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
Regimen, Récher et al. 2011 (LNH03-2B)
Phase III Improved OS Increased toxicity
Induction Regimen
- Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 1200 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 once per day on days1 to 5
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
CNS prophylaxis:
- Methotrexate (MTX) 15 mg intrathecal on day 1
Supportive medications:
- Filgrastim (Neupogen) 300 mcg (for patients <75 kg) or 480 mcg (for patients at least 75 kg) SC once per day on days 6 to 13
14-day cycles x 4 cycles
Consolidation Regimen, part 1
- Methotrexate (MTX) 3000 mg/m2 IV once on day 1
Supportive medications:
14-day cycles x 2 cycles, beginning 4 weeks after completion of induction, then
Consolidation Regimen, part 2
- 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
Consolidation Regimen, part 3
- Cytarabine (Cytosar) 100 mg/m2 SC once per day on days1 to 4
14-day cycles x 2 cycles, beginning 2 weeks after completion of REI
References
- 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
CDOP
CDOP: Cyclophosphamide, Doxil, Oncovin, Prednisone
Regimen, Martino et al. 2002
Phase II
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once over 30 minutes on day 1
- Doxorubicin liposomal (Doxil) 30 mg/m2 IV once over 1 hour on day 1
- Vincristine (Oncovin) 2 IV once over 15 minutes on day 1
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 5
21-day cycles x 6 to 8 cycles
References
- Martino R, Perea G, Caballero MD, Mateos MV, Ribera JM, de Oteyza JP, Arranz R, Terol MJ, Sierra J, San Miguel JF. Cyclophosphamide, pegylated liposomal doxorubicin (Caelyx), vincristine and prednisone (CCOP) in elderly patients with diffuse large B-cell lymphoma: results from a prospective phase II study. Haematologica. 2002 Aug;87(8):822-7. 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
Phase III
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once 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 once per day on days1 to 5
21-day cycles x 8 cycles
Regimen #2, Pfreundschuh et al. 2004 (NHL-B1) & Verdonck et al. 2007
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 once per day on days1 to 5
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 once per day on days 4 to 13
21-day cycles x 6 cycles
Regimen #3, Miller et al. 1998 - CHOP-21 & radiation
Phase III
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once 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 once per day on days1 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 (LNH-98.5)
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) 40 mg/m2 PO once per day on days1 to 5
Supportive medications:
- Filgrastim (Neupogen) used for later cycles if patients developed grade 4 neutropenia or febrile neutropenia
21-day cycles x 8 cycles
Regimen #5, Habermann et al. 2006 (CALGB 9793)
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 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 #6, Pfreundschuh et al. 2004 (NHL-B2)
Phase III
Pre-phase treatment
Recommended "to improve the performance status of patients and to ameliorate side-effects of the first chemotherapy cycle."
- 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 regimen
Main CHOP 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
Supportive medications
- Filgrastim (Neupogen) "at the treating physician's discretion"
21-day cycles x 6 cycles
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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- Update: 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
- 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
- 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
- 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
- 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
- Update: 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
- Update: 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
- Update: 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. 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
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 once per day on days1 to 5
Supportive medications:
- Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 2 to 11, or until ANC is greater than 10,000
14-day cycles x up to 6 cycles
Regimen #2, Verdonck et al. 2007 (I-CHOP)
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 once per day on days1 to 5
Supportive medications:
- Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 2 to 11
14-day cycles x 6 cycles
Regimen #3, Pfreundschuh et al. 2004 (NHL-B2, CHOP-14) & Pfreundschuh et al. 2008 (RICOVER-60)
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
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
14-day cycles x 6 cycles; some patients in Pfreundschuh et al. 2008 received 14-day cycles x 8 cycles
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
- 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
- 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
- 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
- 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
- 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
CHOP Modified
CHOP: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone
Regimen
Phase III
This regimen is designed for elderly patients and is of lower intensity than standard CHOP.
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 30 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1 mg IV once on day 1
- Prednisolone (Millipred) 20 mg PO BID on days 1 to 5
21-day cycles x 6 cycles
References
- Bessell EM, Burton A, Haynes AP, Glaholm J, Child JA, Cullen MH, Davies JM, Smith GM, Ellis IO, Jack A, Jones EL; Central Lymphoma Group UK. A randomised multicentre trial of modified CHOP versus MCOP in patients aged 65 years and over with aggressive non-Hodgkin's lymphoma. Ann Oncol. 2003 Feb;14(2):258-67. link to original article contains verified protocol PubMed
CHOPE, CHOEP
CHOPE: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone, Etoposide
CHOEP: Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Etoposide, Prednisone
Synonyms: CHOEP, VAC0P
Structured Concept: C9702 (NCI-T), C0212922(NCI-MT/UMLS)
Example orders
Regimen, Pfreundschuh et al. 2004 (NHL-B2)
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 once per day on days1 to 5
- Etoposide (Vepesid) 100 mg/m2 IV once per day 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
Supportive medications:
- For 14-day cycles: 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
- Filgrastim (Neupogen) use for 21-day cycles is by discretion of ordering physician
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
References
- 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
- 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
CNOP, MCOP
CNOP: Cyclophosphamide, Novantrone, Oncovin, Prednisone MCOP: Mitoxantrone, Cyclophosphamide, Oncovin, Prednisone
Regimen
Phase III
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
- Mitoxantrone (Novantrone) 10 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1 mg IV once on day 1
- Prednisolone (Millipred) 20 mg PO BID on days 1 to 5
21-day cycles x 6 cycles
References
- Bessell EM, Burton A, Haynes AP, Glaholm J, Child JA, Cullen MH, Davies JM, Smith GM, Ellis IO, Jack A, Jones EL; Central Lymphoma Group UK. A randomised multicentre trial of modified CHOP versus MCOP in patients aged 65 years and over with aggressive non-Hodgkin's lymphoma. Ann Oncol. 2003 Feb;14(2):258-67. link to original article contains verified protocol PubMed
DA-EPOCH
DA-EPOCH: Dose Adjusted Etoposide, Prednisone, Oncovin, Cyclophosphamide, Hydroxydaunorubicin
Synonyms: CHEOP
Structured Concept: C63779 (NCI-T), C1880475 (NCI-MT/UMLS)
Regimen, Wilson et al. 2002 - dose-adjusted EPOCH (DA-EPOCH)
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
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once over 15 minutes on day 5
- Doxorubicin (Adriamycin) 10 mg/m2/day (total dose of 40 mg/m2) IV continuous infusion on days 1 to 4
Supportive medications:
- Filgrastim (Neupogen) 5 mcg/kg SQ once per day, 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 once per day
- 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
- 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
DA-R-EPOCH
DA-R-EPOCH: Dose Adjusted Rituximab, Etoposide, Prednisone, Oncovin, Cyclophosphamide, Hydroxydaunorubicin
Synonyms: DA-EPOCH-R, EPOCH-R, REPOCH
Structured Concept: C63461 (NCI-T), C1882521 (NCI-MT/UMLS)
Regimen
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
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once over 15 minutes on day 5
- Doxorubicin (Adriamycin) 10 mg/m2/day (total dose of 40 mg/m2) IV continuous infusion on days 1 to 4
Supportive medications:
- Filgrastim (Neupogen) 5 mcg/kg SQ once per day, 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 once per day
- Pentamidine (Nebupent) 300 mg nebulized every 28 days
- Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO BID 3 days per week
- Only in García-Suárez et al. 2007: Darbepoetin alfa (Aranesp) 2.25 ug/kg SC when hemoglobin concentration was ≤100 g/l.
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
- 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
- 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
- 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
MACOP-B
MACOP-B: methotrexate, Adriamycin (doxorubicin), Cyclophosphamide, Oncovin (vincristine), Prednisone, Bleomycin
Regimen
Phase III
- Methotrexate (MTX) 400 mg/m2 IV once per week on weeks 2, 6, 10
- Doxorubicin (Adriamycin) 50 mg/m2 IV once per week on weeks 1, 3, 5, 7, 9, 11
- Cyclophosphamide (Cytoxan) 350 mg/m2 IV once per week on weeks 1, 3, 5, 7, 9, 11
- Vincristine (Oncovin) 1.4 mg/m2 IV once per week on weeks 2, 4, 6, 8, 10, 12
- Prednisone (Sterapred) 75 mg PO daily, tapered over last 15 days (schedule not reported)
- Bleomycin (Blenoxane) 10 units/m2 IV once per week on weeks 4, 8, 12
CNS prophylaxis (for patients with bone marrow involvement):
- Methotrexate (MTX) 12 mg IV
Supportive medications:
- Trimethoprim/Sulfamethoxazole (Bactrim DS) 2 tablets (not specified if SS or DS) PO BID
One 12-week course
References
- 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
- 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
Phase III
- Methotrexate (MTX) 200 mg/m2 IV once on days 8 & 15
- 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) once per day 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
Supportive medications:
- Folinic acid (Leucovorin) 10 mg/m2 PO/IV Q6H x 8 doses, starting 24 hours after methotrexate
21-day cycles x 10 cycles
References
- 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
- 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
Phase III
- Prednisone (Prolix) 60 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 120 mg/m2 IV once on day 8
- Doxorubicin (Adriamycin) 25 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 650 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
Supportive medications:
- Folinic acid (Leucovorin) 25 mg/m2 PO Q6H x 4 doses, starting 24 hours after methotrexate
- Trimethoprim/Sulfamethoxazole (Bactrim DS) 160/800 mg PO BID throughout the course of treatment
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
- Patients with initial bone or bone marrow involvement who achieved a CR were treated with 2,400 cGy prophylactic cranial irradiation.
References
- 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
- 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-CDOP
R-CDOP: Rituximab, Cyclophosphamide, Doxil, Oncovin, Prednisone
Regimen
Phase II
Only the dose of liposomal doxorubicin 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
- Doxorubicin liposomal (Doxil) 30 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
- 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 per day on days 1 to 5
21-day cycles x 6 cycles
References
- Zaja F, Tomadini V, Zaccaria A, Lenoci M, Battista M, Molinari AL, Fabbri A, Battista R, Cabras MG, Gallamini A, Fanin R. CHOP-rituximab with pegylated liposomal doxorubicin for the treatment of elderly patients with diffuse large B-cell lymphoma. Leuk Lymphoma. 2006 Oct;47(10):2174-80. link to original article PubMed
R-CEOP
R-CEOP: Rituximab, Cyclophosphamide, Etoposide, Oncovin, Prednisone
Regimen
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 per day 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 per day 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 per day 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
- 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-CHMP
R-CHMP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Marqibo, Prednisone
Regimen
Phase II
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin liposomal (Doxil) 50 mg/m2 IV once on day 1
- Vincristine liposomal (Marqibo) 2 mg/m2 IV once on day 1
- Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
21-day cycles x 6 cycles; stage I patients with no LN > 5 cm received 3 cycles followed by local XRT
References
- Hagemeister F, Rodriguez MA, Deitcher SR, Younes A, Fayad L, Goy A, Dang NH, Forman A, McLaughlin P, Medeiros LJ, Pro B, Romaguera J, Samaniego F, Silverman JA, Sarris A, Cabanillas F. Long term results of a phase 2 study of vincristine sulfate liposome injection (Marqibo(®) ) substituted for non-liposomal vincristine in cyclophosphamide, doxorubicin, vincristine, prednisone with or without rituximab for patients with untreated aggressive non-Hodgkin lymphomas. Br J Haematol. 2013 Sep;162(5):631-8. Epub 2013 Jun 27. link to original article contains verified protocol PubMed
R-CHOEP-14
R-CHOEP-14: Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Etoposide, Prednisone, 14-day cycles
Regimen
Phase III
- Rituximab (Rituxan) 375 mg/m2 IV once on day 0 (cycles 1 to 4, 6, and 8)
- 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
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
- Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
14-day cycles x 8 cycles
- Radiotherapy to 36 Gy in daily fractions "mandatory" for patients with bulky disease (any mass > 7.5cm in diameter, or extranodal involvement)
References
- 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. 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 (LNH-98.5); Delarue et al. 2013 (LNH03-6B)
Phase III Mixed OS Similar toxicity
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
CNS prophylaxis: As described in Delarue et al. 2013 (LNH03-6B):
- Methotrexate (MTX) 15 mg IT once every 21 days x 4 total doses
Supportive medications:
- Filgrastim (Neupogen) used for later cycles if patients developed grade 4 neutropenia or febrile neutropenia
21-day cycles x 8 cycles
Regimen #2, Pfreundschuh et al. 2006 & 2011 (MInT)
Phase III Improved OS Similar toxicity
- 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) 2 mg IV once on day 1
- Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
- Radiation therapy: 30 to 40 Gy given to sites of primary bulky disease; 30 to 40 Gy to primary extranodal disease at physician discretion
Supportive medications:
- Filgrastim (Neupogen) or Lenograstim (Granocyte) used at physician discretion for neutropenia
21-day cycles x 6 cycles
Regimen #3, Habermann et al. 2006 (CALGB 9793)
Phase III
- Rituximab (Rituxan) 375 mg/m2 IV once per day 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)
Phase III
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisone (Sterapred) 100 mg PO/IV once per day on days 1 to 5
Supportive medications:
- Prophylactic G-CSF used for persisting grade 4 neutropenia or febrile neutropenia.
- Cotrimoxazole (dose/schedule not specified) prophylaxis.
- Erythropoietin use was allowed for hemoglobin <11 g/dL.
21-day cycles x 6 cycles
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
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.
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisolone (Millipred) 40 mg/m2 PO once per day on days 1 to 5
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.
Supportive medications:
- Lenograstim (Granocyte) (dose/route not specified) given on days 4 to 12 at physician discretion
- Allopurinol (Zyloprim) 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
21-day cycles x 8 cycles
Regimen #6, Persky et al. 2008 (SWOG S0014)
Phase II
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on days -7, 1, 22, 43 (4 doses total)
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
21-day cycle x 3 cycles, followed by:
Radiation therapy
Involved-field radiation therapy to begin 3 weeks after last cycle of R-CHOP, see paper for details.
References
- 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
- Update: 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
- 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
- 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
- Persky DO, Unger JM, Spier CM, Stea B, LeBlanc M, McCarty MJ, Rimsza LM, Fisher RI, Miller TP; Southwest Oncology Group. Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014. J Clin Oncol. 2008 May 10;26(14):2258-63. Epub 2008 Apr 14. link to original article contains verified protocol PubMed
- Update: 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
- Update: 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
- 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
- Update: 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. Epub 2012 Feb 1. link to original article PubMed
- 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. Epub 2011 Nov 15. link to original article contains verified protocol PubMed
- 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 May;14(6):525-33. Epub 2013 Apr 9. link to original article contains verified protocol PubMed
- 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 May 25;381(9880):1817-26. Epub 2013 Apr 22. 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)
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
- 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) 2 mg IV once on day 1
- Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
Supportive medications:
- Filgrastim (Neupogen) or Lenograstim (Granocyte) (dose/route/frequency not specified) starting on day 4, to continue until count recovery
14-day cycles x 6 to 8 cycles (8 doses of rituximab regardless of total number of cycles)
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)
Phase III
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
CNS prophylaxis:
- Methotrexate (MTX) 15 mg IT once every 14 days x 4 total doses
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."
14-day cycles x 8 cycles
Regimen #3, Cunningham et al. 2013
Phase III
Main R-CHOP-14 regimen
- 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) 2 mg IV once on day 1
- Prednisolone (Millipred) 100 mg PO once per day on days 1 to 5
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.
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
14-day cycles x 6 cycles; then give additional doses of rituximab as described below
Additional doses of Rituximab
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
14-day cycles x 2 cycles
References
- 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
- 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 May;14(6):525-33. Epub 2013 Apr 9. link to original article contains verified protocol PubMed
- 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 May 25;381(9880):1817-26. Epub 2013 Apr 22. 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
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- 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 once per day on days1 to 5
21-day cycles x up to 8 cycles
References
R-miniCEOP
R-miniCEOP: Rituximab, mini, Cyclophosphamide, Epirubicin, O?? (vinblastine), Prednisone
Regimen, Merli et al. 2012 (ANZINTER3)
Phase III
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- 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
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.
21-day cycles x 6 cycles
Radiation therapy
"At the end of chemotherapy, radiotherapy (RT) was scheduled for sites of previous bulky disease or partially responding sites."
References
- 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. Epub 2011 Nov 15. link to original article contains verified protocol PubMed
R2CHOP, LR-CHOP-21
R2CHOP: Rituximab, Revlimid, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone LR-CHOP-21: Lenalidomide, Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin, Prednisone
Regimen #1, Nowakowski et al. 2013
Phase II
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 10
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg per cycle) IV once on day 1
- Prednisone (Sterapred) 100 mg/m2 PO once per day on days 1 to 5
Supportive medications:
- Pegfilgrastim (Neulasta) SC once on day 2
- Aspirin 81 mg PO once per day unless otherwise anticoagulated
21-day cycles x up to 6 cycles
Regimen #2, Chiappella et al. 2013
Phase II
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 14
- 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
Supportive medications:
- Granulocyte-colony stimulants with each cycle (agent not specified)
- Low molecular weight heparin (dose not specified)
- Trimethoprim/Sulfamethoxazole (Bactrim DS) or Pentamidine (Nebupent)
- Lamivudine (Epivir) for occult hepatitis B carriers
21-day cycles x 6 cycles
References
- Nowakowski GS, LaPlant B, Habermann TM, Rivera CE, Macon WR, Inwards DJ, Micallef IN, Johnston PB, Porrata LF, Ansell SM, Klebig RR, Reeder CB, Witzig TE. Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study. Leukemia. 2011 Dec;25(12):1877-81. Epub 2011 Jul 1. link to original article contains verified protocol PubMed
- Nowakowski GS et al. Combination of lenalidomide with R-CHOP (R2CHOP) is well-tolerated and effective as initial therapy for aggressive B-cell lymphomas — A Phase II study. Proc ASH 2012; Abstract 689.
- Chiappella A et al. Rituximab-CHOP21 plus lenalidomide (LR-CHOP21) is effective and feasible in elderly untreated diffuse large B-cell lymphoma (DLBCL): Results of Phase II REAL07 study of the Fondazione Italiana Linfomi (FIL). Proc ASH 2012; Abstract 903.
- Chiappella A, Tucci A, Castellino A, Pavone V, Baldi I, Carella AM, Orsucci L, Zanni M, Salvi F, Liberati AM, Gaidano G, Bottelli C, Rossini B, Perticone S, De Masi P, Ladetto M, Ciccone G, Palumbo A, Rossi G, Vitolo U. Lenalidomide plus cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab is safe and effective in untreated elderly diffuse large B-cell lymphoma patients: phase I study by the Fondazione Italiana Linfomi. Haematologica. 2013 Jun 28. [Epub ahead of print] link to original article contains verified protocol PubMed
DLBCL, relapsed/refractory
BR
BR: Bendamustine, Rituximab
Regimen
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
Supportive medications:
- "Opportunistic infection prophylaxis with Trimethoprim/Sulfamethoxazole (Bactrim DS) and Acyclovir (Zovirax) was recommended."
21-day cycles x up to 6 cycles
References
- 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 Jun 10;31(17):2103-9. Epub 2013 May 6. 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
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
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 15 minutes on day 6
- Doxorubicin (Adriamycin) 10 mg/m2/day (total dose of 40 mg/m2) IV continuous infusion on days 1 to 4
Supportive medications:
- Filgrastim (Neupogen) 5 mcg/kg SQ once per day, 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 once per day
- Pentamidine (Nebupent) 300 mg nebulized every 28 days
21-day cycles x 6 to 8 cycles
References
- 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
ESHA
ESHA: Etoposide, Solumedrol (methylprednisolone) High-dose Ara-C (cytarabine)
Regimen
Phase III
- Etoposide (Vepesid) 40 mg/m2 IV over 1 hour once per day on days 1 to 4
- Methylprednisolone (Solumedrol) 250 to 500 mg IV over 15 minutes once per day on days 1 to 5
- Cytarabine (Cytosar) 2000 mg/m2 IV over 2 hours once on day 5
Supportive medications:
- At least 1 liter normal saline with 25 to 50 g Mannitol once per day throughout chemotherapy
- Metoclopramide (Reglan) 0.5 to 1 mg/kg "given regularly"
21 to 28 day cycles ("after recovery of the toxic effects") x 6 to 8 cycles
References
- 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
ESHAP
ESHAP: Etoposide, Solumedrol (methylprednisolone) High-dose Ara-C (cytarabine), cisPlatin
Regimen
Phase III
- Etoposide (Vepesid) 40 mg/m2 IV over 1 hour once per day on days 1 to 4
- Methylprednisolone (Solumedrol) 250-500 mg IV over 15 minutes once per day on days 1 to 5
- 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
Supportive medications:
- At least 1 liter normal saline with 25 to 50 g Mannitol once per day throughout chemotherapy
- Metoclopramide (Reglan) 0.5 to 1 mg/kg "given regularly"
21 to 28 day cycles ("after recovery of the toxic effects") x 6 to 8 cycles
References
- 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
Everolimus
Regimen, Witzig et al. 2011
Phase II
- Everolimus (Afinitor) 10 mg PO once per day on an empty stomach
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."
28-day cycles, given until progression or unacceptable toxicity
References
- 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. Epub 2010 Dec 7. link to original article contains verified protocol PubMed
ICE
ICE: Ifosfamide, Carboplatin, Etoposide
Regimen, Zelenetz et al. 2003
Phase II
Third cycle intended to be followed by peripheral blood stem cell collection
- Ifosfamide (Ifex) 5,000 mg/m2 IV continuous infusion over 24 hours on day 2, mixed together with mesna
- Carboplatin (Paraplatin) AUC 5 (maximum dose of 800 mg per cycle) IV bolus once on day 2
- Carboplatin AUC calculated based on a 12-hour creatinine clearance
- Etoposide (Vepesid) 100 mg/m2 IV bolus once per day on days 1 to 3
14-day cycles x 3 cycles
Supportive medications:
- Mesna (Mesnex) 5,000 mg/m2 IV continuous infusion over 24 hours on day 2, mixed together with Ifosfamide (Ifex)
- Filgrastim (Neupogen) 5 μg/kg SC once per day on days 5 to 12 (10 μg/kg with cycle 3, given until collection of peripheral blood stem cells)
References
- Zelenetz AD, Hamlin P, Kewalramani T, Yahalom J, Nimer S, Moskowitz CH. Ifosfamide, carboplatin, etoposide (ICE)-based second-line chemotherapy for the management of relapsed and refractory aggressive non-Hodgkin's lymphoma. Ann Oncol. 2003;14 Suppl 1:i5-10. link to original article contains verified protocol PubMed
Ifosfamide (Ifex)
Regimen
Phase III, <20 in this arm
Dose & schedule is as given in Pettengell et al. The original phase II trial (CALGB 8552) used a different dose & schedule.
- Ifosfamide (Ifex) 3000 mg/m2 IV once per day on days 1 & 2
Supportive medications:
- Mesna (Mesnex) dose not specified
28-day cycles
References
- Case DC Jr, Anderson J, Ervin TJ, Gottlieb A. Phase II trial of ifosfamide and mesna in previously treated patients with non-Hodgkin's lymphoma: Cancer and Leukemia Group B study 8552. Hematol Oncol. 1991 Jul-Oct;9(4-5):189-96. PubMed
- Review: Webb MS, Saltman DL, Connors JM, Goldie JH. A literature review of single agent treatment of multiply relapsed aggressive non-Hodgkin's lymphoma. Leuk Lymphoma. 2002 May;43(5):975-82. Review. link to original article PubMed
- 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. Epub 2012 May 30. Erratum in: Lancet Oncol. 2012 Jul;13(7):e285. link to original article contains verified protocol PubMed
Lenalidomide (Revlimid)
Regimen, Wiernik et al. 2008 (NHL-002); Witzig et al. 2011 (NHL-003)
Phase II
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycles until disease progression or unacceptable toxicity
References
- 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
- 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
Lenalidomide & Rituximab
Regimen #1, Zinzani et al. 2011
Phase II
Induction
- Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
- Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1 & 21
28-day cycles x 4 cycles; patients with response of stable disease or better received:
Maintenance
- Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
28-day cycles x 8 months
Regimen #2, Wang et al. 2013
Phase II
- Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
- Rituximab (Rituxan) 375 mg/m2 IV once per week on weeks 1 to 4 of cycle 1, only
28-day cycles
References
- Zinzani PL, Pellegrini C, Gandolfi L, Stefoni V, Quirini F, Derenzini E, Broccoli A, Argnani L, Pileri S, Baccarani M. Combination of lenalidomide and rituximab in elderly patients with relapsed or refractory diffuse large B-cell lymphoma: a phase 2 trial. Clin Lymphoma Myeloma Leuk. 2011 Dec;11(6):462-6. Epub 2011 May 4. link to original article contains verified protocol PubMed
- Wang M, Fowler N, Wagner-Bartak N, Feng L, Romaguera J, Neelapu SS, Hagemeister F, Fanale M, Oki Y, Pro B, Shah J, Thomas S, Younes A, Hosing C, Zhang L, Newberry KJ, Desai M, Cheng N, Badillo M, Bejarano M, Chen Y, Young KH, Champlin R, Kwak L, Fayad L. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase II clinical trial. Leukemia. 2013 Sep;27(9):1902-9. Epub 2013 Apr 2. link to original article contains verified protocol PubMed
MINE-ESHAP
MINE: Mesna, Ifosfamide, Novantrone, Etoposide ESHAP: Etoposide, High dose Ara-C, Platinol
Regimen
Phase II
Part 1: MINE
- Ifosfamide (Ifex) 1.33 g/m2 IV over 1 hour once per day on days 1 to 3
- Mitoxantrone (Novantrone) 8 g/m2 IV once on day 1
- Etoposide (Vepesid) 65 mg/m2 IV over 1 hour once per day on days 1 to 3
Supportive medications:
- Mesna (Mesnex) 1.33 g/m2 IV over 1 hour once per day on days 1 to 3
- Mesna (Mesnex) 500 mg PO once, diluted in water or juice, 4 hours following ifosfamide administration
Part 2: ESHAP
- Etoposide (Vepesid) 60 mg/m2 IV over 1 hour once per day on days 1 to 4
- Methylprednisolone (Solumedrol) 500 mg IV as a short infusion once per day 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
- 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
Obinutuzumab (GA101)
Regimen, Morschhauser et al. 2013 (GAUGUIN)
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.
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
21-day cycles x 8 cycles
References
- Morschhauser FA, Cartron G, Thieblemont C, Solal-Céligny P, Haioun C, Bouabdallah R, Feugier P, Bouabdallah K, Asikanius E, Lei G, Wenger M, Wassner-Fritsch E, Salles GA. Obinutuzumab (GA101) Monotherapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma or Mantle-Cell Lymphoma: Results From the Phase II GAUGUIN Study. J Clin Oncol. 2013 Aug 10;31(23):2912-9. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
O-DHAP
O-DHAP: Ofatumumab, Dexamethasone, High-dose Ara-C (cytarabine), cisPlatin
Regimen
Phase II
- Ofatumumab (Arzerra) 1000 mg IV on cycle 1 days 1 & 8; then on day 1 only of cycles 2 & 3 (total of 4 doses)
- Dexamethasone (Decadron) 40 mg PO/IV once per day on days 1 to 4
- Cytarabine (Cytosar) 2000 mg/m2 IV 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
Supportive medications:
21-day cycles x 3 cycles
References
- Matasar MJ, Czuczman MS, Rodriguez MA, Fennessy M, Shea TC, Spitzer G, Lossos IS, Kharfan-Dabaja MA, Joyce R, Fayad L, Henkel K, Liao Q, Edvardsen K, Jewell RC, Fecteau D, Singh RP, Lisby S, Moskowitz CH. Ofatumumab in combination with ICE or DHAP chemotherapy in relapsed or refractory intermediate grade B-cell lymphoma. Blood. 2013 Jul 25;122(4):499-506. Epub 2013 May 21. link to original article contains verified protocol PubMed
O-ICE
O-ICE: Ofatumumab, Ifosfamide, Carboplatin, Etoposide
Regimen
Phase II
- Ofatumumab (Arzerra) 1000 mg IV on cycle 1 days 1 & 8; then on day 1 only of cycles 2 & 3 (total of 4 doses)
- Ifosfamide (Ifex) 5,000 mg/m2 IV continuous infusion over 24 hours on day 2, mixed together with mesna
- Carboplatin (Paraplatin) AUC 5 (maximum dose of 800 mg per cycle) IV once on day 1 or 2 (1 dose, total)
- Carboplatin AUC calculated based on a 12-hour creatinine clearance
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
Supportive medications:
- Mesna (Mesnex) 5,000 mg/m2 IV continuous infusion over 24 hours on day 2, mixed together with ifosfamide
- G-CSF or Neulasta was recommended (no details given).
21-day cycles x 3 cycles
References
- Matasar MJ, Czuczman MS, Rodriguez MA, Fennessy M, Shea TC, Spitzer G, Lossos IS, Kharfan-Dabaja MA, Joyce R, Fayad L, Henkel K, Liao Q, Edvardsen K, Jewell RC, Fecteau D, Singh RP, Lisby S, Moskowitz CH. Ofatumumab in combination with ICE or DHAP chemotherapy in relapsed or refractory intermediate grade B-cell lymphoma. Blood. 2013 Jul 25;122(4):499-506. Epub 2013 May 21. link to original article contains verified protocol PubMed
Oxaliplatin (Eloxatin)
Regimen
Phase III
Germann et al. give a range of 100 to 130 mg/m2; Oki et al. used the 130 mg/m2 dosage; Pettengell et al. used the 100 mg/m2 dosage.
- Oxaliplatin (Eloxatin) 100 to 130 mg/m2 IV once on day 1
21-day cycles
References
- Germann N, Brienza S, Rotarski M, Emile JF, Di Palma M, Musset M, Reynes M, Soulié P, Cvitkovic E, Misset JL. Preliminary results on the activity of oxaliplatin (L-OHP) in refractory/recurrent non-Hodgkin's lymphoma patients. Ann Oncol. 1999 Mar;10(3):351-4. link to original article contains verified protocol PubMed
- Review: Webb MS, Saltman DL, Connors JM, Goldie JH. A literature review of single agent treatment of multiply relapsed aggressive non-Hodgkin's lymphoma. Leuk Lymphoma. 2002 May;43(5):975-82. Review. link to original article PubMed
- Oki Y, McLaughlin P, Pro B, Hagemeister FB, Bleyer A, Loyer E, Younes A. Phase II study of oxaliplatin in patients with recurrent or refractory non-Hodgkin lymphoma. Cancer. 2005 Aug 15;104(4):781-7. link to original article contains verified protocol PubMed
- 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. Epub 2012 May 30. Erratum in: Lancet Oncol. 2012 Jul;13(7):e285. link to original article contains verified protocol PubMed
Pixantrone (Pixuvri)
Regimen
Phase III
- Pixantrone (Pixuvri) 85 mg/m2 IV once per day on days 1, 8, 15
28-day cycles x up to 6 cycles
References
- 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. 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. 2010 (CORAL)
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 once per day on days 1 to 4
- Cytarabine (Cytosar) 2000 mg/m2 IV over 3 hours Q12H x 2 doses on day 2 (total of 2 doses)
- Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours on day 1
Supportive medications:
- G-CSF "depending on site policy, with R-DHAP, but always after the third cycle until the end of leukaphereses"
21-day cycles x 3 cycles; patients with complete or partial response then received BEAM chemotherapy & autologous stem-cell transplant (ASCT)
References
- 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
- 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. Epub 2010 Jul 26. Erratum in: J Clin Oncol. 2012 May 20;30(15):1896. link to original article contains verified protocol PubMed
R-GDP
R-GDP: Rituximab, Gemcitabine, Dexamethasone, Platinol
Regimen
Non-randomized
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
- Dexamethasone (Decadron) 40 mg IV once per day on days 1 to 4
- Cisplatin (Platinol) 25 mg/m2 IV once per day on days 1 to 3
21-day cycles x up to 6 cycles
References
- Hou Y, Wang HQ, Ba Y. Rituximab, gemcitabine, cisplatin, and dexamethasone in patients with refractory or relapsed aggressive B-cell lymphoma. Med Oncol. 2012 Dec;29(4):2409-16. Epub 2012 Apr 3. link to original article PubMed
R-GemOx
R-GemOx: Rituximab, Gemcitabine, Oxaliplatin
Regimen
Phase II
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV at a fixed dose rate of 10 mg/m2/min once on day 2
- Oxaliplatin (Eloxatin) 100 mg/m2 IV over 2 hours once on day 2
Supportive medications:
- Methylprednisolone (Solumedrol) 1 mg/kg IV once prior to Rituximab (Rituxan)
- Acetaminophen (Tylenol) 1000 mg PO once prior to Rituximab (Rituxan)
- Dexchlorpheniramine (Polaramine) 6 mg PO once prior to Rituximab (Rituxan)
- Primary prophylaxis with G-CSF was not permitted
14-day cycles x up to 8 cycles
References
- El Gnaoui T, Dupuis J, Belhadj K, Jais JP, Rahmouni A, Copie-Bergman C, Gaillard I, Diviné M, Tabah-Fisch I, Reyes F, Haioun C. Rituximab, gemcitabine and oxaliplatin: an effective salvage regimen for patients with relapsed or refractory B-cell lymphoma not candidates for high-dose therapy. Ann Oncol. 2007 Aug;18(8):1363-8. Epub 2007 May 11. link to original article contains verified protocol PubMed
- Mounier N, El-Gnaoui T, Tilly H, Canioni D, Sebban C, Casasnovas RO, Delarue R, Sonet A, Beaussart P, Petrella T, Castaigne S, Bologna S, Salles G, Rahmouni A, Gaulard P, Haioun C. Rituximab plus gemcitabine and oxaliplatin in refractory/relapsed patients with diffuse large B-cell lymphoma who are not candidates for high-dose therapy. A phase II Lymphoma Study Association trial. Haematologica. 2013 Jun 10. [Epub ahead of print] link to original article contains verified protocol PubMed
R-ESHAP
R-ESHAP: Rituximab, Etoposide, Solumedrol (methylprednisolone) High-dose Ara-C (cytarabine), cisPlatin
Regimen
Retrospective
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 per day on days 1 to 4
- Methylprednisolone (Solumedrol) 250 to 500 mg IV over 15 minutes once per day 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
Supportive medications:
- At least 1 liter normal saline with 25 to 50 g Mannitol once per day throughout chemotherapy
- Metoclopramide (Reglan) 0.5 to 1 mg/kg "given regularly"
21 to 28 day cycles ("after recovery of the toxic effects") x 6 to 8 cycles
References
- 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
- 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. Epub 2008 Oct 22. link to original article contains verified protocol PubMed
R-ICE
R-ICE: Rituximab, Ifosfamide, Carboplatin, Etoposide
Regimen #1, Zelenetz et al. 2003 & Kewalramani et al. 2004
Phase II
Third 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
- Carboplatin (Paraplatin) AUC 5 (maximum dose of 800 mg per cycle) IV bolus once on day 4
- Carboplatin AUC calculated based on a 12-hour creatinine clearance
- Etoposide (Vepesid) 100 mg/m2 IV bolus once per day on days 3 to 5
14-day cycles x 3 cycles
Supportive medications (as described by Kewalramani et al. 2004):
- Mesna (Mesnex) 5,000 mg/m2 IV continuous infusion over 24 hours on day 4, mixed together with Ifosfamide (Ifex)
- Acetaminophen (Tylenol) 650 mg PO once as premedication for Rituximab (Rituxan)
- Diphenhydramine (Benadryl) 50 mg IV once as premedication for Rituximab (Rituxan)
- Filgrastim (Neupogen) 5 μg/kg SC once per day on days 7 to 14 (10 μg/kg with cycle 3, given until collection of peripheral blood stem cells)
Regimen #2, Gisselbrecht et al. 2010 (CORAL)
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
- Carboplatin (Paraplatin) AUC 5 IV (maximum dose of 800 mg per cycle) on day 2
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
Supportive medications:
- Mesna (Mesnex) given with Ifosfamide (Ifex); dose & schedule not specified in the paper
- " Granulocyte colony-stimulating factor was administered after R-ICE"
21-day cycles x 3 cycles; patients with complete or partial response then received BEAM chemotherapy & autologous stem-cell transplant (ASCT)
References
- Zelenetz AD, Hamlin P, Kewalramani T, Yahalom J, Nimer S, Moskowitz CH. Ifosfamide, carboplatin, etoposide (ICE)-based second-line chemotherapy for the management of relapsed and refractory aggressive non-Hodgkin's lymphoma. Ann Oncol. 2003;14 Suppl 1:i5-10. link to original article contains verified protocol PubMed
- 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
- 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
- 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. 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
Phase II
- Temsirolimus (Torisel) 25 mg IV over 30 minutes once per week
28-day cycles x up to 6 cycles
References
- 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. Epub 2010 Sep 13. link to original article contains verified protocol PubMed
Regimen
Phase III, <20 in this arm
- Vinorelbine (Navelbine) 30 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycles
References
- Balzarotti M, Santoro A, Tondini C, Fornier M, Bonadonna G. Activity of single agent vinorelbine in pretreated non-Hodgkin's lymphoma. Ann Oncol. 1996 Nov;7(9):970-2. link to original article contains verified protocol PubMed
- Review: Webb MS, Saltman DL, Connors JM, Goldie JH. A literature review of single agent treatment of multiply relapsed aggressive non-Hodgkin's lymphoma. Leuk Lymphoma. 2002 May;43(5):975-82. Review. link to original article PubMed
- 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. Epub 2012 May 30. Erratum in: Lancet Oncol. 2012 Jul;13(7):e285. link to original article contains verified protocol PubMed
DLBCL, post-transplant
Pidilizumab (CT-011)
Phase II
Treatment is to begin within 30 to 90 days after autologous stem-cell transplant for chemoresponsive disease.
- Pidilizumab (CT-011) 1.5 mg/kg IV once
Supportive medications:
- Acetaminophen (Tylenol) or Ibuprofen prior to Pidilizumab (CT-011)
- Diphenhydramine (Benadryl) or Promethazine (Phenergan) prior to Pidilizumab (CT-011)
42-day cycle x 3 cycles
References
- Armand P, Nagler A, Weller EA, Devine SM, Avigan DE, Chen YB, Kaminski MS, Kent Holland H, Winter JN, Mason JR, Fay JW, Rizzieri DA, Hosing CM, Ball ED, Uberti JP, Lazarus HM, Mapara MY, Gregory SA, Timmerman JM, Andorsky D, Or R, Waller EK, Rotem-Yehudar R, Gordon LI. Disabling Immune Tolerance by Programmed Death-1 Blockade With Pidilizumab After Autologous Hematopoietic Stem-Cell Transplantation for Diffuse Large B-Cell Lymphoma: Results of an International Phase II Trial. J Clin Oncol. 2013 Oct 14. [Epub ahead of print] link to original article contains verified protocol PubMed
BL or Burkitt-like lymphoma, untreated
Note: Burkitt-like lymphoma is not considered an entity by the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue 2008 criteria. The correct terminology is "B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma." However, Burkitt-like lymphoma is still used in common parlance and the term is retained here; treatment is usually similar to treatment for Burkitt lymphoma but regimens evaluated on DLBCL are also sometimes used.
BASIC
BASIC: Brief, Anthracycline-Sparing, Intensive Cyclophosphamide
Regimen
Non-randomized
Induction
- Cyclophosphamide (Cytoxan) 1500 mg/m2 IV over 1 hour once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (max dose of 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 per day on days 1 & 8
- Methotrexate (MTX) 3000 mg/m2 IV over 2 hours on day 8
CNS prophylaxis:
- Cytarabine (Cytosar) 100 mg IT (50 mg of Hydrocortisone optional) on days 1, 4, 11 (also day 8 if no IV MTX given)
Supportive medications:
- Mesna (Mesnex) 900 mg/m2 IV "in divided doses" on day 1
- Folinic acid (Leucovorin) 25 mg/m2 IV Q6H, starting 24 hours after start of IV Methotrexate (MTX), until clearance
- Filgrastim (Neupogen) 5 mcg/kg SC daily, starting on day 3 and continuing until post-nadir ANC >500/uL
14-day cycles x 2 cycles, then:
Intensification
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 50 mg/kg IV over 1 to 2 hours once per day on days 2 to 5
Supportive medications:
- Mesna (Mesnex) 40 mg/kg/day IV "in divided doses" on days 2 to 5
- Filgrastim (Neupogen) 5 mcg/kg SC daily, starting on day 11 and continuing until post-nadir ANC >1000/uL
One course, followed by:
- Rituximab (Rituxan) 375 mg/m2 IV once per week x 4 doses, once post-nadir ANC > 1000/uL
CNS treatment (only given in prior CNS involvement):
- Cytarabine (Cytosar) 100 mg IT (50 mg of Hydrocortisone optional) once per week x 4 doses, then once every other week x 4 doses
References
- Kasamon YL, Brodsky RA, Borowitz MJ, Ambinder RF, Crilley PA, Cho SY, Tsai HL, Smith BD, Gladstone DE, Carraway HE, Huff CA, Matsui WH, Bolaños-Meade J, Jones RJ, Swinnen LJ. Brief intensive therapy for older adults with newly diagnosed Burkitt or atypical Burkitt lymphoma/leukemia. Leuk Lymphoma. 2013 Mar;54(3):483-90. Epub 2012 Aug 17. link to original article contains verified protocol PubMed
CODOX-M/IVAC (Modified Magrath)
CODOX-M: Cyclophosphamide, Oncovin, DOXorubicin, M ethotrexate
IVAC: Ifosfamide, Vepesid (etoposide), AC Ara-C (cytarabine)
Regimen
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
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
CNS prophylaxis:
- Cytarabine (Cytosar) 70 mg intrathecal on days 1, 3
- Methotrexate (MTX) 12 mg intrathecal on day 15
Supportive medications:
- Folinic acid (Leucovorin) 15 mg/m2 IV Q3H, starting 36 hours after start of IV Methotrexate (MTX) until 48 hours, then Q6H until methotrexate level undetectable
- Folinic acid (Leucovorin) 15 mg PO once 24 hours after intrathecal Methotrexate (MTX)
- 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:
- Ifosfamide (Ifex) 1500 mg/m2 IV over 1 hour on days 1 to 5
- Etoposide (Vepesid) 60 mg/m2 IV over 1 hour on days 1 to 5
- Cytarabine (Cytosar) 2 g/m2 IV over 3 hours Q12H on days 1,2 (4 doses)
Age more than 65 years:
- Ifosfamide (Ifex) 1000 mg/m2 IV over 1 hour on days 1 to 5
- Etoposide (Vepesid) 60 mg/m2 IV over 1 hour on days 1 to 5
- Cytarabine (Cytosar) 1 g/m2 IV over 3 hours Q12H on days 1,2 (4 doses)
CNS prophylaxis:
- Methotrexate (MTX) 12 mg intrathecal on day 5
Supportive medications:
- Age 65 years or younger: Mesna (Mesnex) 300 mg/m2 (mixed with Ifosfamide (Ifex)) over 1 hour, then 300mg/m2 IV every four hours x 2, on days 1 to 5
- Age more than 65 years: Mesna (Mesnex) 200 mg/m2 (mixed with Ifosfamide (Ifex)) over 1 hour, then 200mg/m2 IV every four hours x 2, on days 1 to 5
- Folinic acid (Leucovorin) 15 mg PO once 24 hours after intrathecal methotrexate
- Filgrastim (Neupogen) 5 mcg/kg SQ daily, starting on day 7 and continuing until ANC >1,000/uL
References
- 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
- 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
- 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. Epub 2008 Jul 8. link to original article contains verified protocol PubMed
- 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. Epub 2010 Dec 1. link to original article contains verified protocol PubMed
DA-R-EPOCH
DA-R-EPOCH: Dose Adjusted Rituximab, Etoposide, Prednisone, Oncovin, Cyclophosphamide, Hydroxydaunorubicin
Synonyms: DA-EPOCH-R, EPOCH-R, REPOCH
Structured Concept: C63461 (NCI-T), C1882521 (NCI-MT/UMLS)
Regimen, Dunleavy et al. 2008, Dunleavy et al. 2013
Phase II
Note: the abstract references Wilson et al. 2002 for dosing, however this is the DA-EPOCH regimen (no rituximab). Thus, we are extrapolating that rituximab was given on day 1 of each cycle based on similar protocols in DLBCL and PMBCL.
- 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
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once over 15 minutes on day 5
- Doxorubicin (Adriamycin) 10 mg/m2/day (total dose of 40 mg/m2) IV continuous infusion on days 1 to 4
CNS prophylaxis:
- Methotrexate (MTX) IT (dose and # of cycles not specified)
Supportive medications: Filgrastim (Neupogen) dose not specified once per day, starting on day 6 and continuing until ANC greater than 5 × 10e9/L above the nadir level
21-day cycles x 6 cycles OR 21-day cycles x 3 to 6 cycles for 1 cycle beyond CR for a minimum of 3 cycles, if HIV-positive
Dose-adjustments for EPOCH protocol, based on Wilson et al. 2002:
- 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.
- 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 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
- Dunleavy K, Little RF, Pittaluga S, Grant N, Shovlin M, Steinberg S, Yarchoan R, Janik J, Jaffe ES, Wilson WH. A prospective study of dose-adjusted (DA) EPOCH with rituximab in adults with newly diagnosed Burkitt lymphoma: a regimen with high efficacy and low toxicity. Ann Oncol 19(suppl4):83-84, abstr.9. 2008 Jun. link to original article contains protocol
- Dunleavy K, Pittaluga S, Shovlin M, Steinberg SM, Cole D, Grant C, Widemann B, Staudt LM, Jaffe ES, Little RF, Wilson WH. Low-intensity therapy in adults with Burkitt's lymphoma. N Engl J Med. 2013 Nov 14;369(20):1915-25. link to original article contains verified protocol PubMed
GMALL-R
GMALL-R: German Multicenter Study Group for the Treatment of Adult Acute Lymphoblastic Leukemia, Rituximab
Regimen, Ribera et al. 2013 (Burkimab)
Phase II
Numbering of days is based on prephase->A->B->C; however, certain patient populations received different ordering of regimen, see below.
Prephase
- Cyclophosphamide (Cytoxan) 200 mg/m2 IV over 1 hour once per day on days 1 to 5
- Prednisone (Sterapred) 60 mg/m2 IV bolus once per day on days 1 to 5
Cycle A
- Rituximab (Rituxan) 375 mg/m2 IV over 4 hours once on day 7
- Vincristine (Oncovin) 2 mg IV bolus once on day 8
- Methotrexate (MTX) 1500 mg/m2 IV over 24 hours once on day 8
- Older than 55 years: reduce Methotrexate (MTX) dose by 50%
- Ifosfamide (Ifex) 800 mg/m2 IV over 1 hour once per day on days 8 to 12
- Dexamethasone (Decadron) 10 mg/m2 IV bolus once per day on days 8 to 12
- Teniposide (Vumon) 100 mg/m2 IV over 1 hour once per day on days 11 & 12
- Cytarabine (Cytosar) 150 mg/m2 IV over 1 hour BID on days 11 & 12
- Older than 55 years: reduce Cytarabine (Cytosar) dose by 50%
Supportive medications:
- Folinic acid (Leucovorin) (dose/route/schedule not specified), starting 12 hours after Methotrexate (MTX) infusion
Cycle B
- Rituximab (Rituxan) 375 mg/m2 IV over 4 hours once on day 28
- Vincristine (Oncovin) 2 mg IV bolus once on day 29
- Methotrexate (MTX) 1500 mg/m2 IV over 24 hours once on day 29
- Older than 55 years: reduce Methotrexate (MTX) dose by 50%
- Cyclophosphamide (Cytoxan) 200 mg/m2 IV over 1 hour once per day on days 29 to 33
- Dexamethasone (Decadron) 10 mg/m2 IV bolus once per day on days 29 to 33
- Doxorubicin (Adriamycin) 25 mg/m2 IV over 15 minutes once per day on days 32 & 33
Supportive medications:
- Folinic acid (Leucovorin) (dose/route/schedule not specified), starting 12 hours after Methotrexate (MTX) infusion
Cycle C
- Rituximab (Rituxan) 375 mg/m2 IV over 4 hours once on day 49
- Vindesine (Eldisine) 3 mg/m2 (maximum dose 5 mg) IV bolus once on day 50
- Methotrexate (MTX) 1500 mg/m2 IV over 24 hours once on day 50
- Older than 55 years: reduce Methotrexate (MTX) dose by 50%
- Dexamethasone (Decadron) 10 mg/m2 IV bolus once per day on days 50 to 54
- Etoposide (Vepesid) 250 mg/m2 IV over 1 hour once per day on days 53 & 54
- Cytarabine (Cytosar) 2000 mg/m2 IV over 3 hours BID on day 54
- Older than 55 years: reduce Cytarabine (Cytosar) dose by 50%
Supportive medications:
- Folinic acid (Leucovorin) (dose/route/schedule not specified), starting 12 hours after Methotrexate (MTX) infusion
Give regimen as follows:
- Advanced stage and younger than 55 years: A->B->C x 2 courses (6 total cycles)
- Older than 55 years: Alternate A & B x 3 courses (6 total cycles)
- Localized stage: 4 total cycles (unclear from protocol if this means A alternating with B or A->B->C->A)
CNS Prophylaxis
- Methotrexate (MTX) 15 mg intrathecal once on days 1, 8, 12, 29, 33
- Cytarabine (Cytosar) 40 mg intrathecal once on days 1, 8, 12, 29, 33
- Dexamethasone (Decadron) 20 mg intrathecal once on days 1, 8, 12, 29, 33
8 doses total
References
- Ribera JM, García O, Grande C, Esteve J, Oriol A, Bergua J, González-Campos J, Vall-Llovera F, Tormo M, Hernández-Rivas JM, García D, Brunet S, Alonso N, Barba P, Miralles P, Llorente A, Montesinos P, Moreno MJ, Hernández-Rivas JÁ, Bernal T. Dose-intensive chemotherapy including rituximab in Burkitt's leukemia or lymphoma regardless of human immunodeficiency virus infection status: final results of a phase 2 study (Burkimab). Cancer. 2013 May 1;119(9):1660-8. Epub 2013 Jan 29. 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)
Regimen
Retrospective
Exact details vary; both studies were retrospective.
Part 1: R-CODOX-M
- Rituximab (Rituxan) 375 mg/m2 IV on day 6 of cycle 1, then 2 days prior to each subsequent cycle
- Cyclophosphamide (Cytoxan) 800 mg/m2 IV once on day 1; 200 mg/m2 IV once per day 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
- Methotrexate (MTX) 536 mg/m2 IV over 1 hour, followed by 107 mg/m2/hr IV over next 23 hours on day 10
CNS Prophylaxis:
- Cytarabine (Cytosar) 40 mg intrathecal once on days 1 & 3 (more if CNS disease present)
- Methotrexate (MTX) 15 mg intrathecal once on day 15
Supportive medications:
- Folinic acid (Leucovorin) starting 36 hours after start of IV Methotrexate (MTX) 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."
- Filgrastim (Neupogen) 5 mcg/kg SQ once per day, starting on day 7 and continuing until ANC >1,000/uL
Part 2: R-IVAC
- Rituximab (Rituxan) 375 mg/m2 IV on day 6 of cycle 1, then 2 days prior to each subsequent cycle
- Ifosfamide (Ifex) 1500 mg/m2 IV over 2 hours once per day on days 1 to 5
- Etoposide (Vepesid) 60 mg/m2 IV over 1 hour once per day on days 1 to 5
- Cytarabine (Cytosar) 2 g/m2 IV over 3 hours Q12H on days 1,2 (4 doses total)
CNS Prophylaxis:
- Methotrexate (MTX) 15 mg intrathecal once on day 5
- Cytarabine (Cytosar) 40 mg intrathecal once on days 7 & 9 ONLY if CNS disease present
Supportive medications:
- Mesna (Mesnex) 300 mg/m2 (mixed with Ifosfamide (Ifex)) over 1 hour, then 300mg/m2 IV every four hours x 2, on days 1 to 5
- Filgrastim (Neupogen) 5 mcg/kg SQ once per day, starting on day 7 and continuing until ANC >1,000/uL
References
- 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. Epub 2010 Dec 1. link to original article contains verified protocol PubMed
- Barnes JA, Lacasce AS, Feng Y, Toomey CE, Neuberg D, Michaelson JS, Hochberg EP, Abramson JS. Evaluation of the addition of rituximab to CODOX-M/IVAC for Burkitt's lymphoma: a retrospective analysis. Ann Oncol. 2011 Aug;22(8):1859-64. Epub 2011 Feb 21. link to original article PubMed
R-CODOX-M/R-IVAC (Doxil substituted)
R-CODOX-M: Rituximab, Cyclophosphamide, Oncovin, DOXil, M ethotrexate
R-IVAC: Rituximab, Ifosfamide, Vepesid (etoposide), AC Ara-C (cytarabine)
Regimen
Phase II
Low risk patients (R-CODOX-M alone)
- Rituximab (Rituxan) 500 mg/m2 IV once on days 0 & 8
- Cyclophosphamide (Cytoxan) 800 mg/m2 IV over 1 hour once on day 1; 200 mg/m2 IV over 1 hour once per day on days 2 to 5
- Vincristine (Oncovin) 1.5 mg/m2 (max dose of 2 mg) IV push once on days 1 & 8
- Doxorubicin liposomal (Doxil) 40 mg/m2 IV once "per protocol" on day 1
- Methotrexate (MTX) 300 mg/m2 IV over 1 hour, followed by 2700 mg/m2 IV over next 23 hours on day 10
CNS Prophylaxis:
- Cytarabine (Cytosar) 70 mg intrathecal once on day 1
- Methotrexate (MTX) 12 mg intrathecal (or 6 mg into Ommaya) once on day 3
Supportive medications:
- Folinic acid (Leucovorin) 200 mg/m2 IV once 36 hours after start of IV Methotrexate (MTX), then 15 mg/m2 IV Q6H until methotrexate level is <5 X 10-8
- Filgrastim (Neupogen) 5 mcg/kg SQ once per day on days 6 & 7, then on day 14 onwards until ANC >1,500/uL
3 consecutive cycles
High risk patients
Part 1: R-CODOX-M
- Rituximab (Rituxan) 500 mg/m2 IV once on days 0 & 8
- Cyclophosphamide (Cytoxan) 800 mg/m2 IV over 1 hour once on day 1; 200 mg/m2 IV over 1 hour once per day on days 2 to 5
- Vincristine (Oncovin) 1.5 mg/m2 (max dose of 2 mg) IV push once on days 1 & 8
- Doxorubicin liposomal (Doxil) 40 mg/m2 IV once "per protocol" on day 1
- Methotrexate (MTX) 300 mg/m2 IV over 1 hour, followed by 2700 mg/m2 IV over next 23 hours on day 10
CNS Prophylaxis:
- Cytarabine (Cytosar) 70 mg intrathecal once on days 1 & 3
- Methotrexate (MTX) 12 mg intrathecal (or 6 mg into Ommaya) once on day 15
Supportive medications:
- Folinic acid (Leucovorin) 200 mg/m2 IV once 36 hours after start of IV Methotrexate (MTX), then 15 mg/m2 IV Q6H until methotrexate level is <5 X 10-8
- Filgrastim (Neupogen) 5 mcg/kg SQ once per day on days 6 & 7, then on day 14 onwards until ANC >1,500/uL
Part 2: R-IVAC
- Rituximab (Rituxan) 375 mg/m2 IV on days 0 & 6 or 7 (2 doses per cycle)
- Ifosfamide (Ifex) 1500 mg/m2 IV over 3 hours once per day on days 1 to 5
- Etoposide (Vepesid) 60 mg/m2 IV over 1 hour once per day on days 1 to 5
- Cytarabine (Cytosar) 2 g/m2 IV over 3 hours Q12H on days 1,2 (4 doses per cycle)
CNS Prophylaxis:
- Methotrexate (MTX) 15 mg intrathecal once on day 5
Supportive medications:
- Mesna (Mesnex) 500 mg/m2 mixed with first Ifosfamide (Ifex), then 1000 mg/m2/day IV continuous infusion on days 1 to 5
- Folinic acid (Leucovorin) 15 mg PO q6h x 4 doses, starting 24 hours after intrathecal Methotrexate (MTX)
- Filgrastim (Neupogen) 5 mcg/kg SQ daily, starting on day 6 or 7 and continuing until ANC >1,500/uL
Four alternating cycles of R-CODOX-M & R-IVAC
References
- Evens AM, Carson KR, Kolesar J, Nabhan C, Helenowski I, Islam N, Jovanovic B, Barr PM, Caimi PF, Gregory SA, Gordon LI. A multicenter phase II study incorporating high-dose rituximab and liposomal doxorubicin into the CODOX-M/IVAC regimen for untreated Burkitt's lymphoma. Ann Oncol. 2013 Oct 20. [Epub ahead of print] link to original article contains verified protocol PubMed
R-Hyper-CVAD
R-Hyper-CVAD: Rituximab, Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin, Dexamethasone
Regimen
Pilot, <20 patients reported
Part A (cycles 1, 3, 5, 7):
- Rituximab (Rituxan) 375 mg/m2 IV over 2 to 6 hours once on days 1 & 11 (cycles 1 & 3, only)
- Cyclophosphamide (Cytoxan) 300 mg/m2 IV over 2 hours Q12H on days 1 to 3 (6 total doses)
- Vincristine (Oncovin) 2 mg IV once on days 4 & 11
- Doxorubicin (Adriamycin) 50 mg/m2 IV over 24 hours on day 4
- Dexamethasone (Decadron) 40 mg PO/IV once daily on days 1 to 4, 11 to 14
CNS prophylaxis:
- Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT on day 2
- Cytarabine (Cytosar) 100 mg IT on day 7
Given each cycle for a total of 16 intrathecal treatments. If CNS disease present, therapy augmented to twice-weekly alternating (MTX, ara-C) treatments until CSF cell count normalizes and cytology is negative, then continues for 4 more alternating weekly treatments; prophylaxis course then resumes.
Supportive care:
- Mesna (Mesnex) 600 mg/m2/day IV continuous infusion on days 1 to 3, starting 1 hour before Cyclophosphamide (Cytoxan) and completed 12 hours after the last dose of Cyclophosphamide (Cytoxan)
- Filgrastim (Neupogen) 10 mcg/kg SC daily starting 24 hours after completion of chemotherapy, given until WBC >3 x 10^9/L or bone pain present
- One of the following antibiotics:
- EITHER Quinolone
- OR Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) dose/route not specified
- Fluconazole (Diflucan) dose/route not specified
- One of the following antivirals:
- EITHER Acyclovir (Zovirax) dose/route not specified
- OR Valacyclovir (Valtrex) dose/route not specified
Dose modifications:
- Vincristine (Oncovin) reduced to 1 mg for bilirubin > 2 mg/dL or NCI common toxicity criteria Grade 2+ peripheral neuropathy, omitted for bilirubin > 3 mg/dL or for ileus
- Doxorubicin (Adriamycin) reduced by 50% for bilirubin 2 to 3 mg/dL, by 75% for bilirubin 3 to 5 mg/dL (eliminated for bilirubin > 5 mg/dL or for gastric/small-bowel involvement with Course 1 to reduce duration of myelosuppression given risk of perforation)
Next cycle to start no sooner than 14 days or as soon as "unmaintained" WBC count is > 3 x 10^9/L and platelet count > 50 x 10^9/L
Part B (cycles 2, 4, 6, 8):
- Rituximab (Rituxan) 375 mg/m2 IV over 2 to 6 hours once on days 2 & 8 (cycles 2 & 4, only)
- Methotrexate (MTX) 1000 mg/m2 IV over 24 hours on day 1
- Cytarabine (Cytosar) 3000 mg/m2 IV over 2 hours Q12H on days 2 & 3 (4 total doses)
CNS prophylaxis:
- Methotrexate (MTX) 12 mg (6 mg if given via Ommaya reservoir) IT on day 2
- Cytarabine (Cytosar) 100 mg IT on day 7
Given each cycle for a total of 16 intrathecal treatments. If CNS disease present, therapy augmented to twice-weekly alternating (MTX, ara-C) treatments until CSF cell count normalizes and cytology is negative, then continues for 4 more alternating weekly treatments; prophylaxis course then resumes.
Supportive care:
- Folinic acid (Leucovorin) 50 mg IV x1 12 hours after Methotrexate (MTX) is complete, then 15 mg IV Q6H x 8 doses until serum methotrexate level <0.1 µM
- Filgrastim (Neupogen) 10 mcg/kg SC daily starting 24 hours after completion of chemotherapy, given until WBC >3 x 10^9/L or bone pain present
- One of the following antibiotics:
- EITHER Quinolone
- OR Trimethoprim/Sulfamethoxazole (Bactrim DS) (160/800 mg) dose/route not specified
- Fluconazole (Diflucan) dose/route not specified
- One of the following antivirals:
- EITHER Acyclovir (Zovirax) dose/route not specified
- OR Valacyclovir (Valtrex) dose/route not specified
Dose modifications:
- Cytarabine (Cytosar) reduced to 1000 mg/m2 for patients ≥60 years old, creatinine ≥1.5 mg/dL or 0 hour MTX level ≥ 20 μmol/L
- Methotrexate (MTX) reduced by 50% for creatinine clearance 10 to 50 mL/min (eliminated for < 10 mL/min), by 25% to 75% for delayed excretion and/or nephrotoxicity with prior course (dependent on severity) or by 50% for pleural effusions/ascites with drainage of fluid as feasible.
Next cycle to start no sooner than 14 days or as soon as "unmaintained" WBC count is > 3 x 10^9/L and platelet count > 50 x 10^9/L
References
- Thomas DA, Faderl S, O'Brien S, Bueso-Ramos C, Cortes J, Garcia-Manero G, Giles FJ, Verstovsek S, Wierda WG, Pierce SA, Shan J, Brandt M, Hagemeister FB, Keating MJ, Cabanillas F, Kantarjian H. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006 Apr 1;106(7):1569-80. 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
- 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. Epub 2012 Mar 7. link to original article PubMed
Anaplastic large-cell lymphoma, relapsed/refractory
Brentuximab vedotin
Regimen
Phase II
- Brentuximab vedotin (Adcetris) 1.8 mg/kg IV over 30 minutes on day 1
Every 21 days up to 16 infusions
References
- 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. 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
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)
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 2 hours once on day 5
- Doxorubicin (Adriamycin) 10 mg/m2/day IV continuous infusion over 96 hours on days 1 to 4 (total dose per cycle: 40 mg/m2)
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
21-day cycles x 6 to 8 cycles
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
- 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. 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
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
- 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
Lenalidomide (Revlimid)
Regimen, Wiernik et al. 2008 (NHL-002); Witzig et al. 2011 (NHL-003)
Phase II
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycles until disease progression or unacceptable toxicity
References
- 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
- 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
Lenalidomide & Rituximab
Regimen, Wang et al. 2013
Phase II, <20 patients reported
- Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
- Rituximab (Rituxan) 375 mg/m2 IV once per week on weeks 1 to 4 of cycle 1, only
28-day cycles
References
- Wang M, Fowler N, Wagner-Bartak N, Feng L, Romaguera J, Neelapu SS, Hagemeister F, Fanale M, Oki Y, Pro B, Shah J, Thomas S, Younes A, Hosing C, Zhang L, Newberry KJ, Desai M, Cheng N, Badillo M, Bejarano M, Chen Y, Young KH, Champlin R, Kwak L, Fayad L. Oral lenalidomide with rituximab in relapsed or refractory diffuse large cell, follicular and transformed lymphoma: a phase II clinical trial. Leukemia. 2013 Sep;27(9):1902-9. Epub 2013 Apr 2. link to original article contains verified protocol PubMed
OFAR
OFAR: Oxaliplatin, Fludarabine, Ara-C, Rituximab
Regimen
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 Oxaliplatin (Eloxatin)
- Cytarabine (Cytosar) 1000 mg/m2 IV over 2 hours once daily on days 2 & 3, 4 hours after Fludarabine (Fludara) 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
Supportive medications:
- Pegfilgrastim (Neulasta) 6 mg SC once on day 6
- Herpes zoster and PCP (Pneumocystis jiroveci pneumonia) prophylaxis used
28-day cycles x up to 6 cycles
References
- 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