Mantle cell lymphoma

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Untreated

BR

BR: Bendamustine, Rituximab

Regimen, Mathias et al. 2012 (StiL NHL1)

Level of Evidence: Phase III

28-day cycles x up to 8 cycles

Supportive medications:

  • "Standard antiemetic prophylaxis"
  • No prophylactic antibiotics
  • Prophylactic use of G-CSF allowed according ASCO guidelines (2006)

References

  1. Mathias J. Rummel, Norbert Niederle, Georg Maschmeyer, Andre G. Banat, Ulrich von Gruenhagen, Christoph Losem, Dorothea Kofahl-Krause, Gerhard Heil, Manfred Welslau, Christina Balser, Ulrich Kaiser, Eckhart Weidmann, Heinz A. Duerk, Harald Ballo, Martina Stauch, Juergen Barth, Axel Hinke, Wolfram Brugger, Study Group Indolent Lymphomas (StiL). Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): Updated results from the StiL NHL1 study. 2012 ASCO Annual Meeting abstract 3. link to abstract ASCO Post article ASCO plenary session video
  2. Ian Flinn et al. An Open-Label, Randomized Study of Bendamustine and Rituximab (BR) Compared with Rituximab, Cyclophosphamide, Vincristine, and Prednisone (R-CVP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in First-Line Treatment of Patients with Advanced Indolent Non-Hodgkin’s Lymphoma (NHL) or Mantle Cell Lymphoma (MCL): The Bright Study. 2012 ASH Annual Meeting abstract 902. link to abstract
  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 Feb 19. pii: S0140-6736(12)61763-2. doi: 10.1016/S0140-6736(12)61763-2. [Epub ahead of print] link to original article contains verified protocol PubMed

CALGB 59909

Regimen

Level of Evidence: Phase II

Treatments 1-2, R-M-CHOP

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

Supportive medications:

  • 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

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:

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

Cladribine

Regimen, Inwards et al. 2008 (NCCTG 95-80-53)

Levels of Evidence: Phase II

28-day cycles x 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

Regimen, Inwards et al. 2008 (NCCTG N0189)

Levels of Evidence: Phase II

28-day cycles x up to 6 cycles

Supportive medications:

OR

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

R-BAC

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

Regimen

Levels of Evidence: Phase II

28-day cycles x 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 Feb 11. [Epub ahead of print] link to original article contains verified protocol PubMed

R-CHOP

Regimen

Level of Evidence: Phase III

To be completed

References

  1. Ian Flinn et al. An Open-Label, Randomized Study of Bendamustine and Rituximab (BR) Compared with Rituximab, Cyclophosphamide, Vincristine, and Prednisone (R-CVP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in First-Line Treatment of Patients with Advanced Indolent Non-Hodgkin’s Lymphoma (NHL) or Mantle Cell Lymphoma (MCL): The Bright Study. 2012 ASH Annual Meeting abstract 902. link to abstract

(R)-CHOP/R-DHAP -> autologous SCT

R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone
R-DHAP: Rituximab, Dexamethasone, High-dose Ara-C (cytarabine), cisPlatin

Levels of Evidence: Phase II

Regimen

Part 1 (CHOP: cycles 1-2)

21-day cycles x up to 2 cycles, +/- intrathecal therapy below, then proceed to part 2 with R-CHOP; patients who progress during CHOP go to part 3 with R-DHAP

Part 2 (R-CHOP: cycle 3)

21-day cycle x 1 cycle, +/- intrathecal therapy below, then proceed to part 3 with R-DHAP

Part 3 (R-DHAP: cycles 4-6)

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.

21-day cycles x 3 cycles, +/- intrathecal therapy below, then proceed to part 4 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:

Part 4 (Stem cell collection and intensified therapy)

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-CVP

Regimen

Level of Evidence: Phase III

To be completed

References

  1. Ian Flinn et al. An Open-Label, Randomized Study of Bendamustine and Rituximab (BR) Compared with Rituximab, Cyclophosphamide, Vincristine, and Prednisone (R-CVP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in First-Line Treatment of Patients with Advanced Indolent Non-Hodgkin’s Lymphoma (NHL) or Mantle Cell Lymphoma (MCL): The Bright Study. 2012 ASH Annual Meeting abstract 902. link to abstract

R-Hyper-CVAD/R-MTX-Ara-C

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

Levels of Evidence: Phase II

Regimen, Romaguera et al. 2005 & 2010; Wang et al. 2008

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 (total dose per cycle: 1800 mg/m2), given second
  • Mesna (Mesnex) 600 mg/m2/day IV continuous infusion over 76 hours on days 2 to 4, starting 1 hour before cyclophosphamide and completed 12 hours after the last dose of cyclophosphamide
    • "Over 76 hours" is not exactly specified in Romaguera et al. 2005; Wang et al. 2008. It is based on the assumption that "completed 12 hours after the last dose of cyclophosphamide" means that it would finish 12 hours after the last dose of cyclophosphamide completes.
  • Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV piggyback once per day on days 5 & 12; day 5 dose is given 12 hours after the last dose of cyclophosphamide
  • Doxorubicin (Adriamycin) 16.6-16.7 (note: Romaguera et al. 2005 had slightly different dosages in the text vs. table 1) mg/m2/day (total dose per cycle: 49.8-50.1 mg/m2) IV continuous infusion over 72 hours on days 5-7
  • Dexamethasone (Decadron) 40 mg PO/IV once per day on days 2 to 5, 12 to 15

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

Supportive medications for Part A:
All medications given for 10 days, starting 24-36 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"

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 (1000 mg/m2 for patients >60 years old or with Cr >1.5) IV over 2 hours Q12H x 4 doses on days 3 & 4 (total dose per cycle: 4000 mg/m2)

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

Supportive medications for Part B:

  • Folinic acid (Leucovorin) 50 mg PO x1 12 hours after methotrexate 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 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"

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
  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. doi: 10.1002/cncr.23880. link to original article contains verified protocol PubMed
  3. 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. doi: 10.1111/j.1365-2141.2010.08228.x. Epub 2010 May 26. Review. Erratum in: Br J Haematol.n 2010 Oct;151(1):111. link to original article PubMed

Nordic regimen, maxi-CHOP, HiDAC, Rituximab (Rituxan)

CHOP: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone
HiDAC: High Dose Ara-C

Levels of Evidence: Phase II

Regimen

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) 375 mg/m2 IV once on day 1 of cycles 2 to 5, and 375 mg/m2 IV once per day on days 1 & 9 of cycle 6

maxi-CHOP

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)

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

Supportive medications:

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

High-dose chemotherapy with BEAM or BEAC started 1 to 2 weeks after completion of cycle 6, followed by 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

VcR-CVAD

VcR-CVAD: Velcade, Rituximab, Cyclophosphamide, Vincristine, Adriamycin, Dexamethasone

Regimen, Kahl et al. 2012 (E1405)

Levels of Evidence: Phase II

21-day cycle x 6 cycles

Patients with SD or better received maintenance rituximab or ASCT, 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. doi: 10.1111/j.1365-2141.2011.08820.x. Epub 2011 Aug 16. link to original article contains verified protocol PubMed
  2. Kahl BS et al. Mature results from ECOG study E1405 — A Phase II study of VcR-CVAD with maintenance rituximab for previously untreated mantle cell lymphoma. Proc ASH 2012;Abstract 153 link to abstract.

Relapsed/refractory

Bortezomib

Regimen #1, Fisher et al. 2006, Goy et al. 2009 (PINNACLE)

Level of Evidence: Phase II

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."

References

  1. 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
  2. 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. doi: 10.1093/annonc/mdn656. Epub 2008 Dec 12. link to original article contains protocol PubMed

BR

BR: Bendamustine, Rituximab

Regimen #1, Rummel et al. 2005

Level of Evidence: Phase II, <20 patients reported

Cycle 1 is started 7 days after the first dose of rituximab

28-day cycles x 5 cycles

Regimen #2, Robinson et al. 2008

Level of Evidence: Phase II, <20 patients reported

Cycle 1 is started 7 days after the first dose of rituximab:

28-day cycles x 4 cycles; however, the paper also said that people "could receive up to six cycles if disease regression was evident between the second and fourth cycles"

One more dose of rituximab 28 days after the fourth cycle:

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 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

Regimen, Inwards et al. 2008 (NCCTG 95-80-53)

Levels of Evidence: Phase II

28-day cycles x 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

Regimen, Renner et al. 2012 (SAKK 36/06)

Level of Evidence: Phase II

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. doi: 10.3324/haematol.2011.053173. Epub 2012 Feb 7. link to original article contains verified protocol PubMed

FCM

FCM: Fludarabine, Cyclophosphamide, Mitoxantrone

Regimen

Level of Evidence: Phase III

28-day cycles x 4 cycles

Responders (PR or CR) were randomized to maintenance rituximab or 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
  2. 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

Ibrutinib (PCI-32765)

Regimen, Wang et al. 2013

Level of Evidence: Phase II

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 Jun 19. [Epub ahead of print] link to original article contains verified protocol PubMed

Lenalidomide (Revlimid)

Regimen, Wiernik et al. 2008 (NHL-002); Witzig et al. 2001 (NHL-003); Goy et al. 2013 (MCL-001, EMERGE)

Level of Evidence: Phase II

Participants in Goy et al. 2013 "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."

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

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. doi:10.1111/j.1365-2141.2009.07626.x. 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
  4. 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 Sep 3. [Epub ahead of print] link to original article PubMed

Lenalidomide & Rituximab

Regimen, Wang et al. 2012

Level of Evidence: Phase II

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

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. doi:10.1016/S1470-2045(12)70200-0. Epub 2012 Jun 6. link to original article contains protocol PubMed

Obinutuzumab (GA101)

Regimen, Morschhauser et al. 2013 (GAUGUIN)

Level of Evidence: Phase II

  • Obinutuzumab (GA101) 1600 mg (diluted to 10 mg/mL) IV once per day on cycle 1 days 1 & 8; then, during cycles 2 to 8, Obinutuzumab (GA101) 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.

21-day cycles x 8 cycles

Supportive medications:

  • Acetaminophen (Tylenol) or paracetamol 650 to 1000 mg PO once 30 minutes prior to obinutuzumab
  • "An antihistamine" 30 minutes prior to obinutuzumab; if there were no infusion-related reactions (IRRs) requiring medication or infusion interruption, antihistamine could be omitted for subsequent infusions
  • Premedication with corticosteroids recommended for patients at high risk of infusion-related reactions (IRRs)
  • Use of G-CSF allowed for severe neutropenia
  • Antibiotic prophylaxis allowed

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. doi: 10.1200/JCO.2012.46.9585. Epub 2013 Jul 8. link to original article contains verified protocol PubMed

PEP-C

PEP-C: Prednisone, Etoposide, Procarbazine, Cyclophosphamide

Regimen

Level of Evidence: Non-randomized

Induction phase

Supportive medication:

  • Ondansetron (dose not specified) with each procarbazine 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

R-FCM

R-FCM: Rituximab, Fludarabine, Cyclophosphamide, Mitoxantrone

Regimen

Level of Evidence: Phase III

28-day cycles x 4 cycles

Responders (PR or CR) were randomized to maintenance rituximab or 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
  2. 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

Regimen #1, Witzig et al. 2005

Level of Evidence: Phase II

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

Supportive medications:

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

Regimen #2, Hess et al. 2009

Level of Evidence: Phase III

21-day course, followed by:

given until progression or unacceptable toxicity

Supportive medications:

  • Antihistamine (no further details given) once 30 minutes prior to temsirolimus.
  • Corticosteroid use was not allowed.

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. 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. doi: 10.1200/JCO.2008.20.7977. Epub 2009 Jul 6. link to original article contains verified protocol PubMed
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