Aggressive Non-Hodgkin lymphoma

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DLBCL, untreated

ACVBP-R

ACVBP-R: Adriamycin, Cyclophosphamide, Vindesine, Bleomycin, Prednisone, Rituximab

Synonyms: R-ACVBP

Structured Concept: none

Level of Evidence: Phase III Improved OS Increased toxicity

Induction Regimen

• Cyclophosphamide (Cytoxan) 1200 mg/m2 IV once on day 1
• Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
• Vindesine (Eldisine) 2 mg/m2 IV once on days 1 & 5
• Bleomycin (Blenoxane) 10 units IV once on days 1 & 5
• Prednisone (Sterapred) 60 mg/m2 PO on days 1 to 5
• Rituximab (Rituxan) 375 mg/m2 IV once on day 1
• Methotrexate (MTX) 15 mg intrathecal on day 1 for CNS prophylaxis

14-day cycles x 4 cycles

Supportive medications:

• Filgrastim (Neupogen) 300 mcg (for patients <75 kg) or 480 mcg (for patients at least 75 kg) SC daily on days 6 to 13

Consolidation Regimen

• Methotrexate (MTX) 3000 mg/m2 IV once on day 1

Supportive medications:

• Calcium folinate - Folinic acid (Leucovorin) rescue

14-day cycles x 2 cycles, beginning 4 weeks after completion of induction, then

• Rituximab (Rituxan) 375 mg/m2 IV once on day 1
• Etoposide (Vepesid) 300 mg/m2 IV once on day 1
• Ifosfamide (Ifex) 1500 mg/m2 IV once on day 1

14-day cycles x 4 cycles, beginning 2 weeks after completion of MTX, then

• Cytarabine (Cytosar) 100 mg/m2 SC on days 1 to 4

14-day cycles x 2 cycles, beginning 2 weeks after completion of REI

References

1. Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, Thiéblemont C, Bosly A, Laurent G, Morschhauser F, Ghesquières H, Jardin F, Bologna S, Fruchart C, Corront B, Gabarre J, Bonnet C, Janvier M, Canioni D, Jais JP, Salles G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26;378(9806):1858-67. link to original article contains verified protocol PubMed

CHOP

CHOP: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone

Synonyms: CHOP-21, ACOP, CAVP, COPA, VACP, VCAP

Structured Concept: C9549 (NCI-T), C0055598 (NCI-MT/UMLS)

Regimen #1, Elias, et al. 1978; Jones, et al. 1979; Fisher, et al. 1993; Miller, et al. 1998

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 15 minutes on day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV bolus over 1 to 2 minutes on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV bolus over 1 to 2 minutes on day 1
• Prednisone (Sterapred) 100 mg PO on days 1 to 5

21-day cycles x 8 cycles

Regimen #2, Pfreundschuh, et al. 2004 & Verdonck, et al. 2007

Level of Evidence: Phase III

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
• Vincristine (Oncovin) 2 mg IV once on day 1
• Prednisone (Sterapred) 100 mg PO on days 1 to 5

21-day cycles x 6 cycles

Supportive medications (only listed in Pfreundschuh, et al. 2004):

• At the discretion of ordering physician: Filgrastim (Neupogen) 300 mcg (for patients <75 kg) or 480 mcg (for patients at least 75 kg) SC daily on days 4 to 13

Regimen #3, Miller, et al. 1998 - CHOP-21 & radiation

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 15 minutes on day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV bolus over 1 to 2 minutes on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV bolus over 1 to 2 minutes on day 1
• Prednisone (Sterapred) 100 mg PO on days 1 to 5

21-day cycles x 3 cycles, then followed by radiation therapy

Radiation therapy, starting 3 weeks after cycle 3 of CHOP:

• Involved field radiation therapy, 180-200 cGy fractions, total dose of 4000-5500 cGy. Total dose was often influenced by whether patients had clinical evidence of residual disease after 4000 cGy.

Regimen #4, Coiffier, et al. 2002 & 2010; Feugier, et al. 2005; Mounier, et al. 2012 - LNH-98.5

• 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) 40 mg/m2 PO on days 1 to 5

21-day cycles x 8 cycles

Supportive medications:

• Filgrastim (Neupogen) used for later cycles if patients developed grade 4 neutropenia or febrile neutropenia

Regimen #5, Habermann, et al. 2006 (CALGB 9793)

• 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 per cycle: 2 mg) IV once on day 1
• Prednisone (Sterapred) 100 mg/m2 PO once daily on days 1 to 5

21-day cycles x 6 to 8 cycles

Supportive medications:

• Filgrastim (Neupogen) "recommended according to guidelines"

References

1. Elias L, Portlock CS, Rosenberg SA. Combination chemotherapy of diffuse histiocytic lymphoma with cyclophosphamide, adriamycin, vincristine and prednisone (CHOP). Cancer. 1978 Oct;42(4):1705-10. contains verified protocol PubMed
2. Jones SE, Grozea PN, Metz EN, Haut A, Stephens RL, Morrison FS, Butler JJ, Byrne GE Jr, Moon TE, Fisher R, Haskins CL, Coltman CA Jr. Superiority of adriamycin-containing combination chemotherapy in the treatment of diffuse lymphoma: a Southwest Oncology Group study. Cancer. 1979 Feb;43(2):417-25. contains verified protocol PubMed
3. Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA Jr, Miller TP. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med. 1993 Apr 8;328(14):1002-6. link to original article PubMed
4. Miller TP, Dahlberg S, Cassady JR, Adelstein DJ, Spier CM, Grogan TM, LeBlanc M, Carlin S, Chase E, Fisher RI. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med. 1998 Jul 2;339(1):21-6. link to original article contains verified protocol PubMed
5. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jan 24;346(4):235-42. link to original article contains verified protocol PubMed
6. Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rudolph C, Reiser M, Hossfeld DK, Metzner B, Hasenclever D, Schmitz N, Glass B, Rübe C, Loeffler M; German High-Grade Non-Hodgkin's Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood. 2004 Aug 1;104(3):626-33. Epub 2004 Feb 24. link to original article contains verified protocol PubMed
7. Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rübe C, Rudolph C, Reiser M, Hossfeld DK, Eimermacher H, Hasenclever D, Schmitz N, Loeffler M; German High-Grade Non-Hodgkin's Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood. 2004 Aug 1;104(3):634-41. Epub 2004 Mar 11. link to original article contains verified protocol PubMed
8. Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Fermé C, Christian B, Lepage E, Tilly H, Morschhauser F, Gaulard P, Salles G, Bosly A, Gisselbrecht C, Reyes F, Coiffier B. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 2005 Jun 20;23(18):4117-26. link to original article contains protocol PubMed
9. Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA, Cohn JB, Dakhil SR, Woda B, Fisher RI, Peterson BA, Horning SJ. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006 Jul 1;24(19):3121-7. Epub 2006 Jun 5. link to original article contains verified protocol PubMed
10. Bonnet C, Fillet G, Mounier N, Ganem G, Molina TJ, Thiéblemont C, Fermé C, Quesnel B, Martin C, Gisselbrecht C, Tilly H, Reyes F; Groupe d'Etude des Lymphomes de l'Adulte. CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 2007 Mar 1;25(7):787-92. Epub 2007 Jan 16. link to original article contains protocol PubMed
11. Verdonck LF, Notenboom A, de Jong DD, MacKenzie MA, Verhoef GE, Kramer MH, Ossenkoppele GJ, Doorduijn JK, Sonneveld P, van Imhoff GW. Intensified 12-week CHOP (I-CHOP) plus G-CSF compared with standard 24-week CHOP (CHOP-21) for patients with intermediate-risk aggressive non-Hodgkin lymphoma: a phase 3 trial of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON). Blood. 2007 Apr 1;109(7):2759-66. link to original article contains verified protocol PubMed
12. Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, Lefort S, Marit G, Macro M, Sebban C, Belhadj K, Bordessoule D, Fermé C, Tilly H. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood. 2010 Sep 23;116(12):2040-5. link to original article contains verified protocol PubMed
13. Mounier N, Heutte N, Thieblemont C, Briere J, Gaulard P, Feugier P, Ghesquieres H, Van Den Neste E, Robu D, Tilly H, Bouabdallah R, Safar V, Coiffier B; Groupe d'Etude des Lymphomes de l'Adulte (GELA). Ten-year relative survival and causes of death in elderly patients treated with R-CHOP or CHOP in the GELA LNH-985 trial. Clin Lymphoma Myeloma Leuk. 2012 Jun;12(3):151-4. doi:10.1016/j.clml.2011.11.004. Epub 2012 Feb 1. link to original article PubMed

CHOP Intensified

CHOP-DI: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone, Dose Intense
I-CHOP: Intensified Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone

Synonyms: CHOP-14, CHOP-DI, I-CHOP

Structured Concept: none

Regimen #1, Blayney, et al. 2003 - CHOP-DI, SWOG 9349

Level of Evidence: Phase II

• Cyclophosphamide (Cytoxan) 1600 mg/m2 IV once on day 1
• Doxorubicin (Adriamycin) 65 mg/m2 IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m2 IV once on day 1
• Prednisone (Sterapred) 100 mg PO on days 1 to 5

14-day cycles x up to 6 cycles

Supportive medications:

• Filgrastim (Neupogen) 5 mcg/kg SC daily on days 2 to 11, or until ANC is greater than 10,000

Regimen #2, Verdonck, et al. 2007 - I-CHOP

Level of Evidence: Phase III Equivalent OS Increased toxicity

• Cyclophosphamide (Cytoxan) 1000 mg/m2 IV once on day 1
• Doxorubicin (Adriamycin) 70 mg/m2 IV once on day 1
• Vincristine (Oncovin) 2 mg IV once on day 1
• Prednisone (Sterapred) 100 mg PO on days 1 to 5

14-day cycles x 6 cycles

Supportive medications:

• Filgrastim (Neupogen) 5 mcg/kg SC daily on days 2 to 11

Regimen #3, Pfreundschuh, et al. 2004 (NHL-B2, CHOP-14) & Pfreundschuh, et al. 2008 (RICOVER-60)

Level of Evidence: Phase III

Pre-phase treatment

Recommended in Pfreundschuh, et al. 2004, but mandatory in Pfreundschuh, et al. 2008 "to improve the performance status of patients and to ameliorate side-effects of the first chemotherapy cycle." A difference was that the prednisone in Pfreundschuh, et al. 2004 could be given for 5 to 7 days.

• Vincristine (Oncovin) 1 mg IV once (day not specified)
• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 7

7-day course, then proceed to main CHOP-14 regimen

Main CHOP-14 regimen

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
• Doxorubicin (Adriamycin) 50 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

14-day cycles x 6 cycles; some patients in Pfreundschuh, et al. 2008 received 14-day cycles x 8 cycles

Supportive medications (per Pfreundschuh, et al. 2004):

• Filgrastim (Neupogen) 300 mcg (for patients <75 kg) or 480 mcg (for patients at least 75 kg) SC once per day on days 4 to 13

Radiation therapy for initial bulky disease

"Initial bulky disease": patients with "lymphoma masses or conglomerates with a diameter ≥7.5 cm) or extranodal involvement"

• Radiation therapy, 36 Gy to areas of initial bulky disease

References

1. Blayney DW, LeBlanc ML, Grogan T, Gaynor ER, Chapman RA, Spiridonidis CH, Taylor SA, Bearman SI, Miller TP, Fisher RI; Southwest Oncology Group. Dose-intense chemotherapy every 2 weeks with dose-intense cyclophosphamide, doxorubicin, vincristine, and prednisone may improve survival in intermediate- and high-grade lymphoma: a phase II study of the Southwest Oncology Group (SWOG 9349). J Clin Oncol. 2003 Jul 1;21(13):2466-73. link to original article contains verified protocol PubMed
2. Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rudolph C, Reiser M, Hossfeld DK, Metzner B, Hasenclever D, Schmitz N, Glass B, Rübe C, Loeffler M; German High-Grade Non-Hodgkin's Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood. 2004 Aug 1;104(3):626-33. Epub 2004 Feb 24. link to original article contains verified protocol PubMed
3. Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rübe C, Rudolph C, Reiser M, Hossfeld DK, Eimermacher H, Hasenclever D, Schmitz N, Loeffler M; German High-Grade Non-Hodgkin's Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood. 2004 Aug 1;104(3):634-41. Epub 2004 Mar 11. link to original article contains verified protocol PubMed
4. Verdonck LF, Notenboom A, de Jong DD, MacKenzie MA, Verhoef GE, Kramer MH, Ossenkoppele GJ, Doorduijn JK, Sonneveld P, van Imhoff GW. Intensified 12-week CHOP (I-CHOP) plus G-CSF compared with standard 24-week CHOP (CHOP-21) for patients with intermediate-risk aggressive non-Hodgkin lymphoma: a phase 3 trial of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON). Blood. 2007 Apr 1;109(7):2759-66. link to original article contains verified protocol PubMed
5. Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trümper L, Balleisen L, Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M; German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008 Feb;9(2):105-16. link to original article contains verified protocol PubMed

CHOPE

CHOPE: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone, Etoposide

Synonyms: CHOEP, VAC0P

Structured Concept: C9702 (NCI-T), C0212922(NCI-MT/UMLS)

Regimen

Level of Evidence: Phase III

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
• Vincristine (Oncovin) 2 mg IV once on day 1
• Prednisone (Sterapred) 100 mg PO on days 1 to 5
• Etoposide (Vepesid) 100 mg/m2 IV once daily on days 1 to 3
• Patients with initial bulky disease (mass conglomerate at least 7.5 cm) received 36 Gy radiation therapy and to extranodal sites of disease when possible

14 or 21-day cycles x 6 cycles, next cycle to start as long as WBC is >2.5 and platelets >80

• CHOEP-14 uses 14-day cycles; CHOEP-21 uses 21-day cycles

• Example orders for CHOEP in lymphoma

Supportive medications:

• For 14-day cycles: Filgrastim (Neupogen) 300 mcg (for patients <75 kg) or 480 mcg (for patients at least 75 kg) SC daily on days 4 to 13
• Filgrastim (Neupogen) use for 21-day cycles is by discretion of ordering physician

References

1. Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rudolph C, Reiser M, Hossfeld DK, Metzner B, Hasenclever D, Schmitz N, Glass B, Rübe C, Loeffler M; German High-Grade Non-Hodgkin's Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood. 2004 Aug 1;104(3):626-33. Epub 2004 Feb 24. link to original article contains verified protocol PubMed
2. Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rübe C, Rudolph C, Reiser M, Hossfeld DK, Eimermacher H, Hasenclever D, Schmitz N, Loeffler M; German High-Grade Non-Hodgkin's Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood. 2004 Aug 1;104(3):634-41. Epub 2004 Mar 11. link to original article contains verified protocol PubMed

Dose-adjusted EPOCH

EPOCH: Etoposide, Prednisone, Oncovin, Cyclophosphamide, Hydroxydaunorubicin

Synonyms: CHEOP, DA-EPOCH

Structured Concept: C63779 (NCI-T), C1880475 (NCI-MT/UMLS)

Regimen, Wilson, et al. 2002 - dose-adjusted EPOCH (DA-EPOCH)

Level of Evidence: Phase II

• Etoposide (Vepesid) 50 mg/m2/day (total dose of 200 mg/m2) IV continuous infusion on days 1 to 4
• Prednisone (Sterapred) 60 mg/m2 PO BID on days 1 to 5
• Vincristine (Oncovin) 0.4 mg/m2/day (total dose of 1.6 mg/m2) IV continuous infusion on days 1 to 4
• Doxorubicin (Adriamycin) 10 mg/m2/day (total dose of 40 mg/m2) IV continuous infusion on days 1 to 4
• Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 15 minutes on day 5

Supportive medications:

• Filgrastim (Neupogen) 5 mcg/kg SQ daily, starting on day 6 and continuing until ANC >5,000/uL past nadir
• PCP prophylaxis with any one of the following:
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO BID 3 days per week
  • Atovaquone (Mepron) 1500 mg PO daily
  • Pentamidine (Nebupent) 300 mg nebulized every 28 days

21-day cycles x 6 to 8 cycles

Dose-adjustments for EPOCH protocol:

• Start cycle 1 as described above.
• Obtain CBCs twice per week for nadir measurements.
• If nadir ANC >500, increase etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
• If nadir ANC <500 on 1 or 2 measurements, use same doses as last cycle.
• If nadir ANC <500 on at least 3 measurements, decrease etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
• And/or if nadir platelet count <25 on at least 1 measurement, decrease etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
• Dose adjustments below the cycle 1 starting dose only applies to cyclophosphamide. The lowest etoposide and doxorubicin would be dosed at is the original cycle 1 dose.
• Can start new cycle every 21 days if ANC >1,000 and platelets >100. If counts are below those levels, check daily CBC and continue growth factor support until counts are adequate and next cycle can start.

References

1. Wilson WH, Grossbard ML, Pittaluga S, Cole D, Pearson D, Drbohlav N, Steinberg SM, Little RF, Janik J, Gutierrez M, Raffeld M, Staudt L, Cheson BD, Longo DL, Harris N, Jaffe ES, Chabner BA, Wittes R, Balis F. Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy. Blood. 2002 Apr 15;99(8):2685-93. link to original article contains verified protocol PubMed

MACOP-B

Regimen

Level of Evidence: Phase III

To be completed

References

1. Klimo P, Connors JM. MACOP-B chemotherapy for the treatment of diffuse large-cell lymphoma. Ann Intern Med. 1985 May;102(5):596-602. link to original article PubMed
2. Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA Jr, Miller TP. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med. 1993 Apr 8;328(14):1002-6. link to original article PubMed

m-BACOD

m-BACOD: methotrexate (moderate dose), Bleomycin, Adriamycin (doxorubicin), Cyclophosphamide, Oncovin (vincristine), Dexamethasone

Structured Concept: C63458 (NCI-T), C1883662 (NCI-MT/UMLS)

Regimen

Level of Evidence: Phase III

• Methotrexate (MTX) 200 mg/m2 IV once on days 8 & 15
• Folinic acid (Leucovorin) 10 mg/m2 PO/IV Q6H x 8 doses, starting 24 hours after methotrexate
• Bleomycin (Blenoxane) 4 units/m2 IV once on day 1
• Doxorubicin (Adriamycin) 45 mg/m2 IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
• Vincristine (Oncovin) 1 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
• Dexamethasone (Decadron) 6 mg/m2 (no route specified) daily on days 1 to 5

Dose adjustments:

• If nadir WBC <1,000 or nadir platelets <50,000: 50% of cyclophosphamide and doxorubicin
• If WBC <1,000, platelets <50,000, or creatinine >50% of baseline on day of treatment, methotrexate was omitted

21-day cycles x 10 cycles

Supportive medications: none reported

References

1. Shipp MA, Yeap BY, Harrington DP, Klatt MM, Pinkus GS, Jochelson MS, Rosenthal DS, Skarin AT, Canellos GP. The m-BACOD combination chemotherapy regimen in large-cell lymphoma: analysis of the completed trial and comparison with the M-BACOD regimen. J Clin Oncol. 1990 Jan;8(1):84-93. link to original article contains verified protocol PubMed
2. Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA Jr, Miller TP. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med. 1993 Apr 8;328(14):1002-6. link to original article PubMed

ProMACE-CytaBOM

ProMACE-CytaBOM: Prolix (prednisone), Methotrexate, Adriamycin (doxorubicin), Cyclophosphamide, Etoposide, Cytarabine, Bleomycin, Oncovin (vincristine), Methotrexate

Structured Concept: C63460 (NCI-T), C1882461 (NCI-MT/UMLS)

Regimen

Level of Evidence: Phase III

• Cyclophosphamide (Cytoxan) 650 mg/m2 IV once on day 1
• Doxorubicin (Adriamycin) 25 mg/m2 IV once on day 1
• Etoposide (Vepesid) 120 mg/m2 IV once on day 1
• Cytarabine (Cytosar) 300 mg/m2 IV once on day 8
• Bleomycin (Blenoxane) 5 units/m2 IV once on day 8
• Vincristine (Oncovin) 1.4 mg/m2 IV once on day 8
• Methotrexate (MTX) 120 mg/m2 IV once on day 8
• Folinic acid (Leucovorin) 25 mg/m2 PO Q6H x 4 doses, starting 24 hours after methotrexate
• Prednisone (Prolix) 60 mg/m2 PO daily on days 1 to 14
• Patients with initial bone or bone marrow involvement who achieved a CR were treated with 2,400 cGy prophylactic cranial irradiation.

Dose adjustments:

• "If WBC is ≥4,000, use 100% doses of all drugs
• If WBC count is 3,000 to 3,999, 100% prednisone, bleomycin, vincristine, cytarabine, and methotrexate; 75% cyclophosphamide, Adriamycin, and etoposide
• If WBC count is 2,000 to 2,999, 100% prednisone, bleomycin, vincristine, and methotrexate; 75% etoposide, cytarabine; 50% cyclophosphamide, Adriamycin
• If WBC count is 1,000 to 1,999, 100% prednisone, bleomycin, vincristine and methotrexate; 25% cyclophosphamide, Adriamycin, etoposide, and cytarabine
• If WBC count is 0 to 999, 100% prednisone, vincristine, and bleomycin; 50% methotrexate, no other drugs
• If platelet count is ≥100,000, use 100% doses of all drugs
• If platelet count is 50,000 to 99,000, 100% prednisone, bleomycin, vincristine, and methotrexate; 50% etoposide and cytarabine; 25% cyclophosphamide and Adriamycin
• If platelet count is 0 to 49,000, 100% prednisone, bleomycin, and vincristine; 50% methotrexate, no other drugs"

21-day cycles x 6 cycles or 2 cycles after maximum clinical response

Supportive medications:

• Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO BID throughout the course of treatment

References

1. Longo DL, DeVita VT Jr, Duffey PL, Wesley MN, Ihde DC, Hubbard SM, Gilliom M, Jaffe ES, Cossman J, Fisher RI, et al. Superiority of ProMACE-CytaBOM over ProMACE-MOPP in the treatment of advanced diffuse aggressive lymphoma: results of a prospective randomized trial. J Clin Oncol. 1991 Jan;9(1):25-38. Erratum in: J Clin Oncol 1991 Apr;9(4):710. link to original article contains verified protocol PubMed
2. Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, Glick JH, Coltman CA Jr, Miller TP. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin's lymphoma. N Engl J Med. 1993 Apr 8;328(14):1002-6. link to original article PubMed

R-CEOP

R-CEOP: Rituximab, Cyclophosphamide, Etoposide, Oncovin, Prednisone

Regimen

Level of Evidence: Retrospective

This regimen is intended for patients with a contraindication to anthracyclines. Only the dose of etoposide and number of cycles used was specified in the abstract. The doses of the other medications and schedule are provided based on the standard R-CHOP regimen, whose references can be found on this page.

• Rituximab (Rituxan) 375 mg/m2 IV once on day 1
• Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
• Etoposide (Vepesid) 50 mg/m2 IV once on day 1; 100 mg/m2 PO once daily on days 2 & 3
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
• Prednisone (Sterapred) 100 mg PO once daily on days 1 to 5
  • Alternate dosing used in the R-CHOP regimens described in Coiffier, et al. 2002 & 2010; Feugier, et al. 2005; Mounier, et al. 2012 - LNH-98.5 is Prednisone (Sterapred) 40 mg/m2 PO once daily on days 1 to 5

21-day cycles x 3 to 4 cycles +/- radiation therapy for patients with limited stage disease; 6 cycles for patients with advanced stage disease

References

1. Moccia, Alden A., Schaff, Kimberly, Hoskins, Paul, Klasa, Richard, Savage, Kerry J., Shenkier, Tamara, Gascoyne, Randy D., Connors, Joseph M., Sehn, Laurie H. R-CHOP with Etoposide Substituted for Doxorubicin (R-CEOP): Excellent Outcome in Diffuse Large B Cell Lymphoma for Patients with a Contraindication to Anthracyclines. ASH Annual Meeting Abstracts 2009 114: 408 link to abstract

R-CHOEP-14

Regimen

Level of Evidence: Phase III

To be completed

References

1. Schmitz N, Nickelsen M, Ziepert M, Haenel M, Borchmann P, Schmidt C, Viardot A, Bentz M, Peter N, Ehninger G, Doelken G, Ruebe C, Truemper L, Rosenwald A, Pfreundschuh M, Loeffler M, Glass B; for the German High-Grade Lymphoma Study Group (DSHNHL). Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1). Lancet Oncol. 2012 Dec;13(12):1250-1259. doi:10.1016/S1470-2045(12)70481-3. Epub 2012 Nov 16. PubMed

R-CHOP

R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone

Synonyms: R-CHOP-21, CHOP-R

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

Regimen #1, Coiffier, et al. 2002; Coiffier, et al. 2010; Feugier, et al. 2005; Mounier, et al. 2012 (LNH-98.5); Delarue, et al. 2013 (LNH03-6B)

Level of Evidence: Phase III Mixed OS Similar toxicity

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

21-day cycles x 8 cycles

Supportive medications:

• Filgrastim (Neupogen) used for later cycles if patients developed grade 4 neutropenia or febrile neutropenia

Neuromeningeal prophylaxis

As described in Delarue, et al. 2013 (LNH03-6B):

• Methotrexate (MTX) 15 mg IT once every 21 days x 4 total doses

Regimen #2, Pfreundschuh, et al. 2006 & 2011 - MInT

Level of Evidence: Phase III Improved OS Similar toxicity

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
• Doxorubicin (Adriamycin) 50 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
• Rituximab (Rituxan) 375 mg/m2 IV once on day 1
• Radiation therapy: 30 to 40 Gy given to sites of primary bulky disease; 30-40 Gy to primary extranodal disease at physician discretion

21-day cycles x 6 cycles

• Example orders for R-CHOP in lymphoma

Supportive medications:

• Filgrastim (Neupogen) or Lenograstim (Granocyte) used at physician discretion for neutropenia

Regimen #3, Habermann, et al. 2006 (CALGB 9793)

• Rituximab (Rituxan) 375 mg/m2 IV once daily on days -7 and -3 of cycle 1; then Rituximab (Rituxan) 375 mg/m2 IV once on day -2 of cycles 2 onwards
• 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 per cycle: 2 mg) IV once on day 1
• Prednisone (Sterapred) 100 mg/m2 PO once per day on days 1 to 5

Supportive medications:

• Filgrastim (Neupogen) "recommended according to guidelines"

21-day cycles x 6 to 8 cycles

Regimen #4, Merli, et al. 2012 (ANZINTER3)

Level of Evidence: Phase III

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

21-day cycles x 6 cycles

Supportive medications:

• Prophylactic G-CSF used for persisting grade 4 neutropenia or febrile neutropenia.
• Cotrimoxazole (dose/route/schedule not specified) prophylaxis.
• Erythropoietin use was allowed for hemoglobin <11 g/dL.

Radiation therapy

"At the end of chemotherapy, radiotherapy (RT) was scheduled for sites of previous bulky disease or partially responding sites."

Regimen #5, Cunningham, et al. 2013

Level of Evidence: Phase III

Note: Cunningham, et al. 2013 said that it based its regimen on Coiffier, et al. 2002, but notably it uses prednisolone instead of prednisone.

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

21-day cycles x 8 cycles

Supportive medications:

• Lenograstim (Granocyte) (dose/route not specified) given on days 4 to 12 at physician discretion
• Allopurinol (Aloprim) 300 mg PO once per day during cycle 1
• Co-trimoxazole 480 mg (route not specified) BID on 3 days per week, taken throughout therapy, ending 2 weeks after chemotherapy is completed

CNS prophylaxis

Per investigator discretion, but Cunningham, et al. 2013 recommended that patients who had involvement of the "bone marrow, peripheral blood, nasal or paranasal sinuses, orbit, and testis" (they probably intended to say "or testis") receive:

• Methotrexate (MTX) 12.5 mg IT "for the first three cycles of treatment, administered as per local guidelines." No other details given.

References

1. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jan 24;346(4):235-42. link to original article contains verified protocol PubMed
2. Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Fermé C, Christian B, Lepage E, Tilly H, Morschhauser F, Gaulard P, Salles G, Bosly A, Gisselbrecht C, Reyes F, Coiffier B. Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol. 2005 Jun 20;23(18):4117-26. link to original article contains protocol PubMed
3. Pfreundschuh M, Trümper L, Osterborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, Walewski J, Zinzani PL, Stahel R, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, López-Guillermo A, Corrado C, Scheliga A, Milpied N, Mendila M, Rashford M, Kuhnt E, Loeffler M; MabThera International Trial Group. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006 May;7(5):379-91. link to original article contains verified protocol PubMed
4. Habermann TM, Weller EA, Morrison VA, Gascoyne RD, Cassileth PA, Cohn JB, Dakhil SR, Woda B, Fisher RI, Peterson BA, Horning SJ. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J Clin Oncol. 2006 Jul 1;24(19):3121-7. Epub 2006 Jun 5. link to original article contains verified protocol PubMed
5. Coiffier B, Thieblemont C, Van Den Neste E, Lepeu G, Plantier I, Castaigne S, Lefort S, Marit G, Macro M, Sebban C, Belhadj K, Bordessoule D, Fermé C, Tilly H. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte. Blood. 2010 Sep 23;116(12):2040-5. link to original article contains verified protocol PubMed content property of HemOnc.org
6. Pfreundschuh M, Kuhnt E, Trümper L, Osterborg A, Trneny M, Shepherd L, Gill DS, Walewski J, Pettengell R, Jaeger U, Zinzani PL, Shpilberg O, Kvaloy S, de Nully Brown P, Stahel R, Milpied N, López-Guillermo A, Poeschel V, Grass S, Loeffler M, Murawski N; MabThera International Trial (MInT) Group. CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol. 2011 Oct;12(11):1013-22. link to original article contains protocol PubMed
7. Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, Thiéblemont C, Bosly A, Laurent G, Morschhauser F, Ghesquières H, Jardin F, Bologna S, Fruchart C, Corront B, Gabarre J, Bonnet C, Janvier M, Canioni D, Jais JP, Salles G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26;378(9806):1858-67. link to original article contains verified protocol PubMed
8. Mounier N, Heutte N, Thieblemont C, Briere J, Gaulard P, Feugier P, Ghesquieres H, Van Den Neste E, Robu D, Tilly H, Bouabdallah R, Safar V, Coiffier B; Groupe d'Etude des Lymphomes de l'Adulte (GELA). Ten-year relative survival and causes of death in elderly patients treated with R-CHOP or CHOP in the GELA LNH-985 trial. Clin Lymphoma Myeloma Leuk. 2012 Jun;12(3):151-4. doi:10.1016/j.clml.2011.11.004. Epub 2012 Feb 1. link to original article PubMed
9. Merli F, Luminari S, Rossi G, Mammi C, Marcheselli L, Tucci A, Ilariucci F, Chiappella A, Musso M, Di Rocco A, Stelitano C, Alvarez I, Baldini L, Mazza P, Salvi F, Arcari A, Fragasso A, Gobbi PG, Liberati AM, Federico M. Cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab versus epirubicin, cyclophosphamide, vinblastine, prednisone and rituximab for the initial treatment of elderly "fit" patients with diffuse large B-cell lymphoma: results from the ANZINTER3 trial of the Intergruppo Italiano Linfomi. Leuk Lymphoma. 2012 Apr;53(4):581-8. doi: 10.3109/10428194.2011.621565. Epub 2011 Nov 15. link to original article contains verified protocol PubMed
10. Delarue R, Tilly H, Mounier N, Petrella T, Salles G, Thieblemont C, Bologna S, Ghesquières H, Hacini M, Fruchart C, Ysebaert L, Fermé C, Casasnovas O, Van Hoof A, Thyss A, Delmer A, Fitoussi O, Molina TJ, Haioun C, Bosly A. Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol. 2013 Apr 8. doi:pii: S1470-2045(13)70122-0. 10.1016/S1470-2045(13)70122-0. [Epub ahead of print] link to original article contains verified protocol PubMed
11. Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, Pocock C, Ardeshna KM, Radford JA, McMillan A, Davies J, Turner D, Kruger A, Johnson P, Gambell J, Linch D. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet. 2013 Apr 19. doi:pii: S0140-6736(13)60313-X.10.1016/S0140-6736(13)60313-X. [Epub ahead of print] link to original article contains verified protocol PubMed

R-CHOP Intensified

R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone

Synonyms: R-CHOP-14, Dose-dense rituximab-CHOP

Structured Concept: none

Regimen #1, Pfreundschuh, et al. 2008 (RICOVER-60)

Level of Evidence: Phase III

Pre-phase treatment

• Vincristine (Oncovin) 1 mg IV once (day not specified)
• Prednisone (Sterapred) 100 mg PO once per day on days 1 to 7

7-day course, then proceed to main R-CHOP-14 regimen

Main R-CHOP-14 regimen

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
• Doxorubicin (Adriamycin) 50 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
• Rituximab (Rituxan) 375 mg/m2 IV once on day 1

14-day cycles x 6 to 8 cycles (8 doses of rituximab regardless of total number of cycles)

Supportive medications:

• Filgrastim (Neupogen) or Lenograstim (Granocyte) (dose/route/frequency not specified) starting on day 4, to continue until count recovery

Radiation therapy for initial bulky disease

"Initial bulky disease": patients with "lymphoma masses or conglomerates with a diameter ≥7.5 cm) or extranodal involvement"

• Radiation therapy, 36 Gy to areas of initial bulky disease

Regimen #2, Delarue, et al. 2013 (LNH03-6B)

Level of Evidence: Phase III

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
• Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
• Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
• Rituximab (Rituxan) 375 mg/m2 IV once on day 1

14-day cycles x 8 cycles

Supportive medications:

• Granulocyte colony-stimulating factor or pegylated G-CSF "according to the treating doctor's decision, fulfilling existing guidelines and product labelling at that time."

Neuromeningeal prophylaxis

• Methotrexate (MTX) 15 mg IT once every 14 days x 4 total doses

Regimen #3, Cunningham, et al. 2013

Level of Evidence: Phase III

Main R-CHOP-14 regimen

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
• Vincristine (Oncovin) 2 mg IV once on day 1
• Prednisolone (Millipred) 100 mg PO once per day on days 1 to 5
• Rituximab (Rituxan) 375 mg/m2 IV once on day 1

14-day cycles x 6 cycles; then give additional doses of rituximab as described below

Supportive medications:

• Lenograstim (Granocyte) (dose/route not specified) given on days 4 to 12
• Allopurinol (Aloprim) 300 mg PO once per day during cycle 1
• Co-trimoxazole 480 mg (route not specified) BID on 3 days per week, taken throughout therapy, ending 2 weeks after treatment is completed

Additional doses of Rituximab

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

14-day cycles x 2 cycles

CNS prophylaxis

Per investigator discretion, but Cunningham, et al. 2013 recommended that patients who had involvement of the "bone marrow, peripheral blood, nasal or paranasal sinuses, orbit, and testis" (they probably intended to say "or testis") receive:

• Methotrexate (MTX) 12.5 mg IT "for the first three cycles of treatment, administered as per local guidelines." No other details given.

References

1. Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trümper L, Balleisen L, Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M; German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008 Feb;9(2):105-16. link to original article contains verified protocol PubMed
2. Delarue R, Tilly H, Mounier N, Petrella T, Salles G, Thieblemont C, Bologna S, Ghesquières H, Hacini M, Fruchart C, Ysebaert L, Fermé C, Casasnovas O, Van Hoof A, Thyss A, Delmer A, Fitoussi O, Molina TJ, Haioun C, Bosly A. Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol. 2013 Apr 8. doi:pii: S1470-2045(13)70122-0. 10.1016/S1470-2045(13)70122-0. [Epub ahead of print] link to original article contains verified protocol PubMed
3. Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, Pocock C, Ardeshna KM, Radford JA, McMillan A, Davies J, Turner D, Kruger A, Johnson P, Gambell J, Linch D. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet. 2013 Apr 19. doi:pii: S0140-6736(13)60313-X.10.1016/S0140-6736(13)60313-X. [Epub ahead of print] link to original article contains verified protocol PubMed

R-CVP

R-CVP: Rituximab, Cyclophosphamide, Vincristine, Prednisone

Structured Concept: C63473 (NCI-T), C1882520 (NCI-MT/UMLS)

Regimen

• Cyclophosphamide (Cytoxan) 750 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) 40 mg/m2 PO on days 1 to 5
• Rituximab (Rituxan) 375 mg/m2 IV once on day 1

21-day cycles x up to 8 cycles

References

See references for CVP

R-EPOCH

R-EPOCH: Rituximab, Etoposide, Prednisone, Oncovin, Cyclophosphamide, Hydroxydaunorubicin

Synonyms: DA-EPOCH-R, EPOCH-R, REPOCH

Structured Concept: C63461 (NCI-T), C1882521 (NCI-MT/UMLS)

Regimen

Level of Evidence: Phase II

• Rituximab (Rituxan) 375 mg/m2 IV once per cycle or day 1 before the start of EPOCH (depending on reference)
• Etoposide (Vepesid) 50 mg/m2/day (total dose of 200 mg/m2) IV continuous infusion on days 1 to 4
• Prednisone (Sterapred) 60 mg/m2 PO BID on days 1 to 5
• Vincristine (Oncovin) 0.4 mg/m2/day (total dose of 1.6 mg/m2) IV continuous infusion on days 1 to 4
• Doxorubicin (Adriamycin) 10 mg/m2/day (total dose of 40 mg/m2) IV continuous infusion on days 1 to 4
• Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 15 minutes on day 5

21-day cycles x 6 to 8 cycles

Supportive medications:

• Filgrastim (Neupogen) 5 mcg/kg SQ daily, starting on day 6 and continuing until ANC >5,000/uL past nadir
• PCP prophylaxis with any one of the following:
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO BID 3 days per week
    • Alternative used only in García-Suárez, et al. 2007: cotrimoxazole 480 mg PO BID 3 days per week
  • Atovaquone (Mepron) 1500 mg PO daily
  • Pentamidine (Nebupent) 300 mg nebulized every 28 days
• Only in García-Suárez, et al. 2007: Darbepoetin alfa (Aranesp) 2.25 ug/kg SC when hemoglobin concentration was ≤100 g/l.

Dose-adjustments for EPOCH protocol:

• Start cycle 1 as described above.
• Obtain CBCs twice per week for nadir measurements.
• If nadir ANC >500, increase etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
• If nadir ANC <500 on 1 or 2 measurements, use same doses as last cycle.
• If nadir ANC <500 on at least 3 measurements, decrease etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
• And/or if nadir platelet count <25 on at least 1 measurement, decrease etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
• Dose adjustments below the cycle 1 starting dose only applies to cyclophosphamide. The lowest etoposide and doxorubicin would be dosed at is the original cycle 1 dose.
• Can start new cycle every 21 days if ANC >1,000 and platelets >100. If counts are below those levels, check daily CBC and continue growth factor support until counts are adequate and next cycle can start.

21-day cycles x 6 to 8 cycles

Supportive medications:

• EITHER Filgrastim (Neupogen) 5 mcg/kg SQ daily, starting 24 hours after EPOCH is completed and continuing until "neutrophil recovery"--no absolute count specified
• OR Pegfilgrastim (Neulasta) 6 mg SC x1 24 hours after EPOCH is completed
• Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO 3x per week (e.g. Monday, Wednesday, Friday)
• Fluconazole (Diflucan) 100 mg PO daily
• Ciprofloxacin (Cipro) 500 mg PO BID, starting on day 8 and to continue to at least day 15 or postnadir ANC of at least 1000
  • Other fluoroquinolone can be used at discretion of physician

References

1. Wilson WH, Grossbard ML, Pittaluga S, Cole D, Pearson D, Drbohlav N, Steinberg SM, Little RF, Janik J, Gutierrez M, Raffeld M, Staudt L, Cheson BD, Longo DL, Harris N, Jaffe ES, Chabner BA, Wittes R, Balis F. Dose-adjusted EPOCH chemotherapy for untreated large B-cell lymphomas: a pharmacodynamic approach with high efficacy. Blood. 2002 Apr 15;99(8):2685-93. link to original article contains verified protocol PubMed
2. García-Suárez J, Bañas H, Arribas I, De Miguel D, Pascual T, Burgaleta C. Dose-adjusted EPOCH plus rituximab is an effective regimen in patients with poor-prognostic untreated diffuse large B-cell lymphoma: results from a prospective observational study. Br J Haematol. 2007 Jan;136(2):276-85. link to original article contains verified protocol PubMed
3. Wilson WH, Dunleavy K, Pittaluga S, Hegde U, Grant N, Steinberg SM, Raffeld M, Gutierrez M, Chabner BA, Staudt L, Jaffe ES, Janik JE. Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin Oncol. 2008 Jun 1;26(16):2717-24. link to original article PubMed
4. Wilson WH, Jung SH, Porcu P, Hurd D, Johnson J, Martin SE, Czuczman M, Lai R, Said J, Chadburn A, Jones D, Dunleavy K, Canellos G, Zelenetz AD, Cheson BD, Hsi ED; Cancer Leukemia Group B. A Cancer and Leukemia Group B multi-center study of DA-EPOCH-rituximab in untreated diffuse large B-cell lymphoma with analysis of outcome by molecular subtype. Haematologica. 2012 May;97(5):758-65. Epub 2011 Dec 1. link to original article PubMed

R-miniCEOP

R-miniCEOP: Rituximab, mini, Cyclophosphamide, Epirubicin, O?? (vinblastine), Prednisone

Regimen, Merli, et al. 2012 (ANZINTER3)

Level of Evidence: Phase III

• Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
• Epirubicin (Ellence) 50 mg/m2 IV once on day 1
• Vinblastine (Velban) 5 mg/m2 IV once on day 1
• Prednisone (Sterapred) 50 mg/m2 PO/IV once per day on days 1 to 5
• Rituximab (Rituxan) 375 mg/m2 IV once on day 1

21-day cycles x 6 cycles

Supportive medications:

• Prophylactic G-CSF used for persisting grade 4 neutropenia or febrile neutropenia.
• Cotrimoxazole (dose/route/schedule not specified) prophylaxis.
• Erythropoietin use was allowed for hemoglobin <11 g/dL.

Radiation therapy

"At the end of chemotherapy, radiotherapy (RT) was scheduled for sites of previous bulky disease or partially responding sites."

References

1. Merli F, Luminari S, Rossi G, Mammi C, Marcheselli L, Tucci A, Ilariucci F, Chiappella A, Musso M, Di Rocco A, Stelitano C, Alvarez I, Baldini L, Mazza P, Salvi F, Arcari A, Fragasso A, Gobbi PG, Liberati AM, Federico M. Cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab versus epirubicin, cyclophosphamide, vinblastine, prednisone and rituximab for the initial treatment of elderly "fit" patients with diffuse large B-cell lymphoma: results from the ANZINTER3 trial of the Intergruppo Italiano Linfomi. Leuk Lymphoma. 2012 Apr;53(4):581-8. doi: 10.3109/10428194.2011.621565. Epub 2011 Nov 15. link to original article contains verified protocol PubMed

DLBCL, relapsed/refractory

BR

BR: Bendamustine, Rituximab

Regimen

Level of Evidence: Phase II

• Bendamustine (Treanda) 120 mg/m2 IV over 60 minutes once per day on days 2 & 3
• Rituximab (Rituxan) 375 mg/m2 IV once on day 1

21-day cycles x up to 6 cycles

Supportive medications:

• "Opportunistic infection prophylaxis with trimethoprim-sulfamethoxazole and acyclovir was recommended."

References

1. Ohmachi K, Niitsu N, Uchida T, Kim SJ, Ando K, Takahashi N, Takahashi N, Uike N, Eom HS, Chae YS, Terauchi T, Tateishi U, Tatsumi M, Kim WS, Tobinai K, Suh C, Ogura M. Multicenter Phase II Study of Bendamustine Plus Rituximab in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2013 May 6. [Epub ahead of print] link to original article contains verified protocol PubMed

EPOCH

EPOCH: Etoposide, Prednisone, Oncovin, Cyclophosphamide, Hydroxydaunorubicin

Synonyms: CHEOP, DA-EPOCH

Structured Concept: C63779 (NCI-T), C1880475 (NCI-MT/UMLS)

Regimen, Wilson, et al. 1993 - original EPOCH protocol

Level of Evidence: Phase II

• Etoposide (Vepesid) 50 mg/m2/day (total dose of 200 mg/m2) IV continuous infusion on days 1 to 4
• Prednisone (Sterapred) 60 mg/m2 PO on days 1 to 6
• Vincristine (Oncovin) 0.4 mg/m2/day (total dose of 1.6 mg/m2) IV continuous infusion on days 1 to 4
• Doxorubicin (Adriamycin) 10 mg/m2/day (total dose of 40 mg/m2) IV continuous infusion on days 1 to 4
• Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 15 minutes on day 6

Supportive medications:

• Filgrastim (Neupogen) 5 mcg/kg SQ daily, starting on day 6 and continuing until ANC >5,000/uL past nadir
• PCP prophylaxis with any one of the following:
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO BID 3 days per week
  • Atovaquone (Mepron) 1500 mg PO daily
  • Pentamidine (Nebupent) 300 mg nebulized every 28 days

21-day cycles x 6 to 8 cycles

References

1. Wilson WH, Bryant G, Bates S, Fojo A, Wittes RE, Steinberg SM, Kohler DR, Jaffe ES, Herdt J, Cheson BD, et al. EPOCH chemotherapy: toxicity and efficacy in relapsed and refractory non-Hodgkin's lymphoma. J Clin Oncol. 1993 Aug;11(8):1573-82 link to original article contains verified protocol PubMed

Everolimus

Regimen, Witzig, et al. 2011

Level of Evidence: Phase II

• Everolimus (Afinitor) 10 mg PO once per day on an empty stomach

28-day cycles, given until progression or unacceptable toxicity

Supportive medications:

• "Patients could receive white blood cell growth factors, if neutropenia developed at physician's discretion. Erythropoietin treatment for anemia was permitted per standard guidelines."

References

1. Witzig TE, Reeder CB, LaPlant BR, Gupta M, Johnston PB, Micallef IN, Porrata LF, Ansell SM, Colgan JP, Jacobsen ED, Ghobrial IM, Habermann TM. A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. Leukemia. 2011 Feb;25(2):341-7. doi: 10.1038/leu.2010.226. Epub 2010 Dec 7. link to original article contains verified protocol PubMed

MINE-ESHAP

MINE: Mesna, Ifosfamide, Novantrone, Etoposide ESHAP: Etoposide, High dose Ara-C, Platinol

Regimen

Level of Evidence: Phase II

Part 1: MINE

• Mesna (Mesnex) 4 g/m2 IV divided over three days, administered over 1 hour
• Ifosfamide (Ifex) 4 g/m2 IV divided over three days, administered over 1 hour
• Mesna (Mesnex) 500 mg diluted in water or juice, 4 hours following ifosfamide administration
• Mitoxantrone (Novantrone) 8 g/m2 IV once on day 1
• Etoposide (Vepesid) 65 mg/m2 IV over 1 hour, days 1 to 3

Part 2: ESHAP

• Etoposide (Vepesid) 60 mg/m2 IV over 1 hour once daily on days 1 to 4
• Methylprednisolone (Solumedrol) 500 mg IV as a short infusion once daily on days 1 to 4
• Cytarabine (Cytosar) 2000 mg/m2 IV over 2 hours once on day 5
• Cisplatin (Platinol) 25 mg/m2/day IV continuous infusion over 96 hours (total dose per cycle: 100 mg/m2) on days 1 to 4

21-day cycles; patients who achieved a CR received a total of 6 cycles of MINE and then 3 cycles of ESHAP as consolidation therapy. If patients achieved a PR, then MINE was given to the point of maximal response, and then patients were crossed over to ESHAP.

References

1. Rodriguez MA, Cabanillas FC, Velasquez W, Hagemeister FB, McLaughlin P, Swan F, Romaguera JE. Results of a salvage treatment program for relapsing lymphoma: MINE consolidated with ESHAP. J Clin Oncol. 1995 Jul;13(7):1734-41. link to original article contains verified protocol PubMed

Pixantrone (BBR 2778)

Regimen

Level of Evidence: Phase III

• Pixantrone (BBR 2778) 85 mg/m2 IV once daily on days 1, 8, 15

28-day cycles x up to 6 cycles

References

1. Pettengell R, Coiffier B, Narayanan G, de Mendoza FH, Digumarti R, Gomez H, Zinzani PL, Schiller G, Rizzieri D, Boland G, Cernohous P, Wang L, Kuepfer C, Gorbatchevsky I, Singer JW. Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2012 Jul;13(7):696-706. doi:10.1016/S1470-2045(12)70212-7. Epub 2012 May 30. Erratum in: Lancet Oncol. 2012 Jul;13(7):e285. link to original article contains verified protocol PubMed

R-DHAP

R-DHAP: Rituximab, Dexamethasone, High-dose Ara-C (cytarabine), cisPlatin

Regimen, Gisselbrecht et al. 2012

Level of Evidence: Phase III

• Rituximab (Rituxan) 375 mg/m2 IV on cycle 1 day -1 & 1; then on cycle 2 and on, Rituximab (Rituxan) is 375 mg/m2 IV once on day 1; given first before other chemotherapy
• Dexamethasone (Decadron) 40 mg PO daily 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

21-day cycles x 3 cycles; patients with complete or partial response then received BEAM chemotherapy & autologous stem-cell transplant (ASCT)

Supportive medications:

• G-CSF "depending on site policy, with R-DHAP, but always after the third cycle until the end of leukaphereses"

References

1. Hagberg H, Gisselbrecht C; CORAL study group. Randomised phase III study of R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL) followed by high-dose therapy and a second randomisation to maintenance treatment with rituximab or not: an update of the CORAL study. Ann Oncol. 2006 May;17 Suppl 4:iv31-2. link to original article PubMed
2. Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Brière J, Moskowitz CH, Schmitz N. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010 Sep 20;28(27):4184-90. doi: 10.1200/JCO.2010.28.1618. Epub 2010 Jul 26. Erratum in: J Clin Oncol. 2012 May 20;30(15):1896. link to original article contains verified protocol PubMed

R-ESHAP

R-ESHAP: Rituximab, Etoposide, Solumedrol (methylprednisolone) High-dose Ara-C (cytarabine), cisPlatin

Regimen

Regimen details are based on ESHAP paper from 1994. Per retrospective review (Martin et al. 2008), 90% of patients given R-ESHAP received rituximab on day 1, 10% on day 5.

• Rituximab (Rituxan) 375 mg/m2 IV once on day 1 (or day 5)
• Etoposide (Vepesid) 40 mg/m2 IV over 1 hour once daily on days 1 to 4
• Methylprednisolone (Solumedrol) 250-500 mg IV over 15 minutes once daily on days 1 to 5
  • In Martín, et al. 2008, methylprednisolone could either be given on days 1 to 4 or days 1 to 5, with patients receiving total doses of anywhere from 1000 mg per cycle to 2500 mg per cycle
• Cytarabine (Cytosar) 2000 mg/m2 IV over 2 hours once on day 5
• Cisplatin (Platinol) 25 mg/m2/day IV continuous infusion over 96 hours (total dose per cycle: 100 mg/m2) on days 1 to 4

21 to 28 day cycles ("after recovery of the toxic effects") x 6 to 8 cycles

Supportive medications:

• At least 1 liter normal saline with 25-50 g mannitol daily throughout chemotherapy
• Metoclopramide (Reglan) 0.5-1 mg/kg "given regularly"

References

1. Velasquez WS, McLaughlin P, Tucker S, Hagemeister FB, Swan F, Rodriguez MA, Romaguera J, Rubenstein E, Cabanillas F. ESHAP--an effective chemotherapy regimen in refractory and relapsing lymphoma: a 4-year follow-up study. J Clin Oncol. 1994 Jun;12(6):1169-76. link to original article contains verified protocol PubMed
2. Martín A, Conde E, Arnan M, Canales MA, Deben G, Sancho JM, Andreu R, Salar A, García-Sanchez P, Vázquez L, Nistal S, Requena MJ, Donato EM, González JA, León A, Ruiz C, Grande C, González-Barca E, Caballero MD; Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GEL/TAMO Cooperative Group). R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study. Haematologica. 2008 Dec;93(12):1829-36. doi:10.3324/haematol.13440. Epub 2008 Oct 22. link to original article contains verified protocol PubMed

R-ICE

R-ICE: Rituximab, Ifosfamide, Carboplatin, Etoposide

Regimen #1, Kewalramani, et al. 2004

3rd cycle intended to be followed by peripheral blood stem cell collection

• Rituximab (Rituxan) 375 mg/m2 IV once on day 1
  • An additional one-time dose of Rituximab (Rituxan) 375 mg/m2 IV was given 48 hours before the beginning of cycle 1
• Ifosfamide (Ifex) 5,000 mg/m2 IV continuous infusion over 24 hours on day 4, mixed together with mesna
• Mesna (Mesnex) 5,000 mg/m2 IV continuous infusion over 24 hours on day 4, mixed together with ifosfamide
• Carboplatin (Paraplatin) AUC 5 (maximum dose of 800 mg per cycle) IV bolus on day 4
• Etoposide (Vepesid) 100 mg/m2 IV bolus on days 3 to 5

Supportive medications

• Acetaminophen (Tylenol) 650 mg PO as premedication for rituximab
• Diphenhydramine (Benadryl) 50 mg IV as premedication for rituximab
• Filgrastim (Neupogen) 5 μg/kg SC daily on days 7-14 (10 μg/kg with cycle 3)

14-day cycles x 3 cycles

Regimen #2, Gisselbrecht, et al. 2010

Level of Evidence: Phase III

• Rituximab (Rituxan) 375 mg/m2 IV on cycle 1 day -1 & 1; then on cycle 2 and on, Rituximab (Rituxan) is 375 mg/m2 IV once on day 1; given first before other chemotherapy
• Ifosfamide (Ifex) 5,000 mg/m2 IV continuous infusion over 24 hours on day 2
• Mesna (Mesnex) given with ifosfamide; dose & schedule not specified in the paper
• Carboplatin (Paraplatin) AUC 5 IV (maximum dose of 800 mg per cycle) on day 2
• Etoposide (Vepesid) 100 mg/m2 IV daily on days 1 to 3

21-day cycles x 3 cycles; patients with complete or partial response then received BEAM chemotherapy & autologous stem-cell transplant (ASCT)

Supportive medications:

• " Granulocyte colony-stimulating factor was administered after R-ICE"

References

1. Kewalramani T, Zelenetz AD, Nimer SD, Portlock C, Straus D, Noy A, O'Connor O, Filippa DA, Teruya-Feldstein J, Gencarelli A, Qin J, Waxman A, Yahalom J, Moskowitz CH. Rituximab and ICE as second-line therapy before autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma. Blood. 2004 May 15;103(10):3684-8. Epub 2004 Jan 22. link to original article contains regimen PubMed
2. Hagberg H, Gisselbrecht C; CORAL study group. Randomised phase III study of R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL) followed by high-dose therapy and a second randomisation to maintenance treatment with rituximab or not: an update of the CORAL study. Ann Oncol. 2006 May;17 Suppl 4:iv31-2. link to original article PubMed
3. Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Brière J, Moskowitz CH, Schmitz N. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010 Sep 20;28(27):4184-90. doi: 10.1200/JCO.2010.28.1618. Epub 2010 Jul 26. Erratum in: J Clin Oncol. 2012 May 20;30(15):1896. link to original article contains verified protocol PubMed

Temsirolimus (Torisel)

Regimen

Level of Evidence: Phase II

• Temsirolimus (Torisel) 25 mg IV over 30 minutes once per week

28-day cycles x minimum of 2 cycles

References

1. Smith SM, van Besien K, Karrison T, Dancey J, McLaughlin P, Younes A, Smith S, Stiff P, Lester E, Modi S, Doyle LA, Vokes EE, Pro B. Temsirolimus has activity in non-mantle cell non-Hodgkin's lymphoma subtypes: The University of Chicago phase II consortium. J Clin Oncol. 2010 Nov 1;28(31):4740-6. doi: 10.1200/JCO.2010.29.2813. Epub 2010 Sep 13. link to original article contains verified protocol PubMed

BL or Burkitt-like Lymphoma, untreated

CODOX-M/IVAC (Modified Magrath)

CODOX-M: Cyclophosphamide, Oncovin, DOXorubicin, M ethotrexate

IVAC: Ifosfamide, Vepesid (etoposide), AC Ara-C (cytarabine)

Part 1: CODOX-M

• Cyclophosphamide (Cytoxan) 800 mg/m2 IV once on day 1; 200 mg/m2 IV once daily on days 2 to 5
• Vincristine (Oncovin) 1.5 mg/m2 (max dose of 2 mg) IV once on days 1, 8
• Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
• Cytarabine (Cytosar) 70 mg intrathecal on days 1, 3

Age 65 years or younger:

• Methotrexate (MTX) 300 mg/m2 IV over 1 hour on day 10
• Methotrexate (MTX) 2700 mg/m2 IV over next 23 hours on day 10

Age more than 65 years:

• Methotrexate (MTX) 100 mg/m2 IV over 1 hour on day 10
• Methotrexate (MTX) 900 mg/m2 IV over next 23 hours on day 10

• Folinic acid (Leucovorin) 15 mg/m2 IV Q3H, starting 36 hours after start of IV methotrexate until 48 hours, then Q6H until methotrexate level undetectable

• Methotrexate (MTX) 12 mg intrathecal on day 15
• Folinic acid (Leucovorin) 15 mg PO once 24 hours after intrathecal methotrexate

Supportive medications:

• Filgrastim (Neupogen) 5 mcg/kg SQ daily, starting on day 13 and continuing until ANC >1,000/uL

Part 2: IVAC

Age 65 years or younger:

• Cytarabine (Cytosar) 2 g/m2 IV over 3 hours Q12H on days 1,2 (4 doses)
• Etoposide (Vepesid) 60 mg/m2 IV over 1 hour on days 1 to 5
• Ifosfamide (Ifex) 1500 mg/m2 IV over 1 hour on days 1 to 5
• Mesna (Mesnex) 300 mg/m2 (mixed with ifosfamide) over 1 hour, then 300mg/m2 IV every four hours x 2, on days 1 to 5

Age more than 65 years:

• Cytarabine (Cytosar) 1 g/m2 IV over 3 hours Q12H on days 1,2 (4 doses)
• Etoposide (Vepesid) 60 mg/m2 IV over 1 hour on days 1 to 5
• Ifosfamide (Ifex) 1000 mg/m2 IV over 1 hour on days 1 to 5
• Mesna (Mesnex) 200 mg/m2 (mixed with ifosfamide) over 1 hour, then 200mg/m2 IV every four hours x 2, on days 1 to 5

• Methotrexate (MTX) 12 mg intrathecal on day 5
• Folinic acid (Leucovorin) 15 mg PO once 24 hours after intrathecal methotrexate

Supportive medications:

• Filgrastim (Neupogen) 5 mcg/kg SQ daily, starting on day 7 and continuing until ANC >1,000/uL

References

1. Magrath I, Adde M, Shad A, Venzon D, Seibel N, Gootenberg J, Neely J, Arndt C, Nieder M, Jaffe E, Wittes RA, Horak ID. Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. J Clin Oncol. 1996 Mar;14(3):925-34. link to original article contains verified protocol PubMed
2. Mead GM, Sydes MR, Walewski J, Grigg A, Hatton CS, Pescosta N, Guarnaccia C, Lewis MS, McKendrick J, Stenning SP, Wright D; UKLG LY06 collaborators. An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom Lymphoma Group LY06 study. Ann Oncol. 2002 Aug;13(8):1264-74. Erratum in: Ann Oncol. 2002 Dec;13(12):1961. Norbert, P [corrected to Pescosta, N]. link to original article contains verified protocol PubMed
3. Mead GM, Barrans SL, Qian W, Walewski J, Radford JA, Wolf M, Clawson SM, Stenning SP, Yule CL, Jack AS; UK National Cancer Research Institute Lymphoma Clinical Studies Group; Australasian Leukaemia and Lymphoma Group. A prospective clinicopathologic study of dose-modified CODOX-M/IVAC in patients with sporadic Burkitt lymphoma defined using cytogenetic and immunophenotypic criteria (MRC/NCRI LY10 trial). Blood. 2008 Sep 15;112(6):2248-60. doi: 10.1182/blood-2008-03-145128. Epub 2008 Jul 8. link to original article contains verified protocol PubMed
4. Maruyama D, Watanabe T, Maeshima AM, Nomoto J, Taniguchi H, Azuma T, Mori M, Munakata W, Kim SW, Kobayashi Y, Matsuno Y, Tobinai K. Modified cyclophosphamide, vincristine, doxorubicin, and methotrexate (CODOX-M)/ifosfamide, etoposide, and cytarabine (IVAC) therapy with or without rituximab in Japanese adult patients with Burkitt lymphoma (BL) and B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and BL. Int J Hematol. 2010 Dec;92(5):732-43. doi: 10.1007/s12185-010-0728-0. Epub 2010 Dec 1. link to original article contains verified protocol PubMed

R-CODOX-M/R-IVAC

R-CODOX-M: Rituximab, Cyclophosphamide, Oncovin, DOXorubicin, M ethotrexate

R-IVAC: Rituximab, Ifosfamide, Vepesid (etoposide), AC Ara-C (cytarabine)

Part 1: R-CODOX-M

• Cyclophosphamide (Cytoxan) 800 mg/m2 IV once on day 1; 200 mg/m2 IV once daily on days 2 to 5
• Vincristine (Oncovin) 1.5 mg/m2 (max dose of 2 mg) IV once on days 1, 8
• Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
• Cytarabine (Cytosar) 40 mg intrathecal on days 1, 3 (more if CNS disease present)
• Rituximab (Rituxan) 375 mg/m2 on day 6 of cycle 1, then 2 days prior to each subsequent cycle

• Methotrexate (MTX) 536 mg/m2 IV over 1 hour on day 10
• Methotrexate (MTX) 107 mg/m2/hr IV over next 23 hours on day 10

• Folinic acid (Leucovorin) starting 36 hours after start of IV methotrexate until 48 hours, then Q6H until methotrexate level undetectable

• "Commence leucovorin 36 h after the start of MTX infusion; 85.7 mg/m2 i.v. at 36 h and 12 mg/m2 every 6 h thereafter until the serum MTX level is less than 0.05 μM. Leucovorin 12 mg/m2 is given orally first if patients were without nausea; otherwise i.v. administration is allowed."

• Methotrexate (MTX) 15 mg intrathecal on day 15

Supportive medications:

• Filgrastim (Neupogen) 5 mcg/kg SQ daily, starting on day 7 and continuing until ANC >1,000/uL

Part 2: R-IVAC

• Cytarabine (Cytosar) 2 g/m2 IV over 3 hours Q12H on days 1,2 (4 doses)
• Etoposide (Vepesid) 60 mg/m2 IV over 1 hour on days 1 to 5
• Ifosfamide (Ifex) 1500 mg/m2 IV over 2 hours on days 1 to 5
• Mesna (Mesnex) 300 mg/m2 (mixed with ifosfamide) over 1 hour, then 300mg/m2 IV every four hours x 2, on days 1 to 5
• Rituximab (Rituxan) 375 mg/m2 on day 6 of cycle 1, then 2 days prior to each subsequent cycle

• Methotrexate (MTX) 15 mg intrathecal on day 5
• Cytarabine (Cytosar) 40 mg intrathecal on days 7, 9 ONLY if CNS disease present

Supportive medications:

• Filgrastim (Neupogen) 5 mcg/kg SQ daily, starting on day 7 and continuing until ANC >1,000/uL

References

1. Maruyama D, Watanabe T, Maeshima AM, Nomoto J, Taniguchi H, Azuma T, Mori M, Munakata W, Kim SW, Kobayashi Y, Matsuno Y, Tobinai K. Modified cyclophosphamide, vincristine, doxorubicin, and methotrexate (CODOX-M)/ifosfamide, etoposide, and cytarabine (IVAC) therapy with or without rituximab in Japanese adult patients with Burkitt lymphoma (BL) and B cell lymphoma, unclassifiable, with features intermediate between diffuse large B cell lymphoma and BL. Int J Hematol. 2010 Dec;92(5):732-43. doi: 10.1007/s12185-010-0728-0. Epub 2010 Dec 1. link to original article contains verified protocol PubMed

Gastric DLBCL, untreated

Helicobacter pylori eradication therapy

Regimen

Before 1996:

• Amoxicillin 500mg PO q6h x 28 days
• Metronidazole 250mg PO q6h x 28 days
• EITHER bismuth subcitrate 120mg PO q6h x 28 days
• OR omeprazole 20mg PO BID x 28 days

After 1996:

• Amoxicillin 500mg PO q6h x 14 days
• Clarithromycin 500mg PO BID x 14 days
• Omeprazole 20mg PO BID x 14 days

References

1. Kuo SH, Yeh KH, Wu MS, Lin CW, Hsu PN, Wang HP, Chen LT, Cheng AL. Helicobacter pylori eradication therapy is effective in the treatment of early-stage H pylori-positive gastric diffuse large B-cell lymphomas. Blood. 2012 May 24;119(21):4838-44; quiz 5057. doi: 10.1182/blood-2012-01-404194. Epub 2012 Mar 7. link to original article PubMed

Anaplastic large-cell lymphoma, relapsed/refractory

Brentuximab vedotin

Regimen

Level of Evidence: Phase II

• Brentuximab vedotin (Adcetris) 1.8 mg/kg IV over 30 minutes on day 1

Every 21 days up to 16 infusions

References

1. Pro B, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T, Matous J, Ramchandren R, Fanale M, Connors JM, Yang Y, Sievers EL, Kennedy DA, Shustov A. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012 Jun 20;30(18):2190-6. doi: 10.1200/JCO.2011.38.0402. Epub 2012 May 21. link to original article PubMed

Primary mediastinal B-cell lymphoma, untreated

DA-R-EPOCH

DA-R-EPOCH: Dose Adjusted Rituximab, Etoposide, Prednisone, Oncovin, Cyclophosphamide, Hydroxydaunorubicin

Regimen, Dunleavy, et al. 2013

Level of Evidence: Phase II

• Rituximab (Rituxan) 375 mg/m2 IV over 3 hours once on day 1
• Etoposide (Vepesid) 50 mg/m2/day IV continuous infusion over 96 hours on days 1 to 4 (total dose per cycle: 200 mg/m2)
• Prednisone (Sterapred) 60 mg/m2 PO BID on days 1 to 5
• Vincristine (Oncovin) 0.4 mg/m2/day IV continuous infusion over 96 hours on days 1 to 4 (total dose per cycle: 1.6 mg/m2; dose was not capped)
• Doxorubicin (Adriamycin) 10 mg/m2/day IV continuous infusion over 96 hours on days 1 to 4 (total dose per cycle: 40 mg/m2)
• Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 2 hours once on day 5

21-day cycles x 6 to 8 cycles

Supportive medications:

• Filgrastim (Neupogen) 300 mcg SQ once per day, starting on day 6 and continuing until ANC >5,000/uL past nadir
• Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg (or equivalent if allergic) PO once per day on 3 days per week
  • Note: It's assumed this is what the supplement for Dunleavy, et al. 2013 meant by "Baxtrim (sulphametoxazole and trimethoprim)"
• Omeprazole (Prilosec) 20 mg (or equivalent) PO once per day
• Docusate (Colace) (dose not specified) and Sennosides (Senna) 2 tablets PO BID as needed for constipation
• Lactulose 20 g PO Q6H as needed for constipation
• Hepatitis B surface antigen positive patients received daily antiviral therapy until 8 weeks after completion of chemotherapy

Dose adjustments

• Start cycle 1 as described above.
• Obtain CBCs twice per week for nadir measurements.
• If nadir ANC >500, increase etoposide, doxorubicin, and cyclophosphamide by one level (20%) compared to previous cycle.
• If nadir ANC <500, use same doses as last cycle.
• If nadir platelet count <25,000, decrease etoposide, doxorubicin, and cyclophosphamide by 20% compared to the previous cycle.

References

1. Wilson WH, Dunleavy K, Pittaluga S, Hegde U, Grant N, Steinberg SM, Raffeld M, Gutierrez M, Chabner BA, Staudt L, Jaffe ES, Janik JE. Phase II study of dose-adjusted EPOCH and rituximab in untreated diffuse large B-cell lymphoma with analysis of germinal center and post-germinal center biomarkers. J Clin Oncol. 2008 Jun 1;26(16):2717-24. link to original article PubMed
2. Dunleavy K, Pittaluga S, Maeda LS, Advani R, Chen CC, Hessler J, Steinberg SM, Grant C, Wright G, Varma G, Staudt LM, Jaffe ES, Wilson WH. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med. 2013 Apr 11;368(15):1408-16. doi: 10.1056/NEJMoa1214561. link to original article link to supplementary appendix contains verified protocol PubMed

Transformed lymphoma

Transformed lymphoma, often referred to as Richter's transformation, is typically treated as per the histologic subtype, which is usually DLBCL. However, some regimens specific to transformed lymphoma have been developed and are included here.

¹³¹Iodine-Tositumomab (Bexxar)

Regimen

Level of Evidence: Phase II

Also evaluated in low-grade NHL but subtype was not specified.

Dosimetric step

• On Day 0, infusions of:
  • Tositumomab 450 mg IV over 1 hour
  • Tositumomab 35 mg labeled with 5 mCi of Iodine-131 IV over 20 minutes
  • First scan of whole body dosimetry & redistribution
• Day 2, 3, or 4: Second scan of whole body dosimetry & redistribution
• Day 6 or 7: Third scan of whole body dosimetry & redistribution

Therapeutic step

• Any day from day 7-14, infusions of:
  • Tositumomab 450 mg IV over 1 hour
  • Tositumomab 35 mg labeled with an individually calculated dose of Iodine-131 that will provide 75 cGy of radiation to the total body IV over 20 minutes
    • 65 cGy total body dose used for patients with platelet counts of 100-150,000/mm3

Calculated dose of I-131 is based on information from serial total-body gamma-camera counts

References

1. Vose JM, Wahl RL, Saleh M, Rohatiner AZ, Knox SJ, Radford JA, Zelenetz AD, Tidmarsh GF, Stagg RJ, Kaminski MS. Multicenter phase II study of iodine-131 tositumomab for chemotherapy-relapsed/refractory low-grade and transformed low-grade B-cell non-Hodgkin's lymphomas. J Clin Oncol. 2000 Mar;18(6):1316-23. link to original article contains verified protocol PubMed

OFAR

OFAR: Oxaliplatin, Fludarabine, Ara-C, Rituximab

Regimen

Level of Evidence: Phase II

• Oxaliplatin (Eloxatin) 25 mg/m2 IV over 2 hours once daily on days 1 to 4
• Fludarabine (Fludara) 30 mg/m2 IV once daily on days 2 & 3, adminstered within 30 minutes of completion of oxaliplantin
• Cytarabine (Cytosar) 1000 mg/m2 IV over 2 hours once daily on days 2 & 3, 4 hours after fludarabine started
• Rituximab (Rituxan) 375 mg/m2 IV over 4 to 6 hours once on day 3 of cycle 1; then 375 mg/m2 IV over 4 to 6 hours once on day 1 of cycles 2 to 6

28-day cycles x up to 6 cycles

Supportive medications:

• Pegfilgrastim (Neulasta) 6 mg SC once on day 6
• Herpes zoster and PCP (Pneumocystis jiroveci pneumonia) prophylaxis used

References

1. Tsimberidou AM, Wierda WG, Plunkett W, Kurzrock R, O'Brien S, Wen S, Ferrajoli A, Ravandi-Kashani F, Garcia-Manero G, Estrov Z, Kipps TJ, Brown JR, Fiorentino A, Lerner S, Kantarjian HM, Keating MJ. Phase I-II study of oxaliplatin, fludarabine, cytarabine, and rituximab combination therapy in patients with Richter's syndrome or fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2008 Jan 10;26(2):196-203. link to original article contains protocol PubMed