Mantle cell lymphoma

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Untreated (first-line)

BR

BR: Bendamustine, Rituximab

• Regimen is the same as BR in follicular lymphoma, Rummel, et al. 2012 - StiL NHL1

CALGB 59909

Regimen

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
• Folinic acid (Leucovorin) 50 mg/m2 IV every 6 hours x 3 doses, starting 24 hours after completion of methotrexate, then 10 mg/m2 IV/PO every 6 hours until serum methotrexate level <0.05 uM
• 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 daily on days 3-7

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 daily starting on day 4, to continue until ANC >10000 once or >5000 twice
• Levofloxacin (Levaquin) 500 mg PO once daily, starting on day 6, to continue until ANC ≥1500
• Fluconazole (Diflucan) 200 mg PO once daily, 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 1-4
• Cytarabine (Cytosar) 2000 mg/m2 IV over 2 hours BID on days 1-4 (8 total doses)
• Rituximab (Rituxan) 375 mg/m2 IV once daily on days 6 & 13
• Daily leukapheresis to start when WBC ≥5000/uL

Supportive medications:

• Filgrastim (Neupogen) 10 mcg/kg SC once daily starting on day 14, to continue until peripheral blood stem cell collection is complete
• Levofloxacin (Levaquin) 500 mg PO once daily, starting on day 7, to continue until ANC ≥500
• Fluconazole (Diflucan) 200 mg PO once daily, 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"

CBV: Cyclophosphamide, BiCNU, VP-16

• Carmustine (BiCNU) 15 mg/kg (maximum dose of 550 mg/m2) IV over 1 hour once on day -6
• Etoposide (Vepesid) 60 mg/kg IV over 4 hours once on day -4
• Cyclophosphamide (Cytoxan) 100 mg/kg IV over 2 hours once on day -2
• Autologous blood stem cells infused on day 0.

Supportive medications:

• Filgrastim (Neupogen) 5 mcg/kg SC once daily starting on day +4, to continue until ANC >5000 once or >1500 twice
• Levofloxacin (Levaquin) 500 mg PO once daily, starting on day +2, to continue until ANC ≥500
• Fluconazole (Diflucan) 200 mg PO once daily, starting on day +1, to continue until ANC ≥500
• Acyclovir (Zovirax) 200 mg PO TID, starting on day -2, to continue until 1 year after ASCT
• Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO BID on Saturday and Sunday, to continue until 3 months after ASCT

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 1-3; 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

R-BAC

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

Levels of Evidence: Phase II

Regimen

• Rituximab (Rituxan) 375 mg/m2 IV once on day 1 of cycle 1; given on day 2 of subsequent cycles
• Bendamustine (Treanda) 70 mg/m2 IV over 30-60 minutes once daily on days 2 & 3
• Cytarabine (Cytosar) 800 mg/m2 IV over 2 hours once daily on days 2-4, starting 2 hours after bendamustine on days 2 and 3

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/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)

• 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 daily on days 1-5

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)

• 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 daily on days 1-5

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.

• Rituximab (Rituxan) 375 mg/m2 IV once on day 1
• Dexamethasone (Decadron) 40 mg once daily on days 1-4
• 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 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:

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

Part 4 (Stem cell collection and intensified therapy)

• 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-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 2-4 (total dose per cycle: 1800 mg/m2), given second
• Mesna (Mesnex) 600 mg/m2/day IV continuous infusion over 76 hours on days 2-4, 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 daily 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 daily on days 2-5, 12-15

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 daily
• Valacyclovir (Valtrex) 500 mg PO once daily
• Fluconazole (Diflucan) 100 mg PO once daily
• Levofloxacin (Levaquin) 500 mg PO once daily 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 3-9 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 daily
• Valacyclovir (Valtrex) 500 mg PO once daily
• Fluconazole (Diflucan) 100 mg PO once daily
• Levofloxacin (Levaquin) 500 mg PO once daily 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. 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 2-5, and 375 mg/m2 IV once daily on days 1 & 9 of cycle 6

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 daily on days 1-5

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

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 1-2 weeks after completion of cycle 6, followed by stem cell transplant. If transplant was delayed, an additional 1-2 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

Relapsed/Refractory

Everolimus

Regimen

• Everolimus (Afinitor) 10 mg PO once per day

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