	Comparator	Efficacy
Hess et al. 2009	Phase III	Investigator's choice Temsirolimus 175/25	Superior PFS
Dreyling et al. 2015	Phase III	Ibrutinib	Inferior PFS

The most commonly compared regimens in Hess et al. 2009 were single agent gemcitabine and single agent fludarabine.

Chemotherapy

• 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 medications

• Antihistamine once 30 minutes prior to Temsirolimus (Torisel).
• Corticosteroid use was not allowed in Hess et al. 2009.

21-day cycles given until progression or unacceptable toxicity

References

1. 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 verified protocol PubMed
2. 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. link to original article contains verified protocol PubMed

Relapsed/refractory, non-randomized or retrospective data

Arsenic trioxide & chlorambucil

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Regimen

Study	Evidence
Gill et al. 2014	Phase II

Chemotherapy

• Arsenic trioxide (Trisenox) 10 mg PO once per day, reduced to 5 mg PO once per day after 4 weeks
• Chlorambucil (Leukeran) 4 mg PO once per day, increased to 8 mg PO once per day "if leukocyte count allowed"

Supportive medications

• Ascorbic acid (Vitamin C) 1000 mg PO once per day

6-week course

Patients with at least stable disease received maintenance arsenic trioxide and chlorambucil.

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 verified protocol PubMed

BeRT

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BeRT: Bendamustine, Rituximab, Temsirolimus

Regimen

Study	Evidence
Hess et al. 2015	Phase I/II, <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
• 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. 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 verified protocol PubMed

BORID

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BORID: BOrtezomib, RItuximab, Dexamethasone

Regimen

Study	Evidence
Lamm et al. 2011	Phase II, <20 pts reported

Chemotherapy

• 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
• Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4

21-day cycle for 6 cycles

Responding patients received rituximab consolidation.

References

1. 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 verified protocol PubMed

Bortezomib (Velcade)

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Regimen #1

Study	Evidence
Fisher et al. 2006 (PINNACLE)	Phase II

Chemotherapy

• 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 #2

Study	Evidence
O'Connor et al. 2005	Phase II, <20 pts reported

Chemotherapy

• Bortezomib (Velcade) 1.5 mg/m² IV once per day on days 1, 4, 8, 11

Supportive medications

• "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 verified protocol PubMed
2. 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 verified protocol 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 protocol PubMed

BR

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BR: Bendamustine, Rituximab

Regimen

Study	Evidence
Rummel et al. 2005	Phase II, <20 pts in subgroup
Robinson et al. 2008	Phase II, <20 pts in subgroup

Chemotherapy

Note: the bendamustine infusion instructions are for the Treanda formulation, which was discontinued on 3/31/2016.

• 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
• Bendamustine 90 mg/m² IV over 30 to 60 minutes once per day on days 2 & 3

28-day cycle for 4 cycles

Robinson et al. 2008 said that patients "could receive up to six cycles if disease regression was evident between the second and fourth cycles".

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 verified protocol PubMed
2. 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 verified protocol PubMed

Cladribine (Leustatin)

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Regimen

Study	Evidence
Inwards et al. 2008 (NCCTG 95-80-53)	Phase II, <20 pts

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. 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 verified protocol PubMed

Everolimus (Afinitor)

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Regimen

Study	Evidence
Renner et al. 2012 (SAKK 36/06)	Phase II
Wang et al. 2014 (PILLAR-1)	Phase II

Chemotherapy

• Everolimus (Afinitor) 10 mg PO once per day "in a fasting state or with a light fat-free meal"

28-day cycles, given until progression or unacceptable toxicity

References

1. 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; Swiss SAKK and French GOELAMS group from 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 verified protocol PubMed
2. 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 verified protocol PubMed

Ibrutinib & Rituximab

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Regimen

Study	Evidence
Wang et al. 2015	Phase II

Chemotherapy

• 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 8: 375 mg/m² IV once on day 1
  • Cycle 10 onwards: 375 mg/m² IV once on day 1 of every other cycle, up to 2 years

28-day cycles, given until progression of disease or unacceptable toxicity

References

1. 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, Rosa MD, 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 verified protocol PubMed

Lenalidomide & Rituximab

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Regimen #1

Study	Evidence
Wang et al. 2012	Phase II

Chemotherapy

• Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1, 8, 15, 22 of cycle 1 only

28-day cycles, given until until disease progression, stem-cell transplantation, or severe toxicity

Regimen #2

Study	Evidence
Chong et al. 2015	Phase II, <20 pts in subgroup

Chemotherapy

• Lenalidomide (Revlimid) 10 mg PO once per day
• Rituximab (Rituxan) 375 mg/m² IV once per week x 4 doses, given during the 3rd cycle

28-day cycles until progression or intolerance

References

1. 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 protocol PubMed
2. 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 verified protocol PubMed

Obinutuzumab (Gazyva)

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Regimen

Study	Evidence
Morschhauser et al. 2013 (GAUGUIN)	Phase II

Chemotherapy

• 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 medications

• Acetaminophen (Tylenol) or paracetamol 650 to 1000 mg PO once 30 minutes prior to Obinutuzumab (Gazyva)
• An antihistamine 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. 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 verified protocol PubMed

PEP-C

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PEP-C: Prednisone, Etoposide, Procarbazine, Cyclophosphamide

Regimen

Study	Evidence
Coleman et al. 2008	Non-randomized

Induction phase

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

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

Continue until WBC <3 x 10⁹/L, hold until WBC recovery, then titrate in maintenance phase per paper (see publication for details)

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 of at least 3; for example, 5 out of 7 days, every other day, once per week, etc.

References

1. 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 verified protocol PubMed

Rituximab & Temsirolimus

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Regimen

Study	Evidence
Ansell et al. 2011	Phase II

Chemotherapy

• Temsirolimus (Torisel) 25 mg IV once per week on weeks 1 to 4
• Rituximab (Rituxan) 375 mg/m² IV once per week on weeks 1 to 4 of cycle 1, then once on day 1 of every other cycle (cycles 3, 5, 7, 9, 11)

28-day cycle up to 12 cycles

References

1. 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 link to PMC article contains verified protocol PubMed

RT-PEPC

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

Regimen

Study	Evidence
Ruan et al. 2010	Non-randomized

Induction phase

• Rituximab (Rituxan) (dose not specified) IV once per week on weeks 1 to 4 of month 1
• Thalidomide (Thalomid) 50 mg PO once per day during months 1 & 2, then 100 mg PO once per day for month 3
• Prednisone (Sterapred) 20 mg PO once per day after breakfast
• 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 medications

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

3-month course

Maintenance phase

• Rituximab (Rituxan) (dose not specified) IV once per week on weeks 1 to 4 every 4 months
• Thalidomide (Thalomid) 100 mg PO once per day
• PEPC: Same medications and doses given per day as used in the induction phase, but titrated to maintain ANC of at least 2000 cells/µL.

Supportive medications

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

Continued until progression

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 verified protocol PubMed

Temsirolimus (Torisel)

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Regimen #1

Study	Evidence
Ansell et al. 2008	Phase II

Chemotherapy

• Temsirolimus (Torisel) 25 mg in 250 mL normal saline IV over 30 minutes once per day on days 1, 8, 15, 22

Supportive medications

• Diphenhydramine (Benadryl) 25 to 50 mg IV once prior to Temsirolimus (Torisel)

4-week cycle, stopped at various timepoints (see paper for details); maximum of 12 months

Regimen #2

Study	Evidence
Witzig et al. 2005	Phase II

Chemotherapy

• Temsirolimus (Torisel) 250 mg in 250 mL normal saline IV over 30 minutes once per day on days 1, 8, 15, 22

Supportive medications

• Use of white blood cell growth factors at physician discretion if neutropenia occurred.
• Use of erythropoietin for anemia was allowed.

28-day cycles, given until progression, 2 cycles past CR, up to a total of 12 months

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 verified protocol 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. 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 verified protocol PubMed

VR

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VR: Velcade (Bortezomib), Rituximab

Regimen

Study	Evidence
Baiocchi et al. 2011	Phase II, <20 pts

Bortezomib dose was initially 1.5 mg/m² but was reduced due to excess grade 3 neurotoxicity.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once on days 1, 4, 8, 11
• Rituximab (Rituxan) 375 mg/m² IV once per day on days 1 & 8, starting with cycle 2 and thereafter

21-day cycle for up to 5 cycles

Patients without progression could receive maintenance VR.

References

1. 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 verified protocol PubMed

Consolidation and/or maintenance after salvage therapy

Allogeneic stem cell transplant

To be completed. Usually reserved for younger and very fit individuals; preceded by a high-intensity salvage chemotherapy such as those used for DLBCL. See details about preparative regimens.

Arsenic trioxide & chlorambucil

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Regimen

Study	Evidence
Gill et al. 2014	Phase II

Treatment preceded by salvage arsenic trioxide and chlorambucil.

Chemotherapy

• Arsenic trioxide (Trisenox) 3 mg PO once per day
• Chlorambucil (Leukeran) 2 mg PO once per day

Supportive medications

• Ascorbic acid (Vitamin C) 300 mg PO once per day

Continuously until disease progression.

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 verified protocol PubMed

Autologous stem cell transplant

To be completed. Usually preceded by a high-intensity salvage chemotherapy such as those used for DLBCL. See details about preparative regimens.

Lenalidomide (Revlimid)

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Regimen

Study	Evidence
Eve et al. 2012	Phase II

Treatment preceded by salvage lenalidomide.

Chemotherapy

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

28-day cycle to continue until progression of disease or intolerance

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 verified protocol PubMed

Observation

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Regimen #1

Study	Evidence	Comparator	Efficacy
Forstpointner et al. 2004	Phase III	Rituximab	Seems to have inferior response duration

Preceded by FCM versus R-FCM; no further treatment was given.

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
   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 (GLSG). 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

Rituximab (Rituxan)

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Regimen #1

Study	Evidence	Comparator	Efficacy
Forstpointner et al. 2004	Phase III	Observation	Seems to have superior response duration

Treatment preceded by FCM versus R-FCM.

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once per week on days 1, 8, 15, 22

Two courses, given 3 and 6 months after completion of salvage therapy

Regimen #2

Study	Evidence
Lamm et al. 2011	Phase II, <20 pts

Treatment preceded by BORID x 6.

Chemotherapy

• Rituximab (Rituxan) 375 mg/m² IV once every 8 weeks

4 doses

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
   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 (GLSG). 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
2. 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 verified protocol PubMed

VR

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VR: Velcade (Bortezomib), Rituximab

Regimen

Study	Evidence
Baiocchi et al. 2011	Phase II, <20 pts

Treatment preceded by VR x 5.

Chemotherapy

• Bortezomib (Velcade) 1.3 mg/m² IV once per week for two weeks
• Rituximab (Rituxan) 375 mg/m² IV once per week for four weeks

6-month cycle for up to 2 years

References

1. 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 verified protocol PubMed

Investigational agents

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

• Abexinostat (PCI-24781)
• Alisertib (MLN8237)
• Venetoclax (ABT-199)

Prognosis

Mantle cell lymphoma international prognostic index (MIPI)

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Calculation generally require a calculator such as the one provided by BloodRef. The MIPI is calculated using the following formula: [0.03535 × age (in years)] + 0.6978 (if ECOG PS > 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:

• <5.7 points: Low risk
• 5.7 to <6.2 points: Intermediate risk
• ≥ 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 (GLSG); 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

NCI Sponsored International Working Group Criteria (1999)

1. Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, Connors JM, Lister TA, Vose J, Grillo-López A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, Harris NL, Armitage JO, Carter W, Hoppe R, Canellos GP. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999 Apr;17(4):1244. Review. Erratum in: J Clin Oncol 2000 Jun;18(11):2351. link to original article PubMed