Difference between revisions of "Diffuse large B-cell lymphoma"
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====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *CR based on '''CT''' scan: R-CHOP x 2 (4 cycles total), then [[# | + | *CR based on '''CT''' scan: R-CHOP x 2 (4 cycles total), then [[#Ibritumomab_tiuxetan_protocol|ibritumomab tiuxetan consolidation]] |
− | *CRu or PR based on '''CT''' scan: R-CHOP x 4 (6 cycles total), then [[# | + | *CRu or PR based on '''CT''' scan: R-CHOP x 4 (6 cycles total), then [[#Ibritumomab_tiuxetan_protocol|ibritumomab tiuxetan consolidation]] |
===References=== | ===References=== | ||
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====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *SWOG S0313: [[# | + | *SWOG S0313: [[#Ibritumomab_tiuxetan_protocol|Ibritumomab tiuxetan consolidation]] |
===Regimen variant #5, IFRT x 40 to 55 Gy {{#subobject:0cd919|Variant=1}}=== | ===Regimen variant #5, IFRT x 40 to 55 Gy {{#subobject:0cd919|Variant=1}}=== | ||
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====Subsequent treatment==== | ====Subsequent treatment==== | ||
− | *SWOG S0313: [[# | + | *SWOG S0313: [[#Ibritumomab_tiuxetan_protocol|Ibritumumoab tiuxetan consolidation]] |
===References=== | ===References=== |
Revision as of 04:12, 14 February 2020
Section editor | |
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J.C. Villasboas Bisneto, MD Mayo Clinic Rochester, MN |
Are you looking for a regimen, such as CHOP, but can't find it here? It is possible that we've moved it to the historical regimens page. If you still can't find it, please let us know so we can add it!
109 regimens on this page
165 variants on this page
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Guidelines
ESMO
- 2015: Tilly et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Older
- 2013: Ghielmini et al. ESMO Guidelines consensus conference on malignant lymphoma 2011 part 1: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL) PubMed
NCCN
Untreated, pre-phase
Vincristine & Prednisone
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Regimen variant #1, PO vincristine
Study | Evidence |
---|---|
Peyrade et al. 2016 (LYSA LNH09-7B) | Phase II |
Chemotherapy
- Vincristine (Oncovin) 1 mg PO once on day -7
- Prednisone (Sterapred) 60 mg PO once per day on days -7 to -4
7-day course
Subsequent treatment
Regimen variant #2, IV vincristine
Study | Evidence |
---|---|
Pfreundschuh et al. 2004 (NHL-B1) | Non-randomized portion of RCT |
Pfreundschuh et al. 2004 (NHL-B2) | Non-randomized portion of RCT |
Pfreundschuh et al. 2008 (RICOVER-60) | Non-randomized portion of RCT |
Pfreundschuh et al. 2014 (SMARTE-R-CHOP-14) | Phase II |
Recommended in NHL-B1 and NHL-B2 "to improve the performance status of patients and to ameliorate side-effects of the first chemotherapy cycle." Mandated in RICOVER-60 and SMARTE-R-CHOP-14. Note: NHL-B1 gave the option of a 5 to 7 day course of prednisone.
Chemotherapy
- 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
Subsequent treatment
- NHL-B1 and NHL-B2: CHOP versus CHOP-14 versus CHOEP-14 versus CHOEP-21
- RICOVER-60: CHOP-14 versus R-CHOP-14
- SMARTE-R-CHOP-14: R-CHOP-14
References
- NHL-B1: 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
- NHL-B2: 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
- RICOVER-60: 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
- SMARTE-R-CHOP-14: Pfreundschuh M, Poeschel V, Zeynalova S, Hänel M, Held G, Schmitz N, Viardot A, Dreyling MH, Hallek M, Mueller C, Wiesen MH, Witzens-Harig M, Truemper L, Keller U, Rixecker T, Zwick C, Murawski N. Optimization of rituximab for the treatment of diffuse large B-cell lymphoma (II): extended rituximab exposure time in the SMARTE-R-CHOP-14 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group. J Clin Oncol. 2014 Dec 20;32(36):4127-33. Epub 2014 Nov 17. Erratum in: J Clin Oncol. 2015 Jun 10;33(17):1991. link to original article contains verified protocol PubMed
- LYSA LNH09-7B: Peyrade F, Bologna S, Delwail V, Emile JF, Pascal L, Fermé C, Schiano JM, Coiffier B, Corront B, Farhat H, Fruchart C, Ghesquieres H, Macro M, Tilly H, Choufi B, Delarue R, Fitoussi O, Gabarre J, Haioun C, Jardin F. Combination of ofatumumab and reduced-dose CHOP for diffuse large B-cell lymphomas in patients aged 80 years or older: an open-label, multicentre, single-arm, phase 2 trial from the LYSA group. Lancet Haematol. 2017 Jan;4(1):e46-e55. link to original article contains protocol PubMed
Untreated, randomized data
ACVBP-R
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ACVBP-R: Adriamycin (Doxorubicin), Cyclophosphamide, Vindesine, Bleomycin, Prednisone, Rituximab
R-ACVBP: Rituximab, Adriamycin (Doxorubicin), Cyclophosphamide, Vindesine, Bleomycin, Prednisone
Regimen
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Récher et al. 2011 (LNH03-2B) | Phase III (E-esc) | R-CHOP | Superior OS | Increased toxicity |
Ketterer et al. 2013 (LNH03-1B) | Phase III (E-esc) | ACVBP | Seems to have superior PFS | Similar toxicity |
Chemotherapy
- 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 per day on days 1 & 5
- Bleomycin (Blenoxane) 10 units IV once per day on days 1 & 5
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 5
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
CNS prophylaxis
- Methotrexate (MTX) 15 mg IT on day 1
Supportive medications
- Filgrastim (Neupogen) 300 mcg (for patients less than 75 kg) or 480 mcg (for patients greater than or equal to 75 kg) SC once per day on days 6 to 13
14-day cycle for 4 cycles
Subsequent treatment
- Methotrexate consolidation, in 4 weeks
References
- LNH03-2B: 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
- Subgroup analysis: Molina TJ, Canioni D, Copie-Bergman C, Recher C, Brière J, Haioun C, Berger F, Fermé C, Copin MC, Casasnovas O, Thieblemont C, Petrella T, Leroy K, Salles G, Fabiani B, Morschauser F, Mounier N, Coiffier B, Jardin F, Gaulard P, Jais JP, Tilly H. Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d'Etudes des Lymphomes de l'Adulte/lymphoma study association phase III trial LNH 03-2B. J Clin Oncol. 2014 Dec 10;32(35):3996-4003. Epub 2014 Nov 10. link to original article PubMed
- LNH03-1B: Ketterer N, Coiffier B, Thieblemont C, Fermé C, Brière J, Casasnovas O, Bologna S, Christian B, Connerotte T, Récher C, Bordessoule D, Fruchart C, Delarue R, Bonnet C, Morschhauser F, Anglaret B, Soussain C, Fabiani B, Tilly H, Haioun C. Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol. 2013 Apr;24(4):1032-7. Epub 2012 Dec 12. link to original article PubMed
DA-R-EPOCH
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DA-R-EPOCH: Dose Adjusted Rituximab, Etoposide, Prednisone, Oncovin (Vincristine), Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin)
DA-EPOCH-R
Regimen
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
García-Suárez et al. 2007 | Phase II | |||
Wilson et al. 2008 | Phase II | |||
Wilson et al. 2011 (CALGB 50103) | Phase II | |||
Purroy et al. 2014 | Phase II | |||
Bartlett et al. 2019 (CALGB 50303) | Phase III (E-esc) | R-CHOP | Did not meet primary endpoint of EFS | Increased toxicity |
Chemotherapy
- 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 IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 200 mg/m2)
- Prednisone (Sterapred) 60 mg/m2 PO twice per day on days 1 to 5
- Vincristine (Oncovin) 0.4 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 1.6 mg/m2)
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV over 15 minutes once on day 5
- Doxorubicin (Adriamycin) 10 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 40 mg/m2)
Supportive medications
- Growth factor support with one of the following:
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day 6 and continuing until ANC greater than 5000/uL past nadir
- Pegfilgrastim (Neulasta) 6 mg SC once on day 6 (option per Purroy et al. 2014)
- PCP prophylaxis with any one of the following:
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day 3 days per week
- Alternative used only in García-Suárez et al. 2007: cotrimoxazole 480 mg PO twice per day 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 twice per day 3 days per week
- Only in García-Suárez et al. 2007: Darbepoetin alfa (Aranesp) 2.25 mcg/kg SC when hemoglobin concentration was less than or equal to 10 g/dL.
21-day cycle for 6 to 8 cycles
Dose modifications
- Start cycle 1 as described above.
- Obtain CBCs twice per week for nadir measurements.
- If nadir ANC greater than 500/uL, increase etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
- If nadir ANC less than 500/uL on 1 or 2 measurements, use same doses as last cycle.
- If nadir ANC less than 500/uL on at least 3 measurements, decrease etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
- And/or if nadir platelet count less than 25 × 109/L 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 greater than 1000/uL and platelets greater than 100 × 109/L. 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 link to PMC article PubMed
- CALGB 50103: 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 link to PMC article PubMed
- Purroy N, Bergua J, Gallur L, Prieto J, Lopez LA, Sancho JM, García-Marco JA, Castellví J, Montes-Moreno S, Batlle A, de Villambrosia SG, Carnicero F, Ferrando-Lamana L, Piris MA, Lopez A. Long-term follow-up of dose-adjusted EPOCH plus rituximab (DA-EPOCH-R) in untreated patients with poor prognosis large B-cell lymphoma: a phase II study conducted by the Spanish PETHEMA group. Br J Haematol. 2015 Apr;169(2):188-98. Epub 2014 Dec 18. link to original article contains protocol PubMed
- Retrospective: Howlett C, Snedecor SJ, Landsburg DJ, Svoboda J, Chong EA, Schuster SJ, Nasta SD, Feldman T, Rago A, Walsh KM, Weber S, Goy A, Mato A. Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis. Br J Haematol. 2015 Aug;170(4):504-14. Epub 2015 Apr 24. link to original article PubMed
- CALGB 50303: Bartlett NL, Wilson WH, Jung SH, Hsi ED, Maurer MJ, Pederson LD, Polley MC, Pitcher BN, Cheson BD, Kahl BS, Friedberg JW, Staudt LM, Wagner-Johnston ND, Blum KA, Abramson JS, Reddy NM, Winter JN, Chang JE, Gopal AK, Chadburn A, Mathew S, Fisher RI, Richards KL, Schöder H, Zelenetz AD, Leonard JP. Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303. J Clin Oncol. 2019 Jul 20;37(21):1790-1799. Epub 2019 Apr 2. link to original article link to PMC article PubMed
R-CHOEP-14
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R-CHOEP-14: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Etoposide, Prednisone, 14-day cycles
Regimen variant #1, flat-dose vincristine
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Adde et al. 2006 | Phase II | |||
Schmitz et al. 2012 (DSHNHL 2002-1) | Phase III (C) | R-MegaCHOEP | Did not meet primary endpoint of EFS | Decreased toxicity |
Note: to our knowledge, this regimen was not tested as an experimental arm in a RCT prior to becoming a standard comparator arm.
Chemotherapy
- Rituximab (Rituxan) as follows:
- Cycles 1 to 4, 6, 8: 375 mg/m2 IV once on day 0
- 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 cycle for 8 cycles
Subsequent treatment
- "Mandatory" for patients with bulky disease (any mass greater than 7.5cm in diameter, or extranodal involvement): RT x 36 Gy
Regimen variant #2, capped vincristine, with CNS prophylaxis
Study | Evidence |
---|---|
Holte et al. 2012 (NLG LBC-04) | Phase II |
Note: Consolidative radiotherapy "given at the discretion of the individual centers (36 to 45 Gy). Indications for giving radiotherapy after the completion of chemotherapy included bulky disease (greater than or equal to 10 cm) at diagnosis, localized PET-positive residual lesions, and residual disease, not eligible for biopsy at a localized site, and potentially curable by radiotherapy."
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) 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
Supportive medications
- ONE of the following:
- Filgrastim (Neupogen) 5 mcg/kg SC once per day from day 4
- Pegfilgrastim (Neulasta) 6 mg SC once on day 4
14-day cycle for 8 cycles
Subsequent treatment
References
- Adde M, Enblad G, Hagberg H, Sundström C, Laurell A. Outcome for young high-risk aggressive B-cell lymphoma patients treated with CHOEP-14 and rituximab (R-CHOEP-14). Med Oncol. 2006;23(2):283-93. link to original article PubMed
- DSHNHL 2002-1: Schmitz N, Nickelsen M, Ziepert M, Haenel M, Borchmann P, Schmidt C, Viardot A, Bentz M, Peter N, Ehninger G, Doelken G, Ruebe C, Truemper L, Rosenwald A, Pfreundschuh M, Loeffler M, Glass B; for the German High-Grade Lymphoma Study Group (DSHNHL). Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1). Lancet Oncol. 2012 Dec;13(12):1250-1259. Epub 2012 Nov 16. link to original article PubMed
- NLG LBC-04: Holte H, Leppä S, Björkholm M, Fluge O, Jyrkkiö S, Delabie J, Sundström C, Karjalainen-Lindsberg ML, Erlanson M, Kolstad A, Fosså A, Ostenstad B, Löfvenberg E, Nordström M, Janes R, Pedersen LM, Anderson H, Jerkeman M, Eriksson M. Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study. Ann Oncol. 2013 May;24(5):1385-92. Epub 2012 Dec 17. link to original article contains verified protocol PubMed
R-CHOP
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R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone
R-CHOP-21: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone given every 21 days
CHOP-R: Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone, Rituximab
RCHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone
CHOPR: Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone, Rituximab
Example orders
Note: most of the variation between regimen variants is in the dose of prednisone.
Regimen variant #1, prednisone 40 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Coiffier et al. 2002 (LNH 98-5) | 1998-2000 | Phase III (E-RT-esc) | CHOP | Superior OS |
Delarue et al. 2013 (LNH03-6B) | Phase III (C) | R-CHOP-14 | Did not meet primary endpoint of EFS |
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
Supportive medications
- Filgrastim (Neupogen) used for later cycles if patients developed grade 4 neutropenia or febrile neutropenia
21-day cycle for 8 cycles
CNS prophylaxis
As described in Delarue et al. 2013 (LNH03-6B):
- Methotrexate (MTX) 15 mg IT once on day 1
21-day cycle for 4 cycles
Regimen variant #2, prednisone 60 mg/m2
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Récher et al. 2011 (LNH03-2B) | Phase III (C) | ACVBP-R | Inferior OS | Decreased toxicity |
Li et al. 2018 (CSWOG0001) | Phase III (C) | R-CHOP-14 | Did not meet primary endpoint of DFS | Similar toxicities |
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 5
21-day cycle for 8 cycles
Regimen variant #3, prednisone 100 mg, capped vincristine, 4 cycles
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Poeschel et al. 2019 (FLYER) | Phase III (E-de-esc) | R-CHOP x 6 | Non-inferior PFS36 | Less toxic |
Note: Patients in FLYER were 18 to 60 and had no risk factors according to age-adjusted IPI.
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) as follows:
- Cycles 1 to 4: 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) as follows:
- Cycles 1 to 4: 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) as follows:
- Cycles 1 to 4: 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Prednisone (Sterapred) as follows:
- Cycles 1 to 4: 100 mg IV or PO once per day on days 1 to 5
21-day cycle for 6 cycles
Regimen variant #4, prednisone 100 mg, capped vincristine, 6 cycles
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Vose et al. 2001 | Phase II | |||
Merli et al. 2012 (ANZINTER3) | Phase III (C) | R-miniCEOP | Did not meet primary endpoint of EFS | |
Herbrecht et al. 2013 (PIX203) | Phase III (C) | CPOP-R | Inconclusive whether non-inferior CR/CRu rate (*) | |
Oki et al. 2013 (MDACC 2005-0054) | Randomized Phase II (C) | R-Hyper-CVAD/R-MA | Seems to have inferior CRR | |
Seymour et al. 2014 (MAIN) | Phase III (C) | RA-CHOP-21 | Did not meet secondary endpoint of PFS | Better cardiac safety |
Vitolo et al. 2017 (GOYA) | Phase III (C) | G-CHOP | Did not meet primary endpoint of PFS | |
Leonard et al. 2017 (C05013) | Randomized Phase II (C) | VR-CHOP | Did not meet primary endpoint of PFS | |
Hara et al. 2018 | Phase III (C) | R-THP-CHOP | Non-inferior CR rate | |
Younes et al. 2019 (PHOENIX) | Phase III (C) | IR-CHOP | Did not meet primary endpoint of EFS | |
Poeschel et al. 2019 (FLYER) | Phase III (C) | R-CHOP x 4 | Non-inferior PFS36 | More toxic |
Note: patients in Vose et al. 2001 received rituximab 2 days before CHOP, i.e., all CHOP days are moved forward by 2 days. Patients in GOYA received 8 doses of rituximab, regardless of the number of chemotherapy cycles given. While the primary endpoing in PIX203 was inconclusive (non-inferiority by CR/CRu rate), this arm seemed to have superior OS. Hara et al. 2018 does not have dosing information available in the abstract. Patients in FLYER were 18 to 60 and had no risk factors according to age-adjusted IPI.
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Prednisone (Sterapred) 100 mg IV or PO once per day on days 1 to 5
Supportive medications
- Varies per protocol
- Prophylactic G-CSF used for persisting grade 4 neutropenia or febrile neutropenia.
- Cotrimoxazole (dose/schedule not specified) prophylaxis.
- Erythropoietin use was allowed for hemoglobin less than 11 g/dL.
21-day cycle for 6 to 8 cycles (see note)
Subsequent treatment
- Some protocols: Radiation therapy was scheduled for sites of previous bulky disease or partially responding sites
Regimen variant #5, prednisone 100 mg, flat-dose vincristine
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Pfreundschuh et al. 2006 (NCIC CTG LY.9) | Phase III (E-RT-esc) | 1. CHOP 2. CHOEP-21 3. MACOP-B 4. PMitCEBO |
Superior EFS | Similar toxicity |
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 2 mg IV once on day 1
- Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
Supportive medications
- G-CSF with one of the following:
- Filgrastim (Neupogen) used at physician discretion for neutropenia
- Lenograstim (Granocyte) used at physician discretion for neutropenia
21-day cycle for 6 cycles
Subsequent treatment
- Radiation therapy 30 to 40 Gy given to sites of primary bulky disease; 30 to 40 Gy to primary extranodal disease at physician discretion
Regimen variant #6, prednisone 100 mg/m2
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Offner et al. 2015 (LYM-2034) | Randomized Phase II (C) | VR-CAP | Did not meet primary endpoint of CR rate |
This regimen was used for non-germinal center B-cell (non-GCB) DLBCL.
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Prednisone (Sterapred) 100 mg/m2 PO once per day on days 1 to 5
21-day cycle for 6 cycles
Regimen variant #7, rituximab lead-in
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Habermann et al. 2006 (ECOG E4494/CALGB 9793) | 1998-2001 | Phase III (E-RT-esc) | CHOP | Seems to have superior FFS |
Note: an advantage for maintenance was only seen in the group receiving CHOP upfront, which is no longer standard of care.
Chemotherapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once per day on days -7 & -3
- Cycle 2 onwards: 375 mg/m2 IV once on day -2
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Prednisone (Sterapred) 100 mg/m2 PO once per day on days 1 to 5
Supportive medications
- Recommended: Filgrastim (Neupogen) "according to guidelines"
21-day cycle for 6 to 8 cycles
Subsequent treatment
- Rituximab maintenance versus observation
Regimen variant #8, short-course for early stage DLBCL
Study | Evidence |
---|---|
Persky et al. 2008 (SWOG S0014) | Phase II |
Yoon et al. 2017 (CISL 12-09) | Phase II |
Note: CISL 12-09 does not have dosing details.
Preceding treatment
- CISL 12-09: Surgical resection
Chemotherapy
- Rituximab (Rituxan) as follows:
- Prephase: 375 mg/m2 IV once on day -7
- Cycles 1 to 3: 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
21-day cycle for 3 cycles
Subsequent treatment
- SWOG S0014: IFRT to begin 3 weeks after last cycle of R-CHOP
Regimen variant #9, primary testicular DLBCL
Study | Evidence |
---|---|
Vitolo et al. 2011 (IELSG-10) | Phase II |
This regimen is for primary testicular lymphoma, and is a component of a sequential treatment protocol.
Preceding treatment
- Diagnostic orchiectomy prior to starting chemotherapy
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 0 or 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) 100 mg PO once per day on days 1 to 5
21-day cycle for 6 cycles (up to 8 cycles for stage II patients)
CNS prophylaxis
- Methotrexate (MTX) 12 mg IT once per day on days 1, 8, 15, 22
4-week course
Subsequent treatent
Regimen variant #10, 2 cycles with response adaptation
Study | Evidence |
---|---|
Witzig et al. 2015 (ECOG E3402) | Phase II |
This regimen is intended for stage I-II DLBCL based on CT (not PET-CT) imaging.
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Prednisone (Sterapred) 100 mg/m2 PO once per day on days 1 to 5
21-day cycle for 2 cycles
Subsequent treatment
- CR based on CT scan: R-CHOP x 2 (4 cycles total), then ibritumomab tiuxetan consolidation
- CRu or PR based on CT scan: R-CHOP x 4 (6 cycles total), then ibritumomab tiuxetan consolidation
References
- Vose JM, Link BK, Grossbard ML, Czuczman M, Grillo-Lopez A, Gilman P, Lowe A, Kunkel LA, Fisher RI. Phase II study of rituximab in combination with CHOP chemotherapy in patients with previously untreated, aggressive non-Hodgkin's lymphoma. J Clin Oncol. 2001 Jan 15;19(2):389-97. link to original article contains verified protocol PubMed
- LNH 98-5: Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jan 24;346(4):235-42. link to original article contains verified protocol PubMed
- 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
- 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 link to PMC article PubMed content property of HemOnc.org
- 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
- NCIC CTG LY.9: 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
- 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
- ECOG E4494/CALGB 9793: 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
- SWOG S0014: 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
- IELSG-10: Vitolo U, Chiappella A, Ferreri AJ, Martelli M, Baldi I, Balzarotti M, Bottelli C, Conconi A, Gomez H, Lopez-Guillermo A, Martinelli G, Merli F, Novero D, Orsucci L, Pavone V, Ricardi U, Storti S, Gospodarowicz MK, Cavalli F, Sarris AH, Zucca E. First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximab-CHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international phase II trial. J Clin Oncol. 2011 Jul 10;29(20):2766-72. Epub 2011 Jun 6. link to original article contains verified protocol PubMed
- ANZINTER3: 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
- LNH03-2B: 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
- Subgroup analysis: Molina TJ, Canioni D, Copie-Bergman C, Recher C, Brière J, Haioun C, Berger F, Fermé C, Copin MC, Casasnovas O, Thieblemont C, Petrella T, Leroy K, Salles G, Fabiani B, Morschauser F, Mounier N, Coiffier B, Jardin F, Gaulard P, Jais JP, Tilly H. Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d'Etudes des Lymphomes de l'Adulte/lymphoma study association phase III trial LNH 03-2B. J Clin Oncol. 2014 Dec 10;32(35):3996-4003. Epub 2014 Nov 10. link to original article PubMed
- LNH03-6B: 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
- PIX203: Herbrecht R, Cernohous P, Engert A, Le Gouill S, Macdonald D, Machida C, Myint H, Saleh A, Singer J, Wilhelm M, van der Jagt R. Comparison of pixantrone-based regimen (CPOP-R) with doxorubicin-based therapy (CHOP-R) for treatment of diffuse large B-cell lymphoma. Ann Oncol. 2013 Oct;24(10):2618-23. Epub 2013 Aug 14. link to original article contains verified protocol in supplement PubMed
- MDACC 2005-0054: Oki Y, Westin JR, Vega F, Chuang H, Fowler N, Neelapu S, Hagemeister FB, McLaughlin P, Kwak LW, Romaguera JE, Fanale M, Younes A, Rodriguez MA, Orlowski RZ, Wang M, Ouzounian ST, Samaniego F, Fayad L. Prospective phase II study of rituximab with alternating cycles of hyper-CVAD and high-dose methotrexate with cytarabine for young patients with high-risk diffuse large B-cell lymphoma. Br J Haematol. 2013 Dec;163(5):611-20. Epub 2013 Oct 1. link to original article contains verified protocol link to PMC article contains verified protocol PubMed
- SWOG S9704: Stiff PJ, Unger JM, Cook JR, Constine LS, Couban S, Stewart DA, Shea TC, Porcu P, Winter JN, Kahl BS, Miller TP, Tubbs RR, Marcellus D, Friedberg JW, Barton KP, Mills GM, LeBlanc M, Rimsza LM, Forman SJ, Fisher RI. Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med. 2013 Oct 31;369(18):1681-90. link to original article link to PMC article does not contain protocol PubMed
- Subgroup analysis: Puvvada SD, Stiff PJ, Leblanc M, Cook JR, Couban S, Leonard JP, Kahl B, Marcellus D, Shea TC, Winter JN, Li H, Rimsza LM, Friedberg JW, Smith SM. Outcomes of MYC-associated lymphomas after R-CHOP with and without consolidative autologous stem cell transplant: subset analysis of randomized trial intergroup SWOG S9704. Br J Haematol. 2016 Sep;174(5):686-91. Epub 2016 Apr 13. link to original article link to PMC article PubMed
- MAIN: Seymour JF, Pfreundschuh M, Trnený M, Sehn LH, Catalano J, Csinady E, Moore N, Coiffier B; MAIN Study Investigators. R-CHOP with or without bevacizumab in patients with previously untreated diffuse large B-cell lymphoma: final MAIN study outcomes. Haematologica. 2014 Aug;99(8):1343-9. Epub 2014 Jun 3. link to original article link to PMC article does not contain protocol PubMed
- Retrospective: Howlett C, Snedecor SJ, Landsburg DJ, Svoboda J, Chong EA, Schuster SJ, Nasta SD, Feldman T, Rago A, Walsh KM, Weber S, Goy A, Mato A. Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis. Br J Haematol. 2015 Aug;170(4):504-14. Epub 2015 Apr 24. link to original article PubMed
- ECOG E3402: Witzig TE, Hong F, Micallef IN, Gascoyne RD, Dogan A, Wagner H Jr, Kahl BS, Advani RH, Horning SJ. A phase II trial of RCHOP followed by radioimmunotherapy for early stage (stages I/II) diffuse large B-cell non-Hodgkin lymphoma: ECOG3402. Br J Haematol. 2015 Sep;170(5):679-86. Epub 2015 May 14. link to original article contains verified protocol link to PMC article PubMed
- LYM-2034: Offner F, Samoilova O, Osmanov E, Eom HS, Topp MS, Raposo J, Pavlov V, Ricci D, Chaturvedi S, Zhu E, van de Velde H, Enny C, Rizo A, Ferhanoglu B. Frontline rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VR-CAP) or vincristine (R-CHOP) for non-GCB DLBCL. Blood. 2015 Oct 15;126(16):1893-901. Epub 2015 Jul 31. link to original article contains verified protocol link to PMC article PubMed
- CISL 12-09: Yoon DH, Sohn BS, Oh SY, Lee WS, Lee SM, Yang DH, Huh J, Suh C. Feasibility of abbreviated cycles of immunochemotherapy for completely resected limited-stage CD20+ diffuse large B-cell lymphoma (CISL 12-09). Oncotarget. 2017 Feb 21;8(8):13367-13374. link to original article link to PMC article does not contain protocol PubMed
- MabEase: Lugtenburg P, Avivi I, Berenschot H, Ilhan O, Marolleau JP, Nagler A, Rueda A, Tani M, Turgut M, Osborne S, Smith R, Pfreundschuh M. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica. 2017 Nov;102(11):1913-1922. Epub 2017 Sep 21. link to original article contains partial protocol link to PMC article PubMed
- GOYA: Vitolo U, Trněný M, Belada D, Burke JM, Carella AM, Chua N, Abrisqueta P, Demeter J, Flinn I, Hong X, Kim WS, Pinto A, Shi YK, Tatsumi Y, Oestergaard MZ, Wenger M, Fingerle-Rowson G, Catalani O, Nielsen T, Martelli M, Sehn LH. Obinutuzumab or rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated diffuse large B-cell lymphoma. J Clin Oncol. 2017 Nov 1;35(31):3529-3537. Epub 2017 Aug 10. link to original article contains verified protocol PubMed
- C05013: Leonard JP, Kolibaba KS, Reeves JA, Tulpule A, Flinn IW, Kolevska T, Robles R, Flowers CR, Collins R, DiBella NJ, Papish SW, Venugopal P, Horodner A, Tabatabai A, Hajdenberg J, Park J, Neuwirth R, Mulligan G, Suryanarayan K, Esseltine DL, de Vos S. Randomized phase II study of R-CHOP with or without bortezomib in previously untreated patients with non-germinal center B-cell-like diffuse large B-cell lymphoma. J Clin Oncol. 2017 Nov 1;35(31):3538-3546. Epub 2017 Sep 1. link to original article contains verified protocol PubMed
- Hara T, Yoshikawa T, Goto H, Sawada M, Yamada T, Fukuno K, Kasahara S, Shibata Y, Matsumoto T, Mabuchi R, Nakamura N, Nakamura H, Ninomiya S, Kitagawa J, Kanemura N, Nannya Y, Katsumura N, Takahashi T, Kito Y, Takami T, Miyazaki T, Takeuchi T, Shimizu M, Tsurumi H. R-THP-COP versus R-CHOP in patients younger than 70 years with untreated diffuse large B cell lymphoma: A randomized, open-label, noninferiority phase 3 trial. Hematol Oncol. 2018 Oct;36(4):638-644. Epub 2018 Jun 8. link to original article PubMed
- CSWOG0001: Li X, Huang H, Xu B, Guo H, Lin Y, Ye S, Yi J, Li W, Wu X, Wang W, Zhan H, Xie D, Peng J, Cao Y, Pu X, Guo C, Hong H, Wang Z, Fang X, Zhou Y, Lin S, Liu Q, Lin T. Dose-Dense Rituximab-CHOP versus Standard Rituximab-CHOP in Newly Diagnosed Chinese Patients with Diffuse Large B-Cell Lymphoma: A Randomized, Multicenter, Open-Label Phase 3 Trial. Cancer Res Treat. 2019 Jul;51(3):919-932. Epub 2018 Oct 2. link to original article link to PMC article contains verified protocol PubMed
- PHOENIX: Younes A, Sehn LH, Johnson P, Zinzani PL, Hong X, Zhu J, Patti C, Belada D, Samoilova O, Suh C, Leppä S, Rai S, Turgut M, Jurczak W, Cheung MC, Gurion R, Yeh SP, Lopez-Hernandez A, Dührsen U, Thieblemont C, Chiattone CS, Balasubramanian S, Carey J, Liu G, Shreeve SM, Sun S, Zhuang SH, Vermeulen J, Staudt LM, Wilson W; PHOENIX investigators. Randomized phase III trial of ibrutinib and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in non-germinal center B-cell diffuse large B-cell lymphoma. J Clin Oncol. 2019 May 20;37(15):1285-1295. Epub 2019 Mar 22. link to original article link to PMC article PubMed
- CALGB 50303: Bartlett NL, Wilson WH, Jung SH, Hsi ED, Maurer MJ, Pederson LD, Polley MC, Pitcher BN, Cheson BD, Kahl BS, Friedberg JW, Staudt LM, Wagner-Johnston ND, Blum KA, Abramson JS, Reddy NM, Winter JN, Chang JE, Gopal AK, Chadburn A, Mathew S, Fisher RI, Richards KL, Schöder H, Zelenetz AD, Leonard JP. Dose-Adjusted EPOCH-R Compared With R-CHOP as Frontline Therapy for Diffuse Large B-Cell Lymphoma: Clinical Outcomes of the Phase III Intergroup Trial Alliance/CALGB 50303. J Clin Oncol. 2019 Jul 20;37(21):1790-1799. Epub 2019 Apr 2. link to original article link to PMC article PubMed
- FLYER: Poeschel V, Held G, Ziepert M, Witzens-Harig M, Holte H, Thurner L, Borchmann P, Viardot A, Soekler M, Keller U, Schmidt C, Truemper L, Mahlberg R, Marks R, Hoeffkes HG, Metzner B, Dierlamm J, Frickhofen N, Haenel M, Neubauer A, Kneba M, Merli F, Tucci A, de Nully Brown P, Federico M, Lengfelder E, di Rocco A, Trappe R, Rosenwald A, Berdel C, Maisenhoelder M, Shpilberg O, Amam J, Christofyllakis K, Hartmann F, Murawski N, Stilgenbauer S, Nickelsen M, Wulf G, Glass B, Schmitz N, Altmann B, Loeffler M, Pfreundschuh M; FLYER Trial Investigators; German Lymphoma Alliance. Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial. Lancet. 2019 Dec 21;394(10216):2271-2281. link to original article contains protocol PubMed
R-CHOP (Prednisolone)
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R-CHOP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisolone
Example orders
Regimen variant #1, prednisolone 40 mg/m2
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Cunningham et al. 2013 (UK NCRI R-CHOP14v21) | Phase III (C) | R-CHOP-14 | Did not meet primary endpoint of OS | |
Fridrik et al. 2016 (AGMT NHL-14) | Phase III (C) | R-COMP | Did not meet secondary efficacy endpoints | Did not meet primary endpoint of reduced cardiotoxicity |
Note: Cunningham et al. 2013 states that the regimen is based on LNH 98-5, but notably it uses prednisolone instead of prednisone. AGMT NHL-14 states that R-CHOP was "given in standard doses" per LNH 98-5, but this regimen uses prednisone, whereas the title and text of Fridrik et al. 2016 implies that prednisolone was used. The authors have confirmed that prednisolone was used, due to prednisone not being available in Austria.
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) 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
- Described in Cunningham et al. 2013
- 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 80/400 mg PO twice per day on 3 days per week, taken throughout therapy, ending 2 weeks after chemotherapy is completed
21-day cycle for 8 cycles
Regimen variant #2, prednisolone 100 mg, capped vincristine, 4 cycles
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Poeschel et al. 2019 (FLYER) | Phase III (E-de-esc) | R-CHOP x 6 | Non-inferior PFS36 | Less toxic |
Note: Patients in FLYER were 18 to 60 and had no risk factors according to age-adjusted IPI.
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) as follows:
- Cycles 1 to 4: 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) as follows:
- Cycles 1 to 4: 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) as follows:
- Cycles 1 to 4: 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Prednisolone (Millipred) as follows:
- Cycles 1 to 4: 100 mg IV or PO once per day on days 1 to 5
21-day cycle for 6 cycles
Regimen variant #3, prednisolone 100 mg, 6 cycles
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Davies et al. 2019 (REMoDL-B) | Phase III (C) | RB-CHOP | Did not meet primary endpoint of PFS30 | |
Poeschel et al. 2019 (FLYER) | Phase III (C) | R-CHOP x 4 | Non-inferior PFS36 | More toxic |
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Prednisolone (Millipred) 100 mg PO once per day on days 1 to 5
21-day cycle for 6 cycles
Regimen variant #4, prednisolone 100 mg/m2
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Payandeh et al. 2016 | Phase III (C) | R-CHOP-14 | Inferior OS |
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Prednisolone (Millipred) 100 mg/m2 PO once per day on days 1 to 5
21-day cycle for 6 to 8 cycles
References
- UK NCRI R-CHOP14v21: 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
- AGMT NHL-14: Fridrik MA, Jaeger U, Petzer A, Willenbacher W, Keil F, Lang A, Andel J, Burgstaller S, Krieger O, Oberaigner W, Sihorsch K, Greil R. Cardiotoxicity with rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone compared to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in frontline treatment of patients with diffuse large B-cell lymphoma: A randomised phase-III study from the Austrian Cancer Drug Therapy Working Group [Arbeitsgemeinschaft Medikamentöse Tumortherapie AGMT](NHL-14). Eur J Cancer. 2016 May;58:112-21. Epub 2016 Mar 15. link to original article does not contain protocol PubMed
- Payandeh M, Najafi S, Shojaiyan FZ, Sadeghi M. Phase III of study of R-CHOP-21 vs R-CHOP-14 for untreated stage III and IV B-cell non-Hodgkin's lymphoma: a report from Iran. Asian Pac J Cancer Prev. 2016;17(3):1513-7. link to original article contains verified protocol PubMed
- REMoDL-B: Davies A, Cummin TE, Barrans S, Maishman T, Mamot C, Novak U, Caddy J, Stanton L, Kazmi-Stokes S, McMillan A, Fields P, Pocock C, Collins GP, Stephens R, Cucco F, Clipson A, Sha C, Tooze R, Care MA, Griffiths G, Du MQ, Westhead DR, Burton C, Johnson PWM. Gene-expression profiling of bortezomib added to standard chemoimmunotherapy for diffuse large B-cell lymphoma (REMoDL-B): an open-label, randomised, phase 3 trial. Lancet Oncol. 2019 May;20(5):649-662. Epub 2019 Apr 1. link to original article link to PMC article PubMed
- FLYER: Poeschel V, Held G, Ziepert M, Witzens-Harig M, Holte H, Thurner L, Borchmann P, Viardot A, Soekler M, Keller U, Schmidt C, Truemper L, Mahlberg R, Marks R, Hoeffkes HG, Metzner B, Dierlamm J, Frickhofen N, Haenel M, Neubauer A, Kneba M, Merli F, Tucci A, de Nully Brown P, Federico M, Lengfelder E, di Rocco A, Trappe R, Rosenwald A, Berdel C, Maisenhoelder M, Shpilberg O, Amam J, Christofyllakis K, Hartmann F, Murawski N, Stilgenbauer S, Nickelsen M, Wulf G, Glass B, Schmitz N, Altmann B, Loeffler M, Pfreundschuh M; FLYER Trial Investigators; German Lymphoma Alliance. Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial. Lancet. 2019 Dec 21;394(10216):2271-2281. link to original article contains protocol PubMed
R-CHOP (Rituximab Hycela)
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R-CHOP: Rituximab Hycela, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisolone
Example orders
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Lugtenburg et al. 2017 (MabEase) | 2012-NR | Phase III (E-RT-switch-ic) | R-CHOP | Might have superior CR rate |
Note: the details for CHOP are not available in the manuscript or supplement; we have reproduced common CHOP dosing, here. For patients achieving CR after cycle 4, the CHOP could be omitted after cycle 6.
Chemotherapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- Rituximab and hyaluronidase human (Rituxan Hycela) as follows:
- Cycles 2 to 8: 1400 mg SC 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) 100 mg/m2 PO once per day on days 1 to 5
21-day cycle for 6 to 8 cycles
References
- MabEase: Lugtenburg P, Avivi I, Berenschot H, Ilhan O, Marolleau JP, Nagler A, Rueda A, Tani M, Turgut M, Osborne S, Smith R, Pfreundschuh M. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica. 2017 Nov;102(11):1913-1922. Epub 2017 Sep 21. link to original article contains partial protocol link to PMC article PubMed
R-CHOP-14
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R-CHOP-14: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone every 14 days
Synopsis
To be completed. Note that most of the variation below is in the steroid dose.
Regimen variant #1, prednisone 40 mg/m2, 4 to 6 cycles
Study | Evidence |
---|---|
Lamy et al. 2017 (LYSA/GOELAMS 02-03) | Non-randomized portion of RCT |
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
14-day cycle for 4 to 6 cycles
Subsequent treatment
- Observation versus IFRT x 40 Gy
Regimen variant #2, prednisone 40 mg/m2, 8 cycles
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Delarue et al. 2013 (LNH03-6B) | Phase III (E-esc) | R-CHOP21 | Did not meet primary endpoint of EFS |
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
Supportive medications
- ONE of the following, "according to the treating doctor's decision, fulfilling existing guidelines and product labelling at that time."
14-day cycle for 8 cycles
CNS prophylaxis
- Methotrexate (MTX) 15 mg IT once on day 1
14-day cycle for 4 cycles
Regimen variant #3, prednisone 100 mg, BSA-based vincristine, standard-dose IV rituximab
Study | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|
Seymour et al. 2014 (MAIN) | Phase III (C) | RA-CHOP-14 | Did not meet secondary endpoint of PFS | Better cardiac safety |
Cortelazzo et al. 2016 | Phase III (C) | R-HDS | Did not meet primary endpoint of EFS36 | |
Chiappella et al. 2017 (DLCL04) | Phase III (C) | 1. R-MegaCHOP-14 | Not reported | |
2. R-CHOP-14, then R-MAD, then BEAM, then auto HSCT 3. R-MegaCHOP-14, then R-MAD, then BEAM, then auto HSCT |
Did not meet primary endpoint of FFS24 |
Note: in MAIN, CHOP-14 was given for 6 cycles and rituximab for 8 cycles. In Cortelazzo et al. 2016, there is no cap on the vincristine dose, and there is also a discrepancy between the prednisone dose in the body of the manuscript and that in the appendix Figure A1; these discrepancies were clarified by the corresponding author in January 2017. In the abstract of DLCL04, there is no cap on vincristine.
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
Supportive medications
- ONE of the following:
- Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 7 to 11
- Pegfilgrastim (Neulasta)
14-day cycle for 6 to 8 cycles (see note)
Regimen variant #4, prednisone 100 mg, BSA-based vincristine, high-dose IV rituximab
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Pfreundschuh et al. 2014 (SEXIE-R-CHOP-14) | Randomized Phase II (E-esc) | See below | TBD |
Note: two arms were assessed; results are pending from this comparison. These higher doses were for males, only.
Chemotherapy
- Rituximab (Rituxan) by ONE of the following schedules:
- Cycles 1 to 8: 500 mg/m2 IV once on day 1
- 500 mg/m2 IV once per day on days -1, 0, 3, 7, 14, 21, 28, 42
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 2 mg IV once on day 1
- Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
14-day cycle for 6 cycles
Regimen variant #5, prednisone 100 mg, flat dose vincristine, 2 cycles, with response adaptation
Study | Evidence |
---|---|
Dührsen et al. 2018 (PETAL) | Non-randomized portion of RCT |
Preceding treatment
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 2
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 2
- Vincristine (Oncovin) 2 mg IV once on day 2
- Prednisone (Sterapred) 100 mg PO once per day on days 2 to 6
14-day cycle for 2 cycles
Subsequent treatment
- PET-negative: R-CHOP x 4 (6 cycles total) versus R-CHOP x 4, then rituximab x 2
- PET-positive: R-CHOP x 6 (8 cycles total) versus intensive Burkitt lymphoma protocol
Regimen variant #6, prednisone 100 mg, flat dose vincristine, 6 cycles, extended rituximab exposure
Study | Evidence |
---|---|
Pfreundschuh et al. 2014 (SMARTE-R-CHOP-14) | Phase II |
Preceding treatment
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once per day on days -4, 0, 10, 29, 57, 99, 155, 239 (independent of CHOP cycles)
- 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
- ONE of the following starting on day 4, to continue until count recovery:
14-day cycle for 6 cycles
Subsequent treatment
- Patients with initial bulky disease ("lymphoma masses or conglomerates with a diameter greater than or equal to 7.5 cm) or extranodal involvement"): RT x 36 Gy
Regimen variant #7, prednisone 100 mg, flat dose vincristine, 6-8 cycles
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Pfreundschuh et al. 2008 (RICOVER-60) | Phase III (E-esc) | 1. CHOP-14 x 6 | Superior OS |
2. CHOP-14 x 8 | Not reported | ||
3. R-CHOP-14 x 8 | Not reported | ||
Held et al. 2014 (RICOVER-noRTh) | Non-randomized portion of RCT |
Preceding treatment
- RICOVER-60: Pre-phase vincristine & prednisone
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) 2 mg IV once on day 1
- Prednisone (Sterapred) 100 mg PO once per day on days 1 to 5
Supportive medications
- ONE of the following starting on day 4, to continue until count recovery:
14-day cycle for 6 to 8 cycles (8 doses of rituximab regardless of total number of cycles)
Subsequent treatment
- RICOVER-60: Patients with initial bulky disease ("lymphoma masses or conglomerates with a diameter greater than or equal to 7.5 cm) or extranodal involvement"): RT x 36 Gy
- RICOVER-noRTh: RT x 36 Gy versus observation
References
- RICOVER-60: 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
- Abstract: S. Le Gouill, N. J. Milpied, T. Lamy, V. Delwail, R. Gressin, D. Guyotat, G. L. Damaj, C. Foussard, G. Cartron, H. Maisonneuve, E. Deconinck, F. Dreyfus, E. Gyan, L. Sutton, N. Morineau, M. Alexis, F. Perry, M. Sauvezie. First-line rituximab (R) high-dose therapy (R-HDT) versus R-CHOP14 for young adults with diffuse large B-cell lymphoma: Preliminary results of the GOELAMS 075 prospective multicenter randomized trial. Journal of Clinical Oncology 29, no. 15_suppl (May 2011) 8003-8003. link to abstract
- LNH03-6B: 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
- RICOVER-noRTh: Held G, Murawski N, Ziepert M, Fleckenstein J, Pöschel V, Zwick C, Bittenbring J, Hänel M, Wilhelm S, Schubert J, Schmitz N, Löffler M, Rübe C, Pfreundschuh M. Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol. 2014 Apr 10;32(11):1112-8. Epub 2014 Feb 3. link to original article PubMed
- Abstract: Michael Pfreundschuh, Gerhard Held, Samira Zeynalova, Carsten Zwick, Mathias Haenel, Lorenz Truemper, Martin H. Dreyling, Judith Dierlamm, Markus Loeffler, Norbert Schmitz, Niels Murawski, German High-Grad Non-Hodgkin Lymphoma Study Group (DSHNHL). Increased rituximab (R) doses and effect on risk of elderly male patients with aggressive CD20+ B-cell lymphomas: Results from the SEXIE-R-CHOP-14 trial of the DSHNHL. J Clin Oncol 32:5s, 2014 (suppl; abstr 8501) link to original abstract
- MAIN: Seymour JF, Pfreundschuh M, Trnený M, Sehn LH, Catalano J, Csinady E, Moore N, Coiffier B; MAIN Study Investigators. R-CHOP with or without bevacizumab in patients with previously untreated diffuse large B-cell lymphoma: final MAIN study outcomes. Haematologica. 2014 Aug;99(8):1343-9. Epub 2014 Jun 3. link to original article link to PMC article does not contain protocol PubMed
- SMARTE-R-CHOP-14: Pfreundschuh M, Poeschel V, Zeynalova S, Hänel M, Held G, Schmitz N, Viardot A, Dreyling MH, Hallek M, Mueller C, Wiesen MH, Witzens-Harig M, Truemper L, Keller U, Rixecker T, Zwick C, Murawski N. Optimization of rituximab for the treatment of diffuse large B-cell lymphoma (II): extended rituximab exposure time in the SMARTE-R-CHOP-14 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group. J Clin Oncol. 2014 Dec 20;32(36):4127-33. Epub 2014 Nov 17. Erratum in: J Clin Oncol. 2015 Jun 10;33(17):1991. link to original article contains verified protocol PubMed
- Cortelazzo S, Tarella C, Gianni AM, Ladetto M, Barbui AM, Rossi A, Gritti G, Corradini P, Di Nicola M, Patti C, Mulé A, Zanni M, Zoli V, Billio A, Piccin A, Negri G, Castellino C, Di Raimondo F, Ferreri AJ, Benedetti F, La Nasa G, Gini G, Trentin L, Frezzato M, Flenghi L, Falorio S, Chilosi M, Bruna R, Tabanelli V, Pileri S, Masciulli A, Delaini F, Boschini C, Rambaldi A. Randomized trial comparing R-CHOP versus high-dose sequential chemotherapy in high-risk patients with diffuse large B-cell lymphomas. J Clin Oncol. 2016 Nov 20;34(33):4015-4022. Epub 2016 Oct 31. link to original article contains verified protocol PubMed
- DLCL04: Chiappella A, Martelli M, Angelucci E, Brusamolino E, Evangelista A, Carella AM, Stelitano C, Rossi G, Balzarotti M, Merli F, Gaidano G, Pavone V, Rigacci L, Zaja F, D'Arco A, Cascavilla N, Russo E, Castellino A, Gotti M, Congiu AG, Cabras MG, Tucci A, Agostinelli C, Ciccone G, Pileri SA, Vitolo U. Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study. Lancet Oncol. 2017 Aug;18(8):1076-1088. Epub 2017 Jun 28. link to original article contains protocol PubMed
- MabEase: Lugtenburg P, Avivi I, Berenschot H, Ilhan O, Marolleau JP, Nagler A, Rueda A, Tani M, Turgut M, Osborne S, Smith R, Pfreundschuh M. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica. 2017 Nov;102(11):1913-1922. Epub 2017 Sep 21. link to original article contains partial protocol link to PMC article PubMed
- Lamy T, Damaj G, Soubeyran P, Gyan E, Cartron G, Bouabdallah K, Gressin R, Cornillon J, Banos A, Le Du K, Benchalal M, Moles MP, Le Gouill S, Fleury J, Godmer P, Maisonneuve H, Deconinck E, Houot R, Laribi K, Marolleau JP, Tournilhac O, Branger B, Devillers A, Vuillez JP, Fest T, Colombat P, Costes V, Szablewski V, Béné MC, Delwail V; LYSA Group. R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma. Blood. 2018 Jan 11;131(2):174-181. Epub 2017 Oct 23. link to original article contains verified protocol PubMed
- PETAL: Dührsen U, Müller S, Hertenstein B, Thomssen H, Kotzerke J, Mesters R, Berdel WE, Franzius C, Kroschinsky F, Weckesser M, Kofahl-Krause D, Bengel FM, Dürig J, Matschke J, Schmitz C, Pöppel T, Ose C, Brinkmann M, La Rosée P, Freesmeyer M, Hertel A, Höffkes HG, Behringer D, Prange-Krex G, Wilop S, Krohn T, Holzinger J, Griesshammer M, Giagounidis A, Raghavachar A, Maschmeyer G, Brink I, Bernhard H, Haberkorn U, Gaska T, Kurch L, van Assema DME, Klapper W, Hoelzer D, Geworski L, Jöckel KH, Scherag A, Bockisch A, Rekowski J, Hüttmann A; PETAL Trial Investigators. Positron emission tomography-guided therapy of aggressive non-Hodgkin lymphomas (PETAL): a multicenter, randomized phase III trial. J Clin Oncol. 2018 Jul 10;36(20):2024-2034. Epub 2018 May 11. link to original article contains verified protocol in supplement PubMed
R-CHOP-14 (Prednisolone)
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R-CHOP-14: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisolone every 14 days
Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Cunningham et al. 2013 (UK NCRI R-CHOP14v21) | Phase III (E-esc) | R-CHOP-21 | Did not meet primary endpoint of OS |
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) as follows:
- Cycles 1 to 6: 750 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) as follows:
- Cycles 1 to 6: 50 mg/m2 IV once on day 1
- Vincristine (Oncovin) as follows:
- Cycles 1 to 6: 2 mg IV once on day 1
- Prednisolone (Millipred) as follows:
- Cycles 1 to 6: 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 (Zyloprim) 300 mg PO once per day during cycle 1
- Co-trimoxazole 480 mg (route not specified) twice per day on 3 days per week, taken throughout therapy, ending 2 weeks after treatment is completed
14-day cycle for 8 cycles
References
- UK NCRI R-CHOP14v21: 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-14 (Rituximab Hycela)
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R-CHOP-14: Rituximab hyaluronidaase, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone every 14 days
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Lugtenburg et al. 2017 (MabEase) | 2012-NR | Phase III (E-RT-switch-ic) | R-CHOP-14 | Might have superior CR rate |
Note: the details for CHOP-14 are not available in the manuscript or supplement; we have reproduced common CHOP-14 dosing, here. For patients achieving CR after cycle 4, the CHOP-14 could be omitted after cycle 6.
Chemotherapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once on day 1
- Rituximab and hyaluronidase human (Rituxan Hycela) as follows:
- Cycles 2 to 8: 1400 mg SC 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) 100 mg PO once per day on days 1 to 5
Supportive medications
- ONE of the following:
- Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 7 to 11
- Pegfilgrastim (Neulasta)
14-day cycle for 6 to 8 cycles
References
- MabEase: Lugtenburg P, Avivi I, Berenschot H, Ilhan O, Marolleau JP, Nagler A, Rueda A, Tani M, Turgut M, Osborne S, Smith R, Pfreundschuh M. Efficacy and safety of subcutaneous and intravenous rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone in first-line diffuse large B-cell lymphoma: the randomized MabEase study. Haematologica. 2017 Nov;102(11):1913-1922. Epub 2017 Sep 21. link to original article contains partial protocol link to PMC article PubMed
R-Hyper-CVAD/R-MA
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R-Hyper-CVAD/R-MA: Rituximab, Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone alternating with Rituximab, Methotrexate, Ara-C (Cytarabine)
Protocol
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Oki et al. 2013 (MDACC 2005-0054) | Randomized Phase II (E-esc) | R-CHOP | Seems to have increased CRR |
Intended for high-risk DLBCL (IPI greater than or equal to 3). The authors report "excellent outcome" in patients less than or equal to 45 years old, however patients greater than 45 years old had "unacceptable mortality."
Chemotherapy, part A (cycles 1, 3, 5)
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 300 mg/m2 IV every 12 hours on days 1 to 3 (total dose per cycle: 1800 mg/m2)
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once per day on days 5 & 12
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 5
- Dexamethasone (Decadron) 40 mg IV or PO once per day on days 2 to 5
Supportive medications
- Mesna (Mesnex) 600 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 1800 mg/m2)
- Filgrastim (Neupogen) or Pegfilgrastim (Neulasta) starting 24 to 48 hours after completion of chemotherapy
- Ciprofloxacin (Cipro) 500 mg PO twice per day for 10 days after chemotherapy
- Fluconazole (Diflucan) 100 mg PO once per day for 10 days after chemotherapy
- Valacyclovir (Valtrex) 500 mg PO once per day for 10 days after chemotherapy
Dose modifications
- Vincristine (Oncovin) reduced once by 50% for NCI common toxicity criteria Grade 2+ peripheral neuropathy, omitted if Grade 2+ peripheral neuropathy persists
- Doxorubicin (Adriamycin) and Cyclophosphamide (Cytoxan) reduced by 20% in subsequent A cycles if neutropenic fever occurs, grade 3/4 non-hematological toxicity, or ANC less than 750/uL or platelet count less than 75 × 109/L on day 21
Next cycle to start once ANC is greater than or equal to 1000/uL and platelet count is greater than or equal to 100 × 109/L.
Although the protocol does not specify, it is assumed that if these thresholds are not met by day 21, the next cycle will start with the dose reductions as specified.
Chemotherapy, part B (cycles 2, 4, 6)
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Methotrexate (MTX) 200 mg/m2 IV over 2 hours once on day 1, then 800 mg/m2 IV over 22 hours (total dose per cycle: 1000 mg/m2)
- Cytarabine (Ara-C) 3000 mg/m2 IV over 2 hours every 12 hours on days 3 & 4 (total dose per cycle: 12,000 mg/m2)
Supportive medications
- Folinic acid (Leucovorin) (dose/timing not specified) until serum methotrexate level less than 100 nmol/L
- Sodium bicarbonate 1300 mg PO twice per day until methotrexate level less than 100 nmol/L
- Filgrastim (Neupogen) or Pegfilgrastim (Neulasta) starting 24 to 48 hours after completion of chemotherapy
- Ciprofloxacin (Cipro) 500 mg PO twice per day for 10 days after chemotherapy
- Fluconazole (Diflucan) 100 mg PO once per day for 10 days after chemotherapy
- Valacyclovir (Valtrex) 500 mg PO once per day for 10 days after chemotherapy
Dose modifications
- Methotrexate (MTX) reduced by 25% in subsequent B cycles if neutropenic fever occurs, grade 3/4 non-hematological toxicity, or ANC less than 750/uL or platelet count less than 75 × 109/L on day 21
- Cytarabine (Ara-C) reduced by 33% in subsequent B cycles if neutropenic fever occurs, grade 3/4 non-hematological toxicity, or ANC less than 750/uL or platelet count less than 75 × 109/L on day 21
21-day cycles
CNS prophylaxis
"Recommended in patients with paraspinal disease, paranasal sinus disease, testicular disease, bone marrow disease, diffuse osseous disease or greater than or equal to 2 sites of extranodal disease. Actual administration of prophylactic intrathecal chemotherapy was at the treating physician's discretion."
References
- Oki Y, Westin JR, Vega F, Chuang H, Fowler N, Neelapu S, Hagemeister FB, McLaughlin P, Kwak LW, Romaguera JE, Fanale M, Younes A, Rodriguez MA, Orlowski RZ, Wang M, Ouzounian ST, Samaniego F, Fayad L. Prospective phase II study of rituximab with alternating cycles of hyper-CVAD and high-dose methotrexate with cytarabine for young patients with high-risk diffuse large B-cell lymphoma. Br J Haematol. 2013 Dec;163(5):611-20. Epub 2013 Oct 1. link to original article contains verified protocol link to PMC article PubMed
- Retrospective: Howlett C, Snedecor SJ, Landsburg DJ, Svoboda J, Chong EA, Schuster SJ, Nasta SD, Feldman T, Rago A, Walsh KM, Weber S, Goy A, Mato A. Front-line, dose-escalated immunochemotherapy is associated with a significant progression-free survival advantage in patients with double-hit lymphomas: a systematic review and meta-analysis. Br J Haematol. 2015 Aug;170(4):504-14. Epub 2015 Apr 24. link to original article PubMed
R-MegaCHOP-14
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R-MegaCHOP-14: Rituximab, "Mega" (high-dose) Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne every 14 days
Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Chiappella et al. 2017 (DLCL04) | Phase III (E-esc) | 1. R-CHOP-14 | Not reported |
2. R-CHOP-14, then R-MAD, then BEAM, then auto HSCT 3. R-MegaCHOP-14, then R-MAD, then BEAM, then auto HSCT |
Did not meet primary endpoint of FFS24 |
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 1200 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 70 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 days 1 to 5
14-day cycle for 6 cycles
References
- Chiappella A, Martelli M, Angelucci E, Brusamolino E, Evangelista A, Carella AM, Stelitano C, Rossi G, Balzarotti M, Merli F, Gaidano G, Pavone V, Rigacci L, Zaja F, D'Arco A, Cascavilla N, Russo E, Castellino A, Gotti M, Congiu AG, Cabras MG, Tucci A, Agostinelli C, Ciccone G, Pileri SA, Vitolo U. Rituximab-dose-dense chemotherapy with or without high-dose chemotherapy plus autologous stem-cell transplantation in high-risk diffuse large B-cell lymphoma (DLCL04): final results of a multicentre, open-label, randomised, controlled, phase 3 study. Lancet Oncol. 2017 Aug;18(8):1076-1088. Epub 2017 Jun 28. link to original article contains protocol PubMed
R-miniCEOP
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R-miniCEOP: Rituximab, mini, Cyclophosphamide, Epirubicin, O?? (vinblastine), Prednisone
Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Merli et al. 2012 (ANZINTER3) | Phase III (E-de-esc) | R-CHOP | Did not meet primary endpoint of EFS |
Chemotherapy
- 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 IV or PO 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 less than 11 g/dL.
21-day cycle for 6 cycles
Subsequent treatment
- Patients with initial bulky disease and/or partially responding sites received radiothearpy
References
- ANZINTER3: 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
Untreated, non-randomized or retrospective data
BR
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BR: Bendamustine, Rituximab
Regimen variant #1, 90 mg/m2
Study | Evidence |
---|---|
Park et al. 2016 (LCCC 1011) | Phase II |
Note: this dosing was intended for patients with ECOG PS = 3 at baseline.
Chemotherapy
- Bendamustine 90 mg/m2 IV once per day on days 1 & 2, given first on day 1
- Dose increased to 120 mg/m2 if ECOG PS improved to less than or equal to 2 after 3 cycles
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1, given second
21-day cycle for up to 8 cycles
Regimen variant #2, 120 mg/m2
Study | Evidence |
---|---|
Park et al. 2016 (LCCC 1011) | Phase II |
Chemotherapy
- Bendamustine 120 mg/m2 IV once per day on days 1 & 2, given first on day 1
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1, given second
21-day cycle for up to 8 cycles
References
- LCCC 1011: Park SI, Grover NS, Olajide O, Asch AS, Wall JG, Richards KL, Sobol AL, Deal AM, Ivanova A, Foster MC, Muss HB, Shea TC. A phase II trial of bendamustine in combination with rituximab in older patients with previously untreated diffuse large B-cell lymphoma. Br J Haematol. 2016 Oct;175(2):281-289. link to original article contains verified protocol link to PMC article PubMed
Helicobacter pylori eradication therapy
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Regimen variant #1, before 1996
Study | Evidence |
---|---|
Kuo et al. 2012 | Non-randomized |
Note: This regimen is intended for the treatment of gastric DLBCL only; H. pylori eradication would not be an appropriate treatment for systemic DLBCL.
Antibiotic therapy
- Amoxicillin 500 mg PO every 6 hours
- Metronidazole (Flagyl) 250 mg PO every 6 hours
- One of the following:
- Bismuth subcitrate 120 mg PO every 6 hours
- Omeprazole (Prilosec) 20 mg PO twice per day
28-day course
Regimen variant #2, after 1996
Study | Evidence |
---|---|
Kuo et al. 2012 | Non-randomized |
Note: This regimen is intended for the treatment of gastric DLBCL only; H. pylori eradication would not be an appropriate treatment for systemic DLBCL.
Antibiotic therapy
- Amoxicillin 500 mg PO every 6 hours
- Clarithromycin (Biaxin) 500 mg PO twice per day
- Omeprazole (Prilosec) 20 mg PO twice per day
14-day course
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. Epub 2012 Mar 7. link to original article PubMed
O-miniCHOP
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O-miniCHOP: Ofatumumab, reduced-dose (mini) Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne
Regimen
Study | Evidence |
---|---|
Peyrade et al. 2017 (LYSA LNH09-7B) | Phase II |
Preceding treatment
Chemotherapy
- Ofatumumab (Arzerra) 1000 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 400 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 25 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1 mg IV once on day 1
- Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
Supportive medications
- Acetaminophen (Tylenol) 1000 mg PO once on day 1, prior to Ofatumumab (Arzerra)
- Diphenhydramine (Benadryl) 50 mg (route not specified) once on day 1, prior to Ofatumumab (Arzerra)
21-day cycle for 6 cycles
References
- Peyrade F, Bologna S, Delwail V, Emile JF, Pascal L, Fermé C, Schiano JM, Coiffier B, Corront B, Farhat H, Fruchart C, Ghesquieres H, Macro M, Tilly H, Choufi B, Delarue R, Fitoussi O, Gabarre J, Haioun C, Jardin F. Combination of ofatumumab and reduced-dose CHOP for diffuse large B-cell lymphomas in patients aged 80 years or older: an open-label, multicentre, single-arm, phase 2 trial from the LYSA group. Lancet Haematol. 2017 Jan;4(1):e46-e55. link to original article contains protocol PubMed
R-BL
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R-BL: Rituximab, Bendamustine, Lenalidomide
Regimen
Study | Evidence | Efficacy |
---|---|---|
Hitz et al. 2016 (SAKK 38/08) | Phase II, <20 pts in subgroup | ORR: 61% (95% CI 45-76%) |
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Bendamustine 70 mg/m2 IV once per day on days 1 & 2
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
28-day cycle for 6 cycles
References
- Hitz F, Zucca E, Pabst T, Fischer N, Cairoli A, Samaras P, Caspar CB, Mach N, Krasniqi F, Schmidt A, Rothermundt C, Enoiu M, Eckhardt K, Berardi Vilei S, Rondeau S, Mey U. Rituximab, bendamustine and lenalidomide in patients with aggressive B-cell lymphoma not eligible for anthracycline-based therapy or intensive salvage chemotherapy - SAKK 38/08. Br J Haematol. 2016 Jul;174(2):255-63. Epub 2016 Mar 28. link to original article contains protocol PubMed
R-CDOP
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R-CDOP: Rituximab, Cyclophosphamide, Doxil (Pegylated liposomal doxorubicin), Oncovin (Vincristine), Prednisone
DRCOP: Doxil (Pegylated liposomal doxorubicin), Rituximab, Cyclophosphamide, Oncovin (Vincristine), Prednisone
Regimen variant #1
Study | Evidence |
---|---|
Oki et al. 2014 (MDACC 2004-0305) | Phase II |
Chemotherapy
- Pegylated liposomal doxorubicin (Doxil) 40 mg/m2 (maximum dose of 90 mg) IV over 60 minutes once on day 1
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Vincristine (Oncovin) 2 mg IV once on day 1
- Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
Supportive medications
- Filgrastim (Neupogen) 5 mcg/kg SC once per day from day 2 until ANC greater than 3000/μl
OR
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2
Dose modifications
- Dose reduction level 1 (see paper for triggers):
- Pegylated liposomal doxorubicin (Doxil) reduced to 35 mg/m2
- Cyclophosphamide (Cytoxan) reduced to 600 mg/m2
- Dose reduction level 2 (see paper for triggers):
- Pegylated liposomal doxorubicin (Doxil) reduced to 30 mg/m2
- Cyclophosphamide (Cytoxan) reduced to 450 mg/m2
21-day cycle for 6 to 8 cycles
Regimen variant #2
Study | Evidence |
---|---|
Zaja et al. 2006 | 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.
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Pegylated liposomal doxorubicin (Doxil) 30 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) 100 mg PO once per day on days 1 to 5
21-day cycle for 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
- MDACC 2004-0305: Oki Y, Ewer MS, Lenihan DJ, Fisch MJ, Hagemeister FB, Fanale M, Romaguera J, Pro B, Fowler N, Younes A, Astrow AB, Huang X, Kwak LW, Samaniego F, McLaughlin P, Neelapu SS, Wang M, Fayad LE, Durand JB, Rodriguez MA. Pegylated liposomal doxorubicin replacing conventional doxorubicin in standard R-CHOP chemotherapy for elderly patients with diffuse large B-cell lymphoma: an open label, single arm, phase II trial. Clin Lymphoma Myeloma Leuk. 2015 Mar;15(3):152-8. Epub 2014 Sep 28. link to original article contains verified protocol link to PMC article PubMed
R-CEOP90 (Epirubicin)
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R-CEOP90: Rituximab, Cyclophosphamide, Epirubicin (90 mg/m2 dosing), Oncovin (Vincristine), Prednisone
Regimen variant #1, 4 cycles
Study | Evidence |
---|---|
Cai et al. 2014 | Phase II |
This regimen is intended to reduce cardiotoxicity and was not just for patients with contraindicated doxorubicin. Note that the cycle length is not explicitly defined in the paper but was reported as a median of 21 days (range 21 to 33 days).
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 2
- Epirubicin (Ellence) 90 mg/m2 IV once on day 2
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 2
- Prednisolone (Millipred) 100 mg/day PO on days 2 to 6
21-day cycle for 4 cycles
Subsequent treatment
- Patients with stage IA or IIA disease with bulky disease and extranodal and residual masses: IFRT, 30 to 45 Gy
Regimen variant #2, 6 cycles
Study | Evidence |
---|---|
Cai et al. 2014 | Phase II |
This regimen is intended to reduce cardiotoxicity and was not just for patients with contraindicated doxorubicin. Note that the cycle length is not explicitly defined in the paper but was reported as a median of 21 days (range 21 to 33 days).
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 2
- Epirubicin (Ellence) 90 mg/m2 IV once on day 2
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 2
- Prednisolone (Millipred) 100 mg/day PO on days 2 to 6
'21-day cycle for 6 cycles
References
- Cai QC, Gao Y, Wang XX, Cai QQ, Lin ZX, Bai B, Guo Y, Huang HQ. Long-term results of the R-CEOP90 in the treatment of young patients with chemotherapy-naïve diffuse large B cell lymphoma: a phase II study. Leuk Lymphoma. 2014 Oct;55(10):2387-8. link to original article contains verified protocol PubMed
R-CEOP (Etoposide)
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R-CEOP: Rituximab, Cyclophosphamide, Etoposide, Oncovin (Vincristine), Prednisone
Regimen
Study | Evidence |
---|---|
Moccia et al. 2009 | 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.
Chemotherapy
- 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, then 100 mg/m2 PO once per day on days 2 & 3
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) 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 cycle for 3 to 4 cycles +/- radiation therapy for patients with limited stage disease; 6 cycles for patients with advanced stage disease
References
- Retrospective: Abstract: 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
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R-CHMP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Marqibo (Vincristine liposomal), Prednisone
Regimen variant #1, 3 cycles
Study | Evidence |
---|---|
Hagemeister et al. 2013 | Phase II |
This regimen was intended for stage I patients with no LN greater than 5 cm.
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Pegylated liposomal doxorubicin (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 cycle for 3 cycles
Subsequent treatment
Regimen variant #2, 6 cycles
Study | Evidence |
---|---|
Hagemeister et al. 2013 | Phase II |
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Pegylated liposomal doxorubicin (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 cycle for 6 cycles
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-GCVP
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R-GCVP: Rituximab, Gemcitabine, Cyclophosphamide, Vincristine, Prednisolone
Regimen
Study | Evidence |
---|---|
Fields et al. 2013 (UCL/05/154) | Phase II |
Intended for use in patients unlikely to tolerate anthracyclines due to cardiac comorbidity.
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) as follows:
- Cycle 1: 750 mg/m2 IV over 30 minutes once per day on days 1 & 8
- Cycle 2: 875 mg/m2 IV over 30 minutes once per day on days 1 & 8
- Cycles 3 to 6: 1000 mg/m2 IV over 30 minutes once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) IV once on day 1
- Prednisolone (Millipred) 100 mg PO once per day on days 1 to 5
Supportive medications
- Acetaminophen (Tylenol) 1000 mg (route not specified) once on day 1, prior to Rituximab (Rituxan)
- Chlorpheniramine (Chlor-Trimeton) 10 mg IV once on day 1, prior to Rituximab (Rituxan)
- Pegfilgrastim (Neulasta) 6 mg SC once on day 9
CNS prophylaxis
- Methotrexate (MTX) 12.5 mg IT x 3 cycles (timing not specified) for patients at high risk of CNS relapse
21-day cycle for 6 cycles
References
- UCL/05/154: Fields PA, Townsend W, Webb A, Counsell N, Pocock C, Smith P, Jack A, El-Mehidi N, Johnson PW, Radford J, Linch DC, Cunningham D. De novo treatment of diffuse large B-cell lymphoma with rituximab, cyclophosphamide, vincristine, gemcitabine, and prednisolone in patients with cardiac comorbidity: a United kingdom national cancer research institute trial. J Clin Oncol. 2014 Feb 1;32(4):282-7. Epub 2013 Nov 12. link to original article contains verified protocol PubMed
R-MegaCHOP
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R-MegaCHOP: Rituximab, Mega, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne
Regimen
Study | Evidence |
---|---|
Pardal et al. 2014 (GELTAMO-2006) | Phase II |
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 1500 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) 60 mg/m2 PO once per day on days 1 to 5
Supportive medications
- Pegfilgrastim (Neulasta) given after each cycle
21-day cycle for 3 cycles
Subsequent treatment
- Negative PET-CT after 3 cycles: another 3 cycles of R-MegaCHOP for a total of 6 cycles
- Positive PET-CT after 3 cycles: R-IFE
References
- GELTAMO-2006: Pardal E, Coronado M, Martín A, Grande C, Marín-Niebla A, Panizo C, Bello JL, Conde E, Hernández MT, Arranz R, Bargay J, González-Barca E, Pérez-Ceballos E, Montes-Moreno S, Caballero MD. Intensification treatment based on early FDG-PET in patients with high-risk diffuse large B-cell lymphoma: a phase II GELTAMO trial. Br J Haematol. 2014 Nov;167(3):327-36. Epub 2014 Jul 28. link to original article contains verified protocol PubMed
R-miniCHOP
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R-miniCHOP: Rituximab, reduced-dose (mini) Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne
Regimen
Study | Evidence |
---|---|
Peyrade et al. 2011 | Phase II |
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 400 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 25 mg/m2 IV once on day 1
- Vincristine (Oncovin) 1 mg IV once on day 1
- Prednisone (Sterapred) 40 mg/m2 PO once per day on days 1 to 5
- No dose adjustments for hematologic toxicity. If needed, the subsequent R-miniCHOP cycle was postponed until ANC was greater than or equal to 1000/uL and platelet count was greater than or equal to 100 x 109/L, with a maximum of 28 days between cycles. Treatment was stopped if patients' counts were not adequate within 28 days.
Supportive medications
- "Prevention of tumour lysis syndrome by alkalinisation or hypouricaemic drugs was done if necessary."
- Serotonin (5-HT3) antagonist given every cycle.
- Prophylactic G-CSF or erythropoietin was left to treating physician's discretion.
- Patients with severe neutropenia or neutropenic fever received G-CSF (dose not specified) SC once per day on days 6 to 13 of the subsequent cycle until ANC is greater than or equal to 1000/uL.
21-day cycle for 6 cycles
References
- Peyrade F, Jardin F, Thieblemont C, Thyss A, Emile JF, Castaigne S, Coiffier B, Haioun C, Bologna S, Fitoussi O, Lepeu G, Fruchart C, Bordessoule D, Blanc M, Delarue R, Janvier M, Salles B, André M, Fournier M, Gaulard P, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte (GELA) investigators. Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2011 May;12(5):460-8. link to original article contains verified protocol PubMed
R2CHOP
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R2CHOP: Rituximab, Revlimid (Lenalidomide), Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne
LR-CHOP-21: Lenalidomide, Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Predniso(lo)ne given every 21 days
Regimen variant #1, len 15 mg/day for 14 d/cycle
Study | Evidence | Efficacy |
---|---|---|
Vitolo et al. 2014 (REAL07) | Phase II | ORR: 92% (95% CI 81–97) |
Note: CNS prophylaxis was offered to "at risk" patients.
Chemotherapy
- Lenalidomide (Revlimid) 15 mg PO once per day on days 1 to 14
- 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) as follows:
- Cycles 1 to 4: 12 mg IT once on day 1
Supportive medications
- Granulocyte colony-stimulating factors (dose/duration not specified)
- Low-molecular-weight heparins (dose/duration not specified)
- PCP prophylaxis with one of the following:
- Trimethoprim-Sulfamethoxazole (Bactrim DS) (dose/duration not specified)
- Pentamidine (Nebupent) (dose/duration not specified)
- Carriers of hepatitis B virus: Lamivudine (Epivir) (dose/duration not specified)
21-day cycle for 6 cycles
Regimen variant #2, len 25 mg/day for 10 d/cycle
Study | Evidence | Efficacy |
---|---|---|
Nowakowski et al. 2014 (Mayo Clinic MC078E) | Phase II | ORR: 98% |
Chemotherapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 10
- 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) 100 mg/m2 PO once per day on days 1 to 5
Supportive medications
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2
- Aspirin 81 mg PO once per day unless on therapeutic dose Warfarin (Coumadin) or low molecular weight heparin
21-day cycle for up to 6 cycles
References
- REAL07: Vitolo U, Chiappella A, Franceschetti S, Carella AM, Baldi I, Inghirami G, Spina M, Pavone V, Ladetto M, Liberati AM, Molinari AL, Zinzani P, Salvi F, Fattori PP, Zaccaria A, Dreyling M, Botto B, Castellino A, Congiu A, Gaudiano M, Zanni M, Ciccone G, Gaidano G, Rossi G; Fondazione Italiana Linfomi. Lenalidomide plus R-CHOP21 in elderly patients with untreated diffuse large B-cell lymphoma: results of the REAL07 open-label, multicentre, phase 2 trial. Lancet Oncol. 2014 Jun;15(7):730-7. Epub 2014 May 12. link to original article contains verified protocol PubMed
- Mayo Clinic MC078E: Nowakowski GS, LaPlant B, Macon WR, Reeder CB, Foran JM, Nelson GD, Thompson CA, Rivera CE, Inwards DJ, Micallef IN, Johnston PB, Porrata LF, Ansell SM, Gascoyne RD, Habermann TM, Witzig TE. Lenalidomide combined with R-CHOP overcomes negative prognostic impact of non-germinal center B-cell phenotype in newly diagnosed diffuse large B-cell lymphoma: a phase II study. J Clin Oncol. 2015 Jan 20;33(3):251-7. Epub 2014 Aug 18. link to original article contains verified protocol PubMed
Consolidation after upfront therapy
CBV, then auto HSCT
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Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Stiff et al. 2013 (SWOG S9704) | Phase III (E-esc) | R-CHOP x 8 | Superior PFS |
Preceding treatment
- R-CHOP x 6
Autologous HSCT conditioning regimens
References
- SWOG S9704: Stiff PJ, Unger JM, Cook JR, Constine LS, Couban S, Stewart DA, Shea TC, Porcu P, Winter JN, Kahl BS, Miller TP, Tubbs RR, Marcellus D, Friedberg JW, Barton KP, Mills GM, LeBlanc M, Rimsza LM, Forman SJ, Fisher RI. Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med. 2013 Oct 31;369(18):1681-90. link to original article link to PMC article PubMed
- Subgroup analysis: Puvvada SD, Stiff PJ, Leblanc M, Cook JR, Couban S, Leonard JP, Kahl B, Marcellus D, Shea TC, Winter JN, Li H, Rimsza LM, Friedberg JW, Smith SM. Outcomes of MYC-associated lymphomas after R-CHOP with and without consolidative autologous stem cell transplant: subset analysis of randomized trial intergroup SWOG S9704. Br J Haematol. 2016 Sep;174(5):686-91. Epub 2016 Apr 13. link to original article link to PMC article PubMed
CBVM, then auto HSCT
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Regimen
Study | Evidence |
---|---|
Haioun et al. 2009 (LNH 98-3) | Non-randomized portion of RCT |
Preceding treatment
Chemotherapy
Stem cells reinfused afterwards (unclear which day)
Subsequent treatment
- Observation versus rituximab maintenance
References
- LNH 98-3: Haioun C, Mounier N, Emile JF, Ranta D, Coiffier B, Tilly H, Récher C, Fermé C, Gabarre J, Herbrecht R, Morchhauser F, Gisselbrecht C. Rituximab versus observation after high-dose consolidative first-line chemotherapy with autologous stem-cell transplantation in patients with poor-risk diffuse large B-cell lymphoma. Ann Oncol. 2009 Dec;20(12):1985-92. Epub 2009 Jun 30. link to original article contains verified protocol PubMed
Cytarabine monotherapy
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Regimen
Study | Evidence |
---|---|
Récher et al. 2011 (LNH03-2B) | Non-randomized portion of RCT |
Ketterer et al. 2013 (LNH03-1B) | Non-randomized portion of RCT |
Preceding treatment
Chemotherapy
- Cytarabine (Ara-C) 100 mg/m2 SC once per day on days 1 to 4
14-day cycle for 2 cycles
References
- LNH03-2B: 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
- Subgroup analysis: Molina TJ, Canioni D, Copie-Bergman C, Recher C, Brière J, Haioun C, Berger F, Fermé C, Copin MC, Casasnovas O, Thieblemont C, Petrella T, Leroy K, Salles G, Fabiani B, Morschauser F, Mounier N, Coiffier B, Jardin F, Gaulard P, Jais JP, Tilly H. Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d'Etudes des Lymphomes de l'Adulte/lymphoma study association phase III trial LNH 03-2B. J Clin Oncol. 2014 Dec 10;32(35):3996-4003. Epub 2014 Nov 10. link to original article PubMed
- LNH03-1B: Ketterer N, Coiffier B, Thieblemont C, Fermé C, Brière J, Casasnovas O, Bologna S, Christian B, Connerotte T, Récher C, Bordessoule D, Fruchart C, Delarue R, Bonnet C, Morschhauser F, Anglaret B, Soussain C, Fabiani B, Tilly H, Haioun C. Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol. 2013 Apr;24(4):1032-7. Epub 2012 Dec 12. link to original article PubMed
Ibritumomab tiuxetan protocol
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Regimen variant #1, no cap
Study | Evidence |
---|---|
Witzig et al. 2015 (ECOG E3402) | Phase II |
Preceding treatment
- R-CHOP x 4 to 6
Radioimmunotherapy
- Rituximab (Rituxan) 250 mg/m2 IV once per day on days 1 & 8
- Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 14.8 MBq/kg IV once on day 8
8-day course
Subsequent treatment
- Patients with CT or PET positive disease 12 weeks after radioimmunotherapy: 30 Gy of IFRT
Regimen variant #2, capped dose
Study | Evidence |
---|---|
Persky et al. 2014 (SWOG S0313) | Phase II |
Preceding treatment
Radioimmunotherapy
- Rituximab (Rituxan) 250 mg/m2 IV once per day on days 1 & 8 +/- 1 day, given first on day 7, 8, or 9
- Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day 8 +/- 1 day, given second, within 4 hours of rituximab
References
- SWOG S0313: Persky DO, Miller TP, Unger JM, Spier CM, Puvvada S, Stea BD, Press OW, Constine LS, Barton KP, Friedberg JW, LeBlanc M, Fisher RI. Ibritumomab consolidation after 3 cycles of CHOP plus radiotherapy in high-risk limited-stage aggressive B-cell lymphoma: SWOG S0313. Blood. 2015 Jan 8;125(2):236-41. Epub 2014 Nov 13. link to original article contains verified protocol link to PMC article PubMed
- ECOG E3402: Witzig TE, Hong F, Micallef IN, Gascoyne RD, Dogan A, Wagner H Jr, Kahl BS, Advani RH, Horning SJ. A phase II trial of RCHOP followed by radioimmunotherapy for early stage (stages I/II) diffuse large B-cell non-Hodgkin lymphoma: ECOG3402. Br J Haematol. 2015 Sep;170(5):679-86. Epub 2015 May 14. link to original article contains verified protocol link to PMC article PubMed
Methotrexate monotherapy
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Regimen
Study | Evidence |
---|---|
Récher et al. 2011 (LNH03-2B) | Non-randomized portion of RCT |
Ketterer et al. 2013 (LNH03-1B) | Non-randomized portion of RCT |
Preceding treatment
Chemotherapy
- Methotrexate (MTX) 3000 mg/m2 IV once on day 1
Supportive medications
14-day cycle for 2 cycles
Subsequent treatment
- REI consolidation, in 2 weeks
References
- LNH03-2B: 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
- Subgroup analysis: Molina TJ, Canioni D, Copie-Bergman C, Recher C, Brière J, Haioun C, Berger F, Fermé C, Copin MC, Casasnovas O, Thieblemont C, Petrella T, Leroy K, Salles G, Fabiani B, Morschauser F, Mounier N, Coiffier B, Jardin F, Gaulard P, Jais JP, Tilly H. Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d'Etudes des Lymphomes de l'Adulte/lymphoma study association phase III trial LNH 03-2B. J Clin Oncol. 2014 Dec 10;32(35):3996-4003. Epub 2014 Nov 10. link to original article PubMed
- LNH03-1B: Ketterer N, Coiffier B, Thieblemont C, Fermé C, Brière J, Casasnovas O, Bologna S, Christian B, Connerotte T, Récher C, Bordessoule D, Fruchart C, Delarue R, Bonnet C, Morschhauser F, Anglaret B, Soussain C, Fabiani B, Tilly H, Haioun C. Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol. 2013 Apr;24(4):1032-7. Epub 2012 Dec 12. link to original article PubMed
Radiation therapy
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Regimen variant #1, testicular irradiation
Study | Evidence |
---|---|
Vitolo et al. 2011 (IELSG-10) | Phase II |
Preceding treatment
- R-CHOP x 6 to 8 cycles
Radiotherapy
- External beam radiotherapy 25 to 30 Gy to the contralateral testis. For patients with stage II disease, involved-field radiation therapy was added; see paper for details.
Regimen variant #2, IFRT x 30 Gy
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Horning et al. 2004 (ECOG E1484) | Phase III (E-esc) | Observation | Seems to have superior DFS |
Preceding treatment
- ECOG E1484: CHOP x 8, with CR
Radiotherapy
- IFRT 30 Gy
Regimen variant #3, 36 Gy
Study | Evidence |
---|---|
Pfreundschuh et al. 2004 (NHL-B2) | Non-randomized portion of RCT |
Pfreundschuh et al. 2008 (RICOVER-60) | Non-randomized portion of RCT |
Schmitz et al. 2012 (DSHNHL 2002-1) | Non-randomized portion of RCT |
Pfreundschuh et al. 2014 (SMARTE-R-CHOP-14) | Phase II |
Preceding treatment
- NHL-B2: CHOEP-14 x 6 versus CHOEP-21 x 6 versus CHOP-14 x 6 versus CHOP-21 x 6
- RICOVER-60: CHOP-14 x 6 versus CHOP-14 x 8 versus R-CHOP-14 x 6 versus R-CHOP-14 x 8
- DSHNHL 2002-1: R-CHOEP-14 x 8 versus R-MegaCHOEP
- SMARTE-R-CHOP-14: R-CHOP-14 x 6
Radiotherapy
- External beam radiotherapy 36 Gy in daily fractions
Regimen variant #4, IFRT x 40 Gy
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Horning et al. 2004 (ECOG E1484) | Non-randomized portion of RCT | ||
Bonnet et al. 2007 | Phase III (C) | Observation | Did not meet primary endpoint of EFS |
Persky et al. 2014 (SWOG S0313) | Phase II | ||
Lamy et al. 2017 (LYSA/GOELAMS 02-03) | Phase III (C) | Observation | Non-inferior EFS |
Preceding treatment
- ECOG E1484: CHOP x 8, with PR
- SWOG S0313: CHOP x 3, with CR
- Bonnet et al. 2007: CHOP x 4
- LYSA/GOELAMS 02-03: R-CHOP-14 x 4 to 6
Radiotherapy
- External beam radiotherapy 40 Gy in daily fractions of 1.80 to 2.00 Gy
Subsequent treatment
- SWOG S0313: Ibritumomab tiuxetan consolidation
Regimen variant #5, IFRT x 40 to 55 Gy
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Miller et al. 1998 (SWOG S8736) | Phase III (E-switch-ooc) | See link | See link |
Pfreundschuh et al. 2006 (NCIC CTG LY.9) | Non-randomized portion of RCT | ||
Persky et al. 2008 (SWOG S0014) | Phase II | ||
Persky et al. 2014 (SWOG S0313) | Phase II |
Note: these studies did not specify an exact dose; see papers for details.
Preceding treatment
- SWOG S8736 and SWOG S0014: CHOP x 3
- NCIC CTG LY.9: CHOP-like therapy x 6 versus R-CHOP-like therapy x 6
- SWOG S0313: CHOP x 3, with PR
Radiotherapy
- External beam radiotherapy 46 to 50 Gy in daily fractions of 1.80 to 2.00 Gy
Subsequent treatment
- SWOG S0313: Ibritumumoab tiuxetan consolidation
References
- SWOG S8736: 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
- Update: Stephens DM, Li H, LeBlanc ML, Puvvada SD, Persky D, Friedberg JW, Smith SM. Continued risk of relapse independent of treatment modality in limited-stage diffuse large B-cell lymphoma: Final and long-term analysis of Southwest Oncology Group study S8736. J Clin Oncol. 2016 Sep 1;34(25):2997-3004. Epub 2016 Jul 5. link to original article link to PMC article PubMed
- NHL-B2: 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
- ECOG E1484: Horning SJ, Weller E, Kim K, Earle JD, O'Connell MJ, Habermann TM, Glick JH. Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin's lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol. 2004 Aug 1;22(15):3032-8. Epub 2004 Jun 21. link to original article PubMed
- LNH 93-01: Reyes F, Lepage E, Ganem G, Molina TJ, Brice P, Coiffier B, Morel P, Ferme C, Bosly A, Lederlin P, Laurent G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte (GELA). ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med. 2005 Mar 24;352(12):1197-205. link to original article PubMed
- NCIC CTG LY.9: 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 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 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 verified protocol PubMed
- RICOVER-60: 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
- SWOG S0014: 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 does not contain protocol PubMed
- IELSG-10: Vitolo U, Chiappella A, Ferreri AJ, Martelli M, Baldi I, Balzarotti M, Bottelli C, Conconi A, Gomez H, Lopez-Guillermo A, Martinelli G, Merli F, Novero D, Orsucci L, Pavone V, Ricardi U, Storti S, Gospodarowicz MK, Cavalli F, Sarris AH, Zucca E. First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximab-CHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international phase II trial. J Clin Oncol. 2011 Jul 10;29(20):2766-72. Epub 2011 Jun 6. link to original article contains verified protocol PubMed
- DSHNHL 2002-1: Schmitz N, Nickelsen M, Ziepert M, Haenel M, Borchmann P, Schmidt C, Viardot A, Bentz M, Peter N, Ehninger G, Doelken G, Ruebe C, Truemper L, Rosenwald A, Pfreundschuh M, Loeffler M, Glass B; for the German High-Grade Lymphoma Study Group (DSHNHL). Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1). Lancet Oncol. 2012 Dec;13(12):1250-1259. Epub 2012 Nov 16. link to original article PubMed
- SWOG S0313: Persky DO, Miller TP, Unger JM, Spier CM, Puvvada S, Stea BD, Press OW, Constine LS, Barton KP, Friedberg JW, LeBlanc M, Fisher RI. Ibritumomab consolidation after 3 cycles of CHOP plus radiotherapy in high-risk limited-stage aggressive B-cell lymphoma: SWOG S0313. Blood. 2015 Jan 8;125(2):236-41. Epub 2014 Nov 13. link to original article contains verified protocol link to PMC article PubMed
- SMARTE-R-CHOP-14: Pfreundschuh M, Poeschel V, Zeynalova S, Hänel M, Held G, Schmitz N, Viardot A, Dreyling MH, Hallek M, Mueller C, Wiesen MH, Witzens-Harig M, Truemper L, Keller U, Rixecker T, Zwick C, Murawski N. Optimization of rituximab for the treatment of diffuse large B-cell lymphoma (II): extended rituximab exposure time in the SMARTE-R-CHOP-14 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group. J Clin Oncol. 2014 Dec 20;32(36):4127-33. Epub 2014 Nov 17. Erratum in: J Clin Oncol. 2015 Jun 10;33(17):1991. link to original article contains verified protocol PubMed
- LYSA/GOELAMS 02-03: Lamy T, Damaj G, Soubeyran P, Gyan E, Cartron G, Bouabdallah K, Gressin R, Cornillon J, Banos A, Le Du K, Benchalal M, Moles MP, Le Gouill S, Fleury J, Godmer P, Maisonneuve H, Deconinck E, Houot R, Laribi K, Marolleau JP, Tournilhac O, Branger B, Devillers A, Vuillez JP, Fest T, Colombat P, Costes V, Szablewski V, Béné MC, Delwail V; LYSA Group. R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma. Blood. 2018 Jan 11;131(2):174-181. Epub 2017 Oct 23. link to original article contains verified protocol PubMed
R-IFE
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R-IFE: Rituximab, IFosfamide, Etoposide
REI: Rituximab, Etoposide, Ifosfamide
Regimen
Study | Evidence |
---|---|
Récher et al. 2011 (LNH03-2B) | Non-randomized portion of RCT |
Ketterer et al. 2013 (LNH03-1B) | Non-randomized portion of RCT |
Preceding treatment
Chemotherapy
- 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 cycle for 4 cycles
Subsequent treatment
- Cytarabine consolidation, in 2 weeks
References
- LNH03-2B: 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
- Subgroup analysis: Molina TJ, Canioni D, Copie-Bergman C, Recher C, Brière J, Haioun C, Berger F, Fermé C, Copin MC, Casasnovas O, Thieblemont C, Petrella T, Leroy K, Salles G, Fabiani B, Morschauser F, Mounier N, Coiffier B, Jardin F, Gaulard P, Jais JP, Tilly H. Young patients with non-germinal center B-cell-like diffuse large B-cell lymphoma benefit from intensified chemotherapy with ACVBP plus rituximab compared with CHOP plus rituximab: analysis of data from the Groupe d'Etudes des Lymphomes de l'Adulte/lymphoma study association phase III trial LNH 03-2B. J Clin Oncol. 2014 Dec 10;32(35):3996-4003. Epub 2014 Nov 10. link to original article PubMed
- LNH03-1B: Ketterer N, Coiffier B, Thieblemont C, Fermé C, Brière J, Casasnovas O, Bologna S, Christian B, Connerotte T, Récher C, Bordessoule D, Fruchart C, Delarue R, Bonnet C, Morschhauser F, Anglaret B, Soussain C, Fabiani B, Tilly H, Haioun C. Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol. 2013 Apr;24(4):1032-7. Epub 2012 Dec 12. link to original article PubMed
TBI, then auto HSCT
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Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Stiff et al. 2013 (SWOG S9704) | Phase III (E-esc) | R-CHOP x 8 | Superior PFS |
Preceding treatment
- R-CHOP x 6
Autologous HSCT conditioning regimens Stem cells reinfused on day 0
References
- SWOG S9704: Stiff PJ, Unger JM, Cook JR, Constine LS, Couban S, Stewart DA, Shea TC, Porcu P, Winter JN, Kahl BS, Miller TP, Tubbs RR, Marcellus D, Friedberg JW, Barton KP, Mills GM, LeBlanc M, Rimsza LM, Forman SJ, Fisher RI. Autologous transplantation as consolidation for aggressive non-Hodgkin's lymphoma. N Engl J Med. 2013 Oct 31;369(18):1681-90. link to original article link to PMC article PubMed
- Subgroup analysis: Puvvada SD, Stiff PJ, Leblanc M, Cook JR, Couban S, Leonard JP, Kahl B, Marcellus D, Shea TC, Winter JN, Li H, Rimsza LM, Friedberg JW, Smith SM. Outcomes of MYC-associated lymphomas after R-CHOP with and without consolidative autologous stem cell transplant: subset analysis of randomized trial intergroup SWOG S9704. Br J Haematol. 2016 Sep;174(5):686-91. Epub 2016 Apr 13. link to original article link to PMC article PubMed
Z-BEAM, then auto HSCT
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Z-BEAM: Zevalin (Ibritumomab tiuxetan), BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan
Regimen variant #1
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Shimoni et al. 2012 (SHEBA-07-4466-AN-CTIL) | Randomized Phase II (E-esc) | BEAM | Seems to have superior OS |
Briones et al. 2013 (GELTAMO Z-BEAM LDCGB) | Phase II |
Targeted therapy
- Rituximab (Rituxan) 250 mg/m2 IV once on day -14, given first
Radioconjugate therapy
- Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day -14, given second
Chemotherapy
- Carmustine (BCNU) 300 mg/m2 IV once on day -6
- Etoposide (Vepesid) 200 mg/m2 IV once per day on days -5 to -2
- Cytarabine (Ara-C) 200 mg/m2 IV every 12 hours on days -5 to -2
- Melphalan (Alkeran) 140 mg/m2 IV once on day -1
Supportive therapy
- Autologous stem cells re-infused on day 0
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day +4 (Shimoni et al. 2012) or day +7 (GELTAMO Z-BEAM LDCGB) until engraftment
- Valacyclovir (Valtrex) (dose not specified) for one month (Shimoni et al. 2012)
- Acyclovir (Zovirax) (dose not specified) for one month (Briones et al. 2013)
- Trimethoprim-Sulfamethoxazole (Bactrim DS) (dose/frequency not specified) for six months (3 months in GELTAMO Z-BEAM LDCGB)
One course
Regimen variant #2
Study | Evidence |
---|---|
Fruchart et al. 2014 (ZBEAM2) | Phase II |
Preceding treatment
Targeted therapy
- Rituximab (Rituxan) 250 mg/m2 IV once per day on days -21 & -14, given first on day -14
Radioconjugate therapy
- Ibritumomab tiuxetan & Yttrium-90 (Zevalin) by the following laboratory-based criteria:
- Platelet count 150 x 109/L or more: 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day -14, given second
- Platelet count 100 up to 150 x 109/L: 0.3 mCi/kg (maximum dose of 32 mCi) IV once on day -14, given second
Chemotherapy
- Carmustine (BCNU) 300 mg/m2 IV once on day -7
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days -6 to -3
- Cytarabine (Ara-C) 200 mg/m2 IV every 12 hours on days -6 to -3
- Melphalan (Alkeran) 140 mg/m2 IV once on day -2
Supportive therapy
- Autologous stem cells re-infused on day 0
- "According to standard use"
One course
References
- Shimoni A, Zwas ST, Oksman Y, Hardan I, Shem-Tov N, Yerushalmi R, Avigdor A, Ben-Bassat I, Nagler A. Yttrium-90-ibritumomab tiuxetan (Zevalin) combined with high-dose BEAM chemotherapy and autologous stem cell transplantation for chemo-refractory aggressive non-Hodgkin's lymphoma. Exp Hematol. 2007 Apr;35(4):534-40. link to original article PubMed
- SHEBA-07-4466-AN-CTIL: Shimoni A, Avivi I, Rowe JM, Yeshurun M, Levi I, Or R, Patachenko P, Avigdor A, Zwas T, Nagler A. A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma. Cancer. 2012 Oct 1;118(19):4706-14. Epub 2012 Jan 17. link to original article contains verified protocol PubMed
- GELTAMO Z-BEAM LDCGB: Briones J, Novelli S, García-Marco JA, Tomás JF, Bernal T, Grande C, Canales MA, Torres A, Moraleda JM, Panizo C, Jarque I, Palmero F, Hernández M, González-Barca E, López D, Caballero D. Autologous stem cell transplantation after conditioning with Yttrium-90 ibritumomab tiuxetan plus beam in refractory non-Hodgkin diffuse large B-cell lymphoma: results of a prospective, multicenter, phase II clinical trial. Haematologica. 2014 Mar;99(3):505-10. Epub 2013 Oct 25. link to original article contains verified protocol link to PMC article PubMed
- ZBEAM2: Fruchart C, Tilly H, Morschhauser F, Ghesquières H, Bouteloup M, Fermé C, Van Den Neste E, Bordessoule D, Bouabdallah R, Delmer A, Casasnovas RO, Ysebaert L, Ciappuccini R, Briere J, Gisselbrecht C. Upfront consolidation combining yttrium-90 ibritumomab tiuxetan and high-dose therapy with stem cell transplantation in poor-risk patients with diffuse large B cell lymphoma. Biol Blood Marrow Transplant. 2014 Dec;20(12):1905-11. Epub 2014 Jul 26. link to original article contains verified protocol PubMed
Maintenance after upfront therapy
Lenalidomide monotherapy
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Regimen variant #1, 1 year
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Reddy et al. 2016 (VICC HEM 0835) | Randomized Phase II (E-de-esc) | Lenalidomide & Rituximab | Did not meet primary endpoint of RFS12 |
Preceding treatment
- R-CHOP with or without radiation
Chemotherapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycle for 12 cycles
Regimen variant #2, 2 years
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Thieblemont et al. 2017 (REMARC) | Phase III (E-esc) | Placebo | Seems to have superior PFS |
Preceding treatment
Chemotherapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycle for up to 26 cycles (2 years)
References
- VICC HEM 0835: Reddy NM, Greer JP, Morgan DS, Chen H, Park SI, Richards KL. A phase II randomized study of lenalidomide or lenalidomide and rituximab as maintenance therapy following standard chemotherapy for patients with high/high-intermediate risk diffuse large B-cell lymphoma. Leukemia. 2017 Jan;31(1):241-244. Epub 2016 Sep 22. link to original article link to PMC article contains verified protocol PubMed
- REMARC: Thieblemont C, Tilly H, Gomes da Silva M, Casasnovas RO, Fruchart C, Morschhauser F, Haioun C, Lazarovici J, Grosicka A, Perrot A, Trotman J, Sebban C, Caballero D, Greil R, van Eygen K, Cohen AM, Gonzalez H, Bouabdallah R, Oberic L, Corront B, Choufi B, Lopez-Guillermo A, Catalano J, Van Hoof A, Briere J, Cabeçadas J, Salles G, Gaulard P, Bosly A, Coiffier B. Lenalidomide maintenance compared with placebo in responding elderly patients with diffuse large B-cell lymphoma treated with first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. J Clin Oncol. 2017 Aug 1;35(22):2473-2481. Epub 2017 Apr 20. link to original article contains verified protocol PubMed
Rituximab monotherapy
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Regimen variant #1
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Jaeger et al. 2015 (NHL13) | Phase III (E-esc) | Observation | Did not meet primary endpoint of EFS |
Patients required to be in CR or CRu prior to enrollment. The protocol was amended after the first 69 patients enrolled to increase length of treatment from 1 to 2 years.
Preceding treatment
- Rituximab (375 mg/m2) x 8 and 4 to 8 cycles of CHOP-like chemotherapy
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
2-month cycle for 6 to 12 cycles (1 to 2 years)
Regimen variant #2
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Witzens-Harig et al. 2015 (HD2002) | Phase III (E-esc) | Observation | Superior OS in males |
Preceding treatment
- "Standard treatment" which was not further described in the paper, beyond that a majority of patient received R-CHOP (see Tables)
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
3-month cycle for 8 cycles (2 years)
Regimen variant #3
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Haioun et al. 2009 (LNH 98-3) | Phase III (E-esc) | Observation | Might have superior EFS |
Preceding treatment
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
4-week course
Regimen variant #4
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Habermann et al. 2006 (ECOG E4494/CALGB 9793) | Phase III (E-esc) | Observation | Did not meet primary endpoint of FFS |
Note: in ECOG E4494/CALGB 9793, rituximab maintenance had superior FFS in the group receiving CHOP upfront, which is no longer standard of care.
Preceding treatment
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1, 8, 15, 22
6-month cycle for 4 cycles (2 years)
References
- ECOG E4494/CALGB 9793: 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
- LNH 98-3: Haioun C, Mounier N, Emile JF, Ranta D, Coiffier B, Tilly H, Récher C, Fermé C, Gabarre J, Herbrecht R, Morchhauser F, Gisselbrecht C. Rituximab versus observation after high-dose consolidative first-line chemotherapy with autologous stem-cell transplantation in patients with poor-risk diffuse large B-cell lymphoma. Ann Oncol. 2009 Dec;20(12):1985-92. Epub 2009 Jun 30. link to original article contains verified protocol PubMed
- NHL13: Jaeger U, Trneny M, Melzer H, Praxmarer M, Nawarawong W, Ben Yehuda D, Goldstein D, Mihaljevic B, Ilhan O, Ballova V, Hedenus M, Hsiao LT, Au WY, Burgstaller S, Weidinger G, Keil F, Dittrich C, Skrabs C, Klingler A, Chott A, Fridrik MA, Greil R. Rituximab maintenance for patients with aggressive B-cell lymphoma in first remission: results of the randomized NHL13 trial. Haematologica. 2015 Jul;100(7):955-63. Epub 2015 Apr 24. link to original article contains verified protocol link to PMC article PubMed
- HD2002: Witzens-Harig M, Benner A, McClanahan F, Klemmer J, Brandt J, Brants E, Rieger M, Meissner J, Hensel M, Neben K, Dreger P, Lengfelder E, Schmidt-Wolf I, Krämer A, Ho AD. Rituximab maintenance improves survival in male patients with diffuse large B-cell lymphoma: results of the HD2002 prospective multicentre randomized phase III trial. Br J Haematol. 2015 Dec;171(5):710-9. Epub 2015 Oct 9. link to original article contains verified protocol PubMed
Relapsed or refractory, salvage therapy
O-DHAP
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O-DHAP: Ofatumumab, Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin)
Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Matasar et al. 2013 (GSK 110927) | Phase II | ||
van Imhoff et al. 2016 (ORCHARRD) | Phase III (E-switch-ic) | R-DHAP | Did not meet primary endpoint of PFS |
Chemotherapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 1000 mg IV once per day on days 1 & 8
- Cycles 2 & 3: 1000 mg IV once on day 1
- Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4
- Cytarabine (Ara-C) 2000 mg/m2 IV every 12 hours on day 2 (total dose per cycle: 4000 mg/m2)
- Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 1
Supportive medications
- GSK 110927 recommended: Filgrastim (Neupogen) or Pegfilgrastim (Neulasta)
21-day cycle for 3 cycles
Subsequent treatment
- GSK 110927, responders: Stem-cell mobilization and autologous hematopoietic stem cell transplant (regimen not specified)
- ORCHARRD, responders: BEAM with autologous hematopoietic stem cell transplant except those in Japan who received LEED with autologous hematopoietic stem cell transplant
References
- GSK 110927: 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 link to PMC article PubMed
- ORCHARRD: van Imhoff GW, McMillan A, Matasar MJ, Radford J, Ardeshna KM, Kuliczkowski K, Kim W, Hong X, Goerloev JS, Davies A, Barrigón MD, Ogura M, Leppä S, Fennessy M, Liao Q, van der Holt B, Lisby S, Hagenbeek A. Ofatumumab versus rituximab salvage chemoimmunotherapy in relapsed or refractory diffuse large B-cell lymphoma: The ORCHARRD study. J Clin Oncol. 2017 Feb 10;35(5):544-51. Epub 2016 Dec 28. link to original article link to data supplement verified protocol in supplement PubMed
O-ICE
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O-ICE: Ofatumumab, Ifosfamide, Carboplatin, Etoposide
Regimen
Study | Evidence |
---|---|
Matasar et al. 2013 (GSK 110927) | Phase II |
Note: Subsequent consolidation therapy was not specified.
Chemotherapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 1000 mg IV once per day on days 1 & 8
- Cycles 2 & 3: 1000 mg IV once on day 1
- Ifosfamide (Ifex) 5000 mg/m2 IV continuous infusion over 24 hours, started on day 2, mixed with Mesna (Mesnex)
- Carboplatin (Paraplatin) AUC 5 (maximum dose of 800 mg) IV once on either day 1 or 2
- 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) 5000 mg/m2 IV continuous infusion over 24 hours, started on day 2, mixed with Ifosfamide (Ifex)
- Recommended: Filgrastim (Neupogen) or Pegfilgrastim (Neulasta)
21-day cycle for 3 cycles
References
- GSK 110927: 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 link to PMC article PubMed
R-DexaBEAM
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R-DexaBEAM: Rituximab, Dexamethasone, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan
Regimen
Study | Evidence |
---|---|
Kirschey et al. 2014 (Mz-135) | Phase II |
Note: the dosing in the manuscript is different than below. The below are the correct doses as verified by the authors.
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once per day on days 1 & 8
- Dexamethasone (Decadron) 8 mg PO three times per day on days 1 to 10
- Carmustine (BCNU) 60 mg/m2 IV once on day 3
- Etoposide (Vepesid) 75 mg/m2 IV once per day on days 4 to 7
- Cytarabine (Ara-C) 100 mg/m2 IV twice per day on days 4 to 7
- Melphalan (Alkeran) 20 mg/m2 IV once on day 2
3- to 4-week cycle for 2 cycles
Subsequent treatment
- R-BEAM with autologous hematopoietic stem cell transplant or R-TBI/Cy with autologous hematopoietic stem cell transplant
References
- Mz-135: Kirschey S, Flohr T, Wolf HH, Frickhofen N, Gramatzki M, Link H, Basara N, Peter N, Meyer RG, Schmitz N, Weidmann E, Banat A, Schulz A, Kolbe K, Derigs G, Theobald M, Hess G. Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: mature results of a phase II multicentre study. Br J Haematol. 2015 Mar;168(6):824-34. Epub 2014 Dec 28. link to original article contains verified protocol PubMed
R-DHAOx
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R-DHAOx: Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Oxaliplatin
ROAD: Rituximab, Oxaliplatin, Ara-C (Cytarabine), Dexamethasone
Regimen
Study | Evidence | Efficacy |
---|---|---|
Witzig et al. 2017 (MCCRC MC0485) | Phase II | ORR: 71% (95% CI, 56–84) |
Chemotherapy
- Rituximab (Rituxan) as follows:
- Cycle 1 only: 375 mg/m2 IV once per day on days 1, 8, 15, 22
- Dexamethasone (Decadron) 40 mg IV or PO once per day on days 2 to 5
- Cytarabine (Ara-C) 2000 mg/m2 IV over 3 hours once per day on days 2 & 3
- Second dose to be given no sooner than 12 hours and no later than 24 hours after end of first dose
- Oxaliplatin (Eloxatin) 130 mg/m2 IV over 2 hours once on day 2
Supportive medications
- Pegfilgrastim (Neulasta) 6 mg SC once on day 4
21-day cycles
Subsequent treatment
- Most responders proceeded to high-dose chemotherapy with autologous hematopoietic stem cell transplant after 2 cycles, although this was not mandated in the protocol
References
- MCCRC MC0485: Witzig TE, Johnston PB, LaPlant BR, Kurtin PJ, Pederson LD, Moore DF Jr, Nabbout NH, Nikcevich DA, Rowland KM, Grothey A. Long-term follow-up of chemoimmunotherapy with rituximab, oxaliplatin, cytosine arabinoside, dexamethasone (ROAD) in patients with relapsed CD20+ B-cell non-Hodgkin lymphoma: Results of a study of the Mayo Clinic Cancer Center Research Consortium (MCCRC) MC0485 now known as academic and community cancer research united (ACCRU). Am J Hematol. 2017 Oct;92(10):1004-1010. Epub 2017 Aug 17. link to original article contains verified protocol PubMed
R-DHAP
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R-DHAP: Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin)
Regimen variant #1
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Gisselbrecht et al. 2010 (CORAL) | Phase III (E-switch-ic) | R-ICE | Did not meet primary endpoint of mobilization-adjusted response rate after 3 cycles |
van Imhoff et al. 2016 (ORCHARRD) | Phase III (C) | O-DHAP | Did not meet primary endpoint of PFS |
Note: CORAL makes reference to Velasquez et al. 1988 to describe this regimen, although this reference is for DHAP, not R-DHAP. The paper also contains the following regimen information:
Chemotherapy
- Rituximab (Rituxan) as follows, given first:
- Cycle 1: 375 mg/m2 IV once per day on days -1 & 1 (CORAL) or days 1 & 8 (ORCHARRD)
- Cycle 2: 375 mg/m2 IV once on day 1
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
- Cytarabine (Ara-C) 2000 mg/m2 IV over 3 hours every 12 hours on day 2 (total dose per cycle: 4000 mg/m2)
- Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 1
Supportive medications
- CORAL: G-CSF "depending on site policy, with R-DHAP, but always after the third cycle until the end of leukaphereses"
21-day cycle for 3 cycles
Subsequent treatment
- CORAL, responders: BEAM with autologous hematopoietic stem cell transplant
- ORCHARRD, responders: BEAM with autologous hematopoietic stem cell transplant except those in Japan who received LEED with autologous hematopoietic stem cell transplant
Regimen variant #2
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Crump et al. 2014 (NCIC-CTG LY.12) | Phase III (C) | R-GDP | Non-inferior RR after 2 cycles |
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Dexamethasone (Decadron) 40 mg PO once per day on days 1 to 4
- Cytarabine (Ara-C) 2000 mg/m2 IV over 3 hours every 12 hours on day 2 (total dose per cycle: 4000 mg/m2)
- Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 1
21-day cycle for up to 3 cycles
Subsequent treatment
- Responders: Stem-cell mobilization and high-dose chemotherapy with autologous hematopoietic stem cell transplant (regimen not specified)
Regimen variant #3
Study | Evidence |
---|---|
Mey et al. 2006 | Phase II |
The doses here were used after a mid-protocol amendment pertaining to the first cycle.
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Dexamethasone (Decadron) as follows:
- Cycle 1: 40 mg PO once per day on days 3 to 5
- Cycles 2 to 4: 40 mg PO once per day on days 3 to 6
- Cytarabine (Ara-C) as follows:
- Cycle 1 as follows:
- Younger than 60 years: 1000 mg/m2 IV over 2 hours every 12 hours on day 4 (total dose per cycle: 2000 mg/m2)
- Older than 60 years: 500 mg/m2 IV over 2 hours every 12 hours on day 4 (total dose per cycle: 1000 mg/m2)
- Cycles 2 to 4 as follows:
- Younger than 60 years: 2000 mg/m2 IV over 2 hours every 12 hours on day 4 (total dose per cycle: 4000 mg/m2)
- Older than 60 years: 1000 mg/m2 IV over 2 hours every 12 hours on day 4 (total dose per cycle: 2000 mg/m2)
- Cycle 1 as follows:
- Cisplatin (Platinol) as follows:
- Cycle 1: 25 mg/m2/day IV continuous infusion over 72 hours, started on day 3 (total dose: 75 mg/m2)
- Cycles 2 to 4: 25 mg/m2/day IV continuous infusion over 96 hours, started on day 3 (total dose per cycle: 100 mg/m2)
21-day cycle for up to 4 cycles
Subsequent treatment
- Patients with at least PR were allowed to undergo high-dose chemotherapy with autologous stem-cell transplant (regimen not specified)
References
- Mey UJ, Orlopp KS, Flieger D, Strehl JW, Ho AD, Hensel M, Bopp C, Gorschlüter M, Wilhelm M, Birkmann J, Kaiser U, Neubauer A, Florschütz A, Rabe C, Hahn C, Glasmacher AG, Schmidt-Wolf IG. Dexamethasone, high-dose cytarabine, and cisplatin in combination with rituximab as salvage treatment for patients with relapsed or refractory aggressive non-Hodgkin's lymphoma. Cancer Invest. 2006 Oct;24(6):593-600. link to original article contains verified protocol PubMed
- CORAL: 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 link to PMC article PubMed
- NCIC-CTG LY.12: Crump M, Kuruvilla J, Couban S, MacDonald DA, Kukreti V, Kouroukis CT, Rubinger M, Buckstein R, Imrie KR, Federico M, Di Renzo N, Howson-Jan K, Baetz T, Kaizer L, Voralia M, Olney HJ, Turner AR, Sussman J, Hay AE, Djurfeldt MS, Meyer RM, Chen BE, Shepherd LE. Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol. 2014 Nov 1;32(31):3490-6. Epub 2014 Sep 29. link to original article contains verified protocol PubMed
- ORCHARRD: van Imhoff GW, McMillan A, Matasar MJ, Radford J, Ardeshna KM, Kuliczkowski K, Kim W, Hong X, Goerloev JS, Davies A, Barrigón MD, Ogura M, Leppä S, Fennessy M, Liao Q, van der Holt B, Lisby S, Hagenbeek A. Ofatumumab versus rituximab salvage chemoimmunotherapy in relapsed or refractory diffuse large B-cell lymphoma: the ORCHARRD study. J Clin Oncol. 2017 Feb 10;35(5):544-51. Epub 2016 Dec 28. link to original article link to data supplement verified protocol in supplement PubMed
R-DHAP/R-VIM
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R-DHAP/R-VIM: Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin) alternating with Rituximab, VP-16 (Etoposide), Ifosfamide, Methotrexate
Protocol
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Vellenga et al. 2008 (HOVON-44) | Phase III (E-esc) | DHAP/VIM | Superior PFS |
Note: per the paper, "in case patients were non-responsive to R-DHAP but responsive to R-VIM, it was allowed to repeat the R-VIM regimen as the third cycle of reinduction chemotherapy." No statement is made as to whether Mesna is used in the VIM protocol.
Chemotherapy, R-DHAP portion
- Rituximab (Rituxan) 375 mg/m2 IV once on day 5
- Dexamethasone (Decadron) 40 mg IV or PO once per day on days 1 to 4
- Cytarabine (Ara-C) 2000 mg/m2 IV over 3 hours every 12 hours on day 2 (total dose per cycle: 4000 mg/m2)
- Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 1
28-day cycle for 2 cycles, with VIM interposed
Chemotherapy, R-VIM portion
- Rituximab (Rituxan) 375 mg/m2 IV once on day 6
- Etoposide (Vepesid) 90 mg/m2 IV once per day on days 1, 3, 5
- Ifosfamide (Ifex) 1200 mg/m2 IV once per day on days 1 to 5
- Methotrexate (MTX) 30 mg/m2 IV once per day on days 1 & 5
28-day cycle for 1 cycle, given in-between R-DHAP cycles
Subsequent treatment
- Responders: Stem-cell mobilization, then BEAM with autologous hematopoietic stem cell transplant
References
- Vellenga E, van Putten WL, van 't Veer MB, Zijlstra JM, Fibbe WE, van Oers MH, Verdonck LF, Wijermans PW, van Imhoff GW, Lugtenburg PJ, Huijgens PC. Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: a prospective randomized HOVON trial. Blood. 2008 Jan 15;111(2):537-43. link to original article contains verified protocol PubMed
R-EPOCH
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R-EPOCH: Rituximab, Etoposide, Prednisone, Oncovin (Vincristine), Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin)
Regimen
Study | Evidence |
---|---|
Jermann et al. 2004 | Phase II |
Note: this is not the dose-adjusted R-EPOCH regimen
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Etoposide (Vepesid) 65 mg/m2/day IV continuous infusion over 72 hours, started on day 2 (total dose per cycle: 195 mg/m2)
- Prednisone (Sterapred) 60 mg/m2/day PO on days 1 to 14
- Vincristine (Oncovin) 0.5 mg/m2/day IV continuous infusion over 72 hours, started on day 2 (total dose per cycle: 1.5 mg/m2)
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 5
- Doxorubicin (Adriamycin) 15 mg/m2/day IV continuous infusion over 72 hours, started on day 2 (total dose per cycle: 45 mg/m2)
21-day cycle for 4 to 6 cycles
Subsequent treatment
- Patients younger than 60 who achieved at least PR: High-dose chemotherapy with autologous hematopoietic stem-cell transplantation (regimen not specified)
References
- Jermann M, Jost LM, Taverna Ch, Jacky E, Honegger HP, Betticher DC, Egli F, Kroner T, Stahel RA. Rituximab-EPOCH, an effective salvage therapy for relapsed, refractory or transformed B-cell lymphomas: results of a phase II study. Ann Oncol. 2004 Mar;15(3):511-6. link to original article contains verified protocol PubMed
R-ESHAP
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R-ESHAP: Rituximab, Etoposide, Solumedrol (Methylprednisolone) High-dose Ara-C (Cytarabine), Platinol (Cisplatin)
Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Martín et al. 2008 | Retrospective | ||
Avilés et al. 2010 | Phase III (E-esc) | ESHAP | Did not meet efficacy endpoints |
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.
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1 (or day 5)
- Etoposide (Vepesid) 40 mg/m2 IV over 60 minutes 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, 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 (Ara-C) 2000 mg/m2 IV over 2 hours once on day 5
- Cisplatin (Platinol) 25 mg/m2/day IV continuous infusion over 96 hours, started on day 1 (total dose per cycle: 100 mg/m2)
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 (route not specified) "given regularly"
21- to 28-day cycles for 6 to 8 cycles ("after recovery of the toxic effects")
References
- Retrospective: 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
- Avilés A, Neri N, Huerta-Guzmán J, de Jesús Nambo M. ESHAP versus rituximab-ESHAP in frail patients with refractory diffuse large B-cell lymphoma. Clin Lymphoma Myeloma Leuk. 2010 Apr;10(2):125-8. link to original article PubMed
R-GDP
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R-GDP: Rituximab, Gemcitabine, Dexamethasone, Platinol (Cisplatin)
Regimen variant #1, 1 day of cisplatin/cycle
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Crump et al. 2014 (NCIC-CTG LY.12) | Phase III (E-switch-ic) | R-DHAP | Non-inferior RR after 2 cycles |
Chemotherapy
- 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 PO once per day on days 1 to 4
- Cisplatin (Platinol) 75 mg/m2 IV once on day 1
21-day cycle for up to 3 cycles
Subsequent treatment
- Responders: Stem-cell mobilization and high-dose chemotherapy with autologous hematopoietic stem cell transplant (regimen not specified)
Regimen variant #2, 3 days of cisplatin/cycle
Study | Evidence |
---|---|
Hou et al. 2012 | Non-randomized |
Chemotherapy
- 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 cycle for 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
- NCIC-CTG LY.12: Crump M, Kuruvilla J, Couban S, MacDonald DA, Kukreti V, Kouroukis CT, Rubinger M, Buckstein R, Imrie KR, Federico M, Di Renzo N, Howson-Jan K, Baetz T, Kaizer L, Voralia M, Olney HJ, Turner AR, Sussman J, Hay AE, Djurfeldt MS, Meyer RM, Chen BE, Shepherd LE. Randomized comparison of gemcitabine, dexamethasone, and cisplatin versus dexamethasone, cytarabine, and cisplatin chemotherapy before autologous stem-cell transplantation for relapsed and refractory aggressive lymphomas: NCIC-CTG LY.12. J Clin Oncol. 2014 Nov 1;32(31):3490-6. Epub 2014 Sep 29. link to original article contains verified protocol PubMed
R-ICE
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R-ICE: Rituximab, Ifosfamide, Carboplatin, Etoposide
ICE-R: Ifosfamide, Carboplatin, Etoposide, Rituximab
Regimen variant #1
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Gisselbrecht et al. 2010 (CORAL) | Phase III (E-switch-ic) | R-DHAP | Did not meet primary endpoint of mobilization-adjusted response rate after 3 cycles |
Fayad et al. 2015 (SG040-0005) | Randomized Phase IIb (C) | R-ICE + Dacetuzumab | Did not meet primary endpoint of CR rate |
Note: Gisselbrecht et al. 2010 refers to the non-randomized regimen described in variant #3 below, although it has slightly different day numbering. Doses are the same.
Chemotherapy
- Rituximab (Rituxan) as follows (given first before other chemotherapy):
- Cycle 1: 375 mg/m2 IV once per day on days -1 & 1
- Cycles 2 & 3: 375 mg/m2 IV once on day 1
- Ifosfamide (Ifex) 5000 mg/m2 IV continuous infusion over 24 hours, started on day 2
- Carboplatin (Paraplatin) AUC 5 (maximum dose of 800 mg) IV once 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)
- " Granulocyte colony-stimulating factor was administered after R-ICE"
21-day cycle for 3 cycles
Subsequent treatment
- CORAL with complete or partial response: BEAM with autologous hematopoietic stem cell transplant
Regimen variant #2
Study | Evidence | Efficacy |
---|---|---|
Guo et al. 2014 | Phase II | ORR: 78% |
Note: original article is in Chinese; this information is from the English abstract.
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Ifosfamide (Ifex) 1600 mg/m2 IV once per day on days 2 to 4
- Carboplatin (Paraplatin) AUC 5 (maximum dose of 800 mg) IV once on day 3
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 2 to 4
3 cycles; duration of cycles not specified in the abstract
Regimen variant #3
Study | Evidence | Efficacy |
---|---|---|
Zelenetz et al. 2003 | Phase II | ORR: 81% (*) |
Kewalramani et al. 2004 | Phase II | ORR: 78% (*) |
Third cycle intended to be followed by peripheral blood hematopoietic stem cell collection. ORR reported in Zelenetz et al. 2003 is for the subset of DLBCL patients who received R-ICE; it is unclear if these patients were exposed to rituximab previously. None of the patients in Kewalaramani et al. 2004 had previously received rituximab.
Chemotherapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once per day on days -2 & 1
- Cycles 2 & 3: 375 mg/m2 IV once on day 1
- Ifosfamide (Ifex) 5000 mg/m2 IV continuous infusion over 24 hours, started on day 4, mixed with Mesna (Mesnex)
- Carboplatin (Paraplatin) AUC 5 (maximum dose of 800 mg) 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
Supportive medications
- (as described by Kewalramani et al. 2004):
- Mesna (Mesnex) 5000 mg/m2 IV continuous infusion over 24 hours, started on day 4, mixed 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 mcg/kg SC once per day on days 7 to 14 (10 mcg/kg with cycle 3, given until collection of peripheral blood hematopoietic stem cells)
14-day cycle for 3 cycles
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 protocol 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 link to PMC article PubMed
- Guo Y, Chen Y, Hong X, Yu L, Ma J, Shi Y, Liu T, Jiang W, Zhu J, Jin J, Zou P, Wu D, Shen Z. [A phase II multicenter study to investigate R-ICE as a salvage therapy for relapsed diffuse large B-cell lymphoma]. Zhonghua Xue Ye Xue Za Zhi. 2014 Apr;35(4):314-7. Chinese. link to original article contains protocol PubMed
- SG040-0005: Fayad L, Ansell SM, Advani R, Coiffier B, Stuart R, Bartlett NL, Forero-Torres A, Kuliczkowski K, Belada D, Ng E, Drachman JG. Dacetuzumab plus rituximab, ifosfamide, carboplatin and etoposide as salvage therapy for patients with diffuse large B-cell lymphoma relapsing after rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone: a randomized, double-blind, placebo-controlled phase 2b trial. Leuk Lymphoma. 2015;56(9):2569-78. Epub 2015 Feb 26. link to original article PubMed
RICER
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RICER: Rituximab, Ifosfamide, Carboplatin, Etoposide, Revlimid (Lenalidomide)
Regimen
Study | Evidence |
---|---|
Feldman et al. 2014 (RV-DLBCL-PI-0463) | Phase II |
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Ifosfamide (Ifex) 5000 mg/m2 IV continuous infusion over 24 hours, started on day 2, mixed with Mesna (Mesnex)
- Carboplatin (Paraplatin) AUC 5 (maximum dose of 800 mg) IV once on day 2
- Etoposide (Vepesid) 100 mg/m2 IV bolus once per day on days 2 to 4
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 7
Supportive medications
- Mesna (Mesnex) 5000 mg/m2 IV continuous infusion over 24 hours, started on day 2, mixed with Ifosfamide (Ifex)
- Aspirin 81 mg PO once per day from day 1 until platelets less than 50 × 109/L
- Low dose LMWH for patients intolerant of Aspirin
- " Granulocyte colony-stimulating factor was administered after R-ICE"
14-day cycle for 2 cycles
Subsequent treatment
- Responders received a 3rd cycle with hematopoietic stem cell collection 10 to 14 days afterwards, then BEAM with autologous hematopoietic stem cell transplant (details not described)
References
- RV-DLBCL-PI-0463: Feldman T, Mato AR, Chow KF, Protomastro EA, Yannotti KM, Bhattacharyya P, Yang X, Donato ML, Rowley SD, Carini C, Valentinetti M, Smith J, Gadaleta G, Bejot C, Stives S, Timberg M, Kdiry S, Pecora AL, Beaven AW, Goy A. Addition of lenalidomide to rituximab, ifosfamide, carboplatin, etoposide (RICER) in first-relapse/primary refractory diffuse large B-cell lymphoma. Br J Haematol. 2014 Jul;166(1):77-83. Epub 2014 Mar 25. link to original article contains verified protocol link to PMC article PubMed
R-IFE
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R-IFE: Rituximab, IFosfamide, Etoposide
Regimen
Study | Evidence |
---|---|
Pardal et al. 2014 (GELTAMO-2006) | Phase II |
These were patients with PET-positive disease at interim assessment.
Preceding treatment
- R-MegaCHOP x 3
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Ifosfamide (Ifex) 3333 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 10,000 mg/m2)
- Etoposide (Vepesid) 150 mg/m2 IV over 12 hours once per day on days 1 to 3
Supportive medications
- Mesna (Mesnex) given after R-IFE; details not supplied in manuscript
- Pegfilgrastim (Neulasta) given after each cycle
2 cycles (duration not specified)
Subsequent treatment
References
- GELTAMO-2006: Pardal E, Coronado M, Martín A, Grande C, Marín-Niebla A, Panizo C, Bello JL, Conde E, Hernández MT, Arranz R, Bargay J, González-Barca E, Pérez-Ceballos E, Montes-Moreno S, Caballero MD. Intensification treatment based on early FDG-PET in patients with high-risk diffuse large B-cell lymphoma: a phase II GELTAMO trial. Br J Haematol. 2014 Nov;167(3):327-36. Epub 2014 Jul 28. link to original article contains verified protocol PubMed
R-NIMP
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R-NIMP: Rituximab, Navelbine (Vinorelbine), Ifosfamide, Mitoxantrone, Prednisone
Regimen
Study | Evidence | Efficacy |
---|---|---|
Gyan et al. 2013 | Phase II | 68% (95%CI: 53–79) |
BSA was capped at 2 for all dose calculations.
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1 & 15
- Ifosfamide (Ifex) 1000 mg/m2/day IV continuous infusion over 120 hours, started on day 1 (total dose per cycle: 5000 mg/m2)
- Mitoxantrone (Novantrone) 10 mg/m2 IV once on day 1
- Prednisone (Sterapred) 1 mg/kg (route not specified) once per day on days 1 to 5
Supportive medications
- Mesna (Mesnex) given with Ifosfamide (Ifex) "at the same dose"; schedule not specified in the paper
- Recommended: Pegfilgrastim (Neulasta) 6 mg SC once on day 7
- Recommended: Epoietin alpha support for hemoglobin less than 10 g/dL
28-day cycle for 3 cycles
Subsequent treatment
- Responders were recommended to undergo 3 additional cycles of R-NIMP (if transplant ineligible) or high-dose chemotherapy with autologous hematopoietic stem cell transplant (regimen not specified).
References
- Gyan E, Damotte D, Courby S, Sénécal D, Quittet P, Schmidt-Tanguy A, Banos A, Le Gouill S, Lamy T, Fontan J, Maisonneuve H, Alexis M, Dreyfus F, Tournilhac O, Laribi K, Solal-Céligny P, Arakelyan N, Cartron G, Gressin R; GOELAMS Group. High response rate and acceptable toxicity of a combination of rituximab, vinorelbine, ifosfamide, mitoxantrone and prednisone for the treatment of diffuse large B-cell lymphoma in first relapse: results of the R-NIMP GOELAMS study. Br J Haematol. 2013 Jul;162(2):240-9. Epub 2013 May 21. link to original article contains verified protocol PubMed
Consolidation after salvage therapy
BEAC, then auto HSCT
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BEAC: Rituximab, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Cyclophosphamide
Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Philip et al. 1991 (Parma) | Prospective pilot | ||
Philip et al. 1995 (PARMA) | Phase III (E-esc) | DHAP x 4 | Seems to have superior OS |
Preceding treatment
DHAP x 2; radiation was also given to sites of bulky disease (>5cm) Autologous HSCT conditioning regimens
References
- Philip T, Chauvin F, Armitage J, Bron D, Hagenbeek A, Biron P, Spitzer G, Velasquez W, Weisenburger DD, Fernandez-Ranada J, Somers R, Rizzoli V, Harousseau JL, Sotto JJ, Cahn JY, Guilhot F, Biggs J, Sonneveld P, Misset JL, Manna A, Jagannath S, Guglielmi C, Chevreau C, Delmer A, Santini G, Coiffier B. Parma international protocol: pilot study of DHAP followed by involved-field radiotherapy and BEAC with autologous bone marrow transplantation. Blood. 1991 Apr 1;77(7):1587-92. link to original article contains verified protocol PubMed
- PARMA: Philip T, Guglielmi C, Hagenbeek A, Somers R, Van der Lelie H, Bron D, Sonneveld P, Gisselbrecht C, Cahn JY, Harousseau JL, Coiffier B, Biron P, Mandelli F, Chauvin F. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin's lymphoma. N Engl J Med. 1995 Dec 7;333(23):1540-5. link to original article PubMed
BEAM, then allo HSCT
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BEAM: BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan
Regimen
Study | Evidence |
---|---|
Przepiorka et al. 1999 | Phase II |
Chemotherapy
- Carmustine (BCNU) 300 mg/m2 IV once on day -6
- Etoposide (Vepesid) 200 mg/m2 IV twice per day on days -5 to -2
- Cytarabine (Ara-C) 200 mg/m2 IV twice per day on days -5 to -2
- Melphalan (Alkeran) 140 mg/m2 IV once on day -1
Immunotherapy
- Allogeneic stem cells transfused on day 0
GVHD prophylaxis
Supportive therapy
- "Prophylactic antibiotics"
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day +7 and continued until engraftment
One course
Immunotherapy
Stem cells transfused on day 0
References
- Przepiorka D, van Besien K, Khouri I, Hagemeister F, Samuels B, Folloder J, Ueno NT, Molldrem J, Mehra R, Körbling M, Giralt S, Gajewski J, Donato M, Cleary K, Claxton D, Braunschweig I, Andersson B, Anderlini P, Champlin R. Carmustine, etoposide, cytarabine and melphalan as a preparative regimen for allogeneic transplantation for high-risk malignant lymphoma. Ann Oncol. 1999 May;10(5):527-32. link to original article contains protocol PubMed
BEAM, then auto HSCT
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BEAM: Rituximab, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan
Regimen variant #1
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Shimoni et al. 2012 (SHEBA-07-4466-AN-CTIL) | Randomized Phase II (C) | Z-BEAM | Seems to have inferior OS |
Pardal et al. 2014 (GELTAMO-2006) | Phase II | ||
van Imhoff et al. 2016 (ORCHARRD) | Non-randomized portion of RCT |
Preceding treatment
- GELTAMO-2006: R-MegaCHOP x 3, then R-IFE x 2
- ORCHARRD: O-DHAP x 3 versus R-DHAP x 3
Chemotherapy
- Carmustine (BCNU) 300 mg/m2 IV once on day -6
- Etoposide (Vepesid) 200 mg/m2 IV once per day on days -5 to -2
- Cytarabine (Ara-C) 200 mg/m2 IV every 12 hours on days -5 to -2 (total dose: 1600 mg/m2)
- Melphalan (Alkeran) 140 mg/m2 IV once on day -1
Supportive therapy
- Autologous stem cells re-infused on day 0
- Variously described:
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day +4 "until engraftment"
- Valacyclovir (Valtrex) (dose not specified) for one month
- Trimethoprim-Sulfamethoxazole (Bactrim DS) (dose/frequency not specified) for six months
One course
Stem cells reinfused on day 0
Regimen variant #2
Study | Evidence |
---|---|
Vellenga et al. 2008 (HOVON-44) | Non-randomized portion of RCT |
Gisselbrecht et al. 2010 (CORAL) | Non-randomized portion of RCT |
Preceding treatment
- HOVON-44: DHAP/VIM versus R-DHAP/R-VIM
- CORAL: R-ICE x 3 versus R-DHAP x 3
Chemotherapy
- Carmustine (BCNU) 300 mg/m2 IV once on day -6
- Etoposide (Vepesid) 200 mg/m2 IV once per day on days -5 to -2
- Cytarabine (Ara-C) 200 mg/m2 IV once per day on days -5 to -2
- Melphalan (Alkeran) 140 mg/m2 IV once on day -1
Supportive therapy
- Autologous stem cells re-infused on day 0
One course
Stem cells reinfused on day 0
Subsequent treatment
- CORAL: Rituximab maintenance versus observation
Regimen variant #3, 300/100q12/200/140
Study | Evidence |
---|---|
Philip et al. 1987 | Non-randomized |
Chemotherapy
- Carmustine (BCNU) 300 mg/m2 IV once on day 1
- Etoposide (Vepesid) 100 mg/m2 IV over 60 minutes every 12 hours on days 2 to 5 (total dose: 800 mg/m2)
- Cytarabine (Ara-C) 200 mg/m2 IV once per day on days 2 to 5
- Melphalan (Alkeran) 140 mg/m2 IV over 5 minutes once on day 6
Supportive therapy
- Autologous stem cells re-infused on unspecified day
One course
References
- Philip T, Armitage JO, Spitzer G, Chauvin F, Jagannath S, Cahn JY, Colombat P, Goldstone AH, Gorin NC, Flesh M, Laporte JP, Maraninchi D, Pico J, Bosly A, Anderson C, Schots R, Biron P, Cabanillas F, Dicke K. High-dose therapy and autologous bone marrow transplantation after failure of conventional chemotherapy in adults with intermediate-grade or high-grade non-Hodgkin's lymphoma. N Engl J Med. 1987 Jun 11;316(24):1493-8. link to original article contains verified protocol PubMed
- HOVON-44: Vellenga E, van Putten WL, van 't Veer MB, Zijlstra JM, Fibbe WE, van Oers MH, Verdonck LF, Wijermans PW, van Imhoff GW, Lugtenburg PJ, Huijgens PC. Rituximab improves the treatment results of DHAP-VIM-DHAP and ASCT in relapsed/progressive aggressive CD20+ NHL: a prospective randomized HOVON trial. Blood. 2008 Jan 15;111(2):537-43. link to original article contains verified protocol PubMed
- CORAL: 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 link to PMC article PubMed
- SHEBA-07-4466-AN-CTIL: Shimoni A, Avivi I, Rowe JM, Yeshurun M, Levi I, Or R, Patachenko P, Avigdor A, Zwas T, Nagler A. A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma. Cancer. 2012 Oct 1;118(19):4706-14. Epub 2012 Jan 17. link to original article contains verified protocol PubMed
- GELTAMO-2006: Pardal E, Coronado M, Martín A, Grande C, Marín-Niebla A, Panizo C, Bello JL, Conde E, Hernández MT, Arranz R, Bargay J, González-Barca E, Pérez-Ceballos E, Montes-Moreno S, Caballero MD. Intensification treatment based on early FDG-PET in patients with high-risk diffuse large B-cell lymphoma: a phase II GELTAMO trial. Br J Haematol. 2014 Nov;167(3):327-36. Epub 2014 Jul 28. link to original article contains verified protocol PubMed
- ORCHARRD: van Imhoff GW, McMillan A, Matasar MJ, Radford J, Ardeshna KM, Kuliczkowski K, Kim W, Hong X, Goerloev JS, Davies A, Barrigón MD, Ogura M, Leppä S, Fennessy M, Liao Q, van der Holt B, Lisby S, Hagenbeek A. Ofatumumab versus rituximab salvage chemoimmunotherapy in relapsed or refractory diffuse large B-cell lymphoma: the ORCHARRD study. J Clin Oncol. 2017 Feb 10;35(5):544-51. Epub 2016 Dec 28. link to original article link to data supplement verified protocol in supplement PubMed
BeEAM, then auto HSCT
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BeEAM: Bendamustine, Etoposide, Ara-C (Cytarabine), Melphalan
Regimen
Study | Evidence |
---|---|
Visani et al. 2011 | Phase I/II, <20 pts in this subgroup |
Chemotherapy
- Bendamustine 200 mg/m2 IV once per day on days -7 & -6
- Etoposide (Vepesid) 200 mg/m2 IV once per day on days -5 to -2
- Cytarabine (Ara-C) 400 mg/m2 IV once per day on days -5 to -2
- Melphalan (Alkeran) 140 mg/m2 IV once on day -1
Supportive therapy
- Autologous stem cells re-infused on day 0
One course
References
- Visani G, Malerba L, Stefani PM, Capria S, Galieni P, Gaudio F, Specchia G, Meloni G, Gherlinzoni F, Giardini C, Falcioni S, Cuberli F, Gobbi M, Sarina B, Santoro A, Ferrara F, Rocchi M, Ocio EM, Caballero MD, Isidori A. BeEAM (bendamustine, etoposide, cytarabine, melphalan) before autologous stem cell transplantation is safe and effective for resistant/relapsed lymphoma patients. Blood. 2011 Sep 22;118(12):3419-25. Epub 2011 Aug 3. link to original article contains verified protocol PubMed
CBV, then auto HSCT
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CBV: Cyclophosphamide, BiCNU (Carmustine), VP-16 (Etoposide)
Regimen
Study | Evidence |
---|---|
Stiff et al. 1998 | Phase II |
Chemotherapy
- Cyclophosphamide (Cytoxan) 100 mg/kg IV over 2 hours once on day -2
- Carmustine (BCNU) 15 mg/kg (maximum dose of 550 mg/m2) IV over 60 minutes once on day -6
- Etoposide (Vepesid) 60 mg/kg IV over 4 hours once on day -4
Supportive therapy
- Autologous stem cells re-infused on day 0
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day +4, to continue until ANC greater than 5000/μL once or greater than 1500/μL twice
- Levofloxacin (Levaquin) 500 mg PO once per day, starting on day +2, to continue until ANC at least 500/μL
- Fluconazole (Diflucan) 200 mg PO once per day, starting on day +1, to continue until ANC at least 500/μL
- Acyclovir (Zovirax) 200 mg PO three times per day, starting on day -2, to continue until 1 year after HSCT
- Trimethoprim-Sulfamethoxazole (Bactrim DS) 160/800 mg PO twice per day on Saturday and Sunday, to continue until 3 months after HSCT
Additional considerations
If any patient appeared to be experiencing carmustine-induced pneumonitis:
- Prednisone (Sterapred) 0.5 mg/kg PO twice per day x 2 weeks, then tapered over 4 weeks
One course
References
- Stiff PJ, Dahlberg S, Forman SJ, McCall AR, Horning SJ, Nademanee AP, Blume KG, LeBlanc M, Fisher RI. Autologous bone marrow transplantation for patients with relapsed or refractory diffuse aggressive non-Hodgkin's lymphoma: value of augmented preparative regimens--a Southwest Oncology Group trial. J Clin Oncol. 1998 Jan;16(1):48-55. link to original article contains verified protocol PubMed
Cyclophosphamide & TBI, then auto HSCT
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Cy/TBI: Cyclophosphamide & Total Body Irradiation
Regimen
Study | Evidence |
---|---|
Phillips et al. 1984 | Non-randomized |
Chemotherapy
- Cyclophosphamide (Cytoxan) 60 mg/kg IV once per day on days -3 & -2
Radiotherapy
- Total body irradiation (TBI) 1200 cGy in fractions on days –6 to –4 (pulmonary dosage was limited to 800 cGy)
Supportive therapy
- Autologous stem cells re-infused on day 0
One course
References
- Phillips GL, Herzig RH, Lazarus HM, Fay JW, Wolff SN, Mill WB, Lin H, Thomas PR, Glasgow GP, Shina DC, Herzig GP. Treatment of resistant malignant lymphoma with cyclophosphamide, total body irradiation, and transplantation of cryopreserved autologous marrow. N Engl J Med. 1984 Jun 14;310(24):1557-61. link to original article PubMed
FEAM, then auto HSCT
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FEAM: Fotemustine, Etoposide, Ara-C (Cytarabine), Melphalan
Regimen
Study | Evidence |
---|---|
Musso et al. 2009 | Phase II |
Chemotherapy
- Fotemustine (Muphoran) 150 mg/m2 IV once per day on days -7 & -6 (total dose: 300 mg/m2)
- Etoposide (Vepesid) 200 mg/m2 IV once per day on days -5 to -2 (total dose: 800 mg/m2)
- Cytarabine (Ara-C) 400 mg/m2 IV once per day on days -5 to -2 (total dose: 1600 mg/m2)
- Melphalan (Alkeran) 140 mg/m2 IV once on day -1
Supportive therapy
- Autologous stem cells re-infused on day 0
One course
References
- Musso M, Scalone R, Marcacci G, Lanza F, Di Renzo N, Cascavilla N, Di Bartolomeo P, Crescimanno A, Perrone T, Pinto A. Fotemustine plus etoposide, cytarabine and melphalan (FEAM) as a new conditioning regimen for lymphoma patients undergoing auto-SCT: a multicenter feasibility study. Bone Marrow Transplant. 2010 Jul;45(7):1147-53. Epub 2009 Nov 9. link to original article PubMed
FluBuCy, then allo HSCT
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FluBuCy: Fludarabine, Busulfan, Cyclophosphamide
Regimen
Study | Evidence |
---|---|
Glass et al. 2014 (DSHNHL R3) | Phase II |
Chemotherapy
- Fludarabine (Fludara) 25 mg/m2/day IV on days -8 to -4
- Busulfan (Myleran) 4 mg/kg/day PO on days -6 to -4
- Cyclophosphamide (Cytoxan) 60 mg/kg/day IV on days -3 and -2
Immunotherapy
- Allogeneic stem cells transfused on day 0
GVHD prophylaxis
- Antithymocyte globulin, rabbit ATG (Thymoglobulin) 2 mg/kg IV from day -3 to -1 (unclear if this is a total dose or a daily dose)
- Option also to use ATG-Fresenius S at a higher dose of 10 mg/kg
- Tacrolimus (Prograf) 8 to 12 mcg/L (route/frequency not specified) starting on day -1, tapered from day +100 in absence of GVHD
- Mycophenolate mofetil (CellCept) 1000 mg (route not specified) twice per day from day +1 to +28
One course
Immunotherapy
Stem cells transfused on day 0
References
- DSHNHL R3: Glass B, Hasenkamp J, Wulf G, Dreger P, Pfreundschuh M, Gramatzki M, Silling G, Wilhelm C, Zeis M, Görlitz A, Pfeiffer S, Hilgers R, Truemper L, Schmitz N; German High-Grade Lymphoma Study Group. Rituximab after lymphoma-directed conditioning and allogeneic stem-cell transplantation for relapsed and refractory aggressive non-Hodgkin lymphoma (DSHNHL R3): an open-label, randomised, phase 2 trial. Lancet Oncol. 2014 Jun;15(7):757-66. Epub 2014 May 11. link to original article link to original protocol (in German) contains verified protocol PubMed
Fludarabine, Busulfan, ATG, Ibritumomab tiuxetan, then allo HSCT
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Regimen
Study | Evidence |
---|---|
Bouabdallah et al. 2015 (ZEVALLO) | Phase II |
Chemotherapy
- Fludarabine (Fludara) 30 mg/m2 IV once per day on days -6 to -2
- Busulfan (Myleran) 3.2 mg/kg/day (route not specified) on days -5 & -4
Targeted therapy
- Rituximab (Rituxan) 250 mg/m2 IV once per day on days -21 & -14
Radioconjugate therapy
- Ibritumomab tiuxetan (Zevalin) 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day -14
Immunotherapy
- Allogeneic stem cells transfused on day 0
GVHD prophylaxis
- Antithymocyte globulin, rabbit ATG (Thymoglobulin) 2.5 mg/kg IV once on day -1
- Cyclosporine (dose not specified) until day +90 and tapered off by day +180 based on chimerism and GVHD
- Methotrexate (MTX) by the following donor-based criteria:
- Unrelated donors with HLA mismatch: 15 mg/m2 (route not specified) once on day +1, then 10 mg/m2 (route not specified) once per day on days +3 & +6
One course
Immunotherapy
Stem cells transfused on day 0
References
- ZEVALLO: Bouabdallah K, Furst S, Asselineau J, Chevalier P, Tournilhac O, Ceballos P, Vigouroux S, Tabrizi R, Doussau A, Bouabdallah R, Mohty M, Le Gouill S, Blaise D, Milpied N. 90Y-ibritumomab tiuxetan, fludarabine, busulfan and antithymocyte globulin reduced-intensity allogeneic transplant conditioning for patients with advanced and high-risk B-cell lymphomas. Ann Oncol. 2015 Jan;26(1):193-8. Epub 2014 Oct 30. link to original article contains verified protocol PubMed
LEED, then auto HSCT
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LEED: L-PAM (Melphalan), Endoxan (Cyclophosphamide), Etoposide, Dexamethasone
Regimen
Study | Evidence |
---|---|
van Imhoff et al. 2016 (ORCHARRD) | Non-randomized portion of RCT |
Preceding treatment
Autologous HSCT conditioning regimens Stem cells reinfused on day 0
References
- ORCHARRD: van Imhoff GW, McMillan A, Matasar MJ, Radford J, Ardeshna KM, Kuliczkowski K, Kim W, Hong X, Goerloev JS, Davies A, Barrigón MD, Ogura M, Leppä S, Fennessy M, Liao Q, van der Holt B, Lisby S, Hagenbeek A. Ofatumumab versus rituximab salvage chemoimmunotherapy in relapsed or refractory diffuse large B-cell lymphoma: the ORCHARRD study. J Clin Oncol. 2017 Feb 10;35(5):544-51. Epub 2016 Dec 28. link to original article link to data supplement verified protocol in supplement PubMed
R-BEAM, then auto HSCT
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R-BEAM: Rituximab, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan
Regimen variant #1, 750/300/800/800/140
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Vose et al. 2013 (BMT CTN 0401) | Phase III (C) | B-BEAM | Did not meet primary endpoint of PFS24 |
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Targeted therapy
- Rituximab (Rituxan) 375 mg/m2 IV once per day on days -19 & -12
Chemotherapy
- Carmustine (BCNU) 300 mg/m2 IV once on day -6
- Etoposide (Vepesid) 100 mg/m2 IV twice per day on days -5 to -2
- Cytarabine (Ara-C) 100 mg/m2 IV twice per day on days -5 to -2
- Melphalan (Alkeran) 140 mg/m2 IV once on day -1
Supportive therapy
- Autologous stem cells re-infused on day 0
One course
Regimen variant #2, 750/300/1600/3200/140
Study | Evidence |
---|---|
Kirschey et al. 2014 (Mz-135) | Phase II |
A minimum number of 2 × 106/kg bw CD34-positive cells were required to proceed.
Preceding treatment
- R-DexaBEAM x 2
Autologous HSCT conditioning regimens
References
- BMT CTN 0401: Vose JM, Carter S, Burns LJ, Ayala E, Press OW, Moskowitz CH, Stadtmauer EA, Mineshi S, Ambinder R, Fenske T, Horowitz M, Fisher R, Tomblyn M. Phase III randomized study of rituximab/carmustine, etoposide, cytarabine, and melphalan (BEAM) compared with iodine-131 tositumomab/BEAM with autologous hematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: results from the BMT CTN 0401 trial. J Clin Oncol. 2013 May 1;31(13):1662-8. Epub 2013 Mar 11. link to original article link to PMC article contains verified protocol PubMed
- Mz-135: Kirschey S, Flohr T, Wolf HH, Frickhofen N, Gramatzki M, Link H, Basara N, Peter N, Meyer RG, Schmitz N, Weidmann E, Banat A, Schulz A, Kolbe K, Derigs G, Theobald M, Hess G. Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: mature results of a phase II multicentre study. Br J Haematol. 2015 Mar;168(6):824-34. Epub 2014 Dec 28. link to original article contains verified protocol PubMed
R-TBI/Cy, then auto HSCT
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R-TBI/Cy: Rituximab, Total, Body, Irradiation, Cyclophosphamide
Regimen
Study | Evidence |
---|---|
Kirschey et al. 2014 (Mz-135) | Phase II |
Preceding treatment
- R-DexaBEAM x 2
Autologous HSCT conditioning regimens Stem cells reinfused on day 0
References
- Mz-135: Kirschey S, Flohr T, Wolf HH, Frickhofen N, Gramatzki M, Link H, Basara N, Peter N, Meyer RG, Schmitz N, Weidmann E, Banat A, Schulz A, Kolbe K, Derigs G, Theobald M, Hess G. Rituximab combined with DexaBEAM followed by high dose therapy as salvage therapy in patients with relapsed or refractory B-cell lymphoma: mature results of a phase II multicentre study. Br J Haematol. 2015 Mar;168(6):824-34. Epub 2014 Dec 28. link to original article contains verified protocol PubMed
Z-BEAM, then auto HSCT
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Z-BEAM: Zevalin (Ibritumomab tiuxetan), BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan
Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Shimoni et al. 2007 | Phase II | ||
Shimoni et al. 2012 (SHEBA-07-4466-AN-CTIL) | Randomized Phase II (E-esc) | BEAM | Seems to have superior OS |
Briones et al. 2013 (GELTAMO Z-BEAM LDCGB) | Phase II |
Patients in SHEBA-07-4466-AN-CTIL had primary induction failure or were chemosensitive to salvage therapy. Patients in GELTAMO Z-BEAM LDCGB had primary induction failure or were refractory to salvage therapy.
Targeted therapy
- Rituximab (Rituxan) 250 mg/m2 IV once on day -14, given first
Radioconjugate therapy
- Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day -14, given second
Chemotherapy
- Carmustine (BCNU) 300 mg/m2 IV once on day -6
- Etoposide (Vepesid) 200 mg/m2 IV once per day on days -5 to -2
- Cytarabine (Ara-C) 200 mg/m2 IV every 12 hours on days -5 to -2
- Melphalan (Alkeran) 140 mg/m2 IV once on day -1
Supportive therapy
- Autologous stem cells re-infused on day 0
- Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day +4 (Shimoni et al. 2012) or day +7 (GELTAMO Z-BEAM LDCGB) until engraftment
- Valacyclovir (Valtrex) (dose not specified) for one month (Shimoni et al. 2012)
- Acyclovir (Zovirax) (dose not specified) for one month (Briones et al. 2013)
- Trimethoprim-Sulfamethoxazole (Bactrim DS) (dose/frequency not specified) for six months (3 months in GELTAMO Z-BEAM LDCGB)
One course
References
- Shimoni A, Zwas ST, Oksman Y, Hardan I, Shem-Tov N, Yerushalmi R, Avigdor A, Ben-Bassat I, Nagler A. Yttrium-90-ibritumomab tiuxetan (Zevalin) combined with high-dose BEAM chemotherapy and autologous stem cell transplantation for chemo-refractory aggressive non-Hodgkin's lymphoma. Exp Hematol. 2007 Apr;35(4):534-40. link to original article PubMed
- SHEBA-07-4466-AN-CTIL: Shimoni A, Avivi I, Rowe JM, Yeshurun M, Levi I, Or R, Patachenko P, Avigdor A, Zwas T, Nagler A. A randomized study comparing yttrium-90 ibritumomab tiuxetan (Zevalin) and high-dose BEAM chemotherapy versus BEAM alone as the conditioning regimen before autologous stem cell transplantation in patients with aggressive lymphoma. Cancer. 2012 Oct 1;118(19):4706-14. Epub 2012 Jan 17. link to original article contains verified protocol PubMed
- GELTAMO Z-BEAM LDCGB: Briones J, Novelli S, García-Marco JA, Tomás JF, Bernal T, Grande C, Canales MA, Torres A, Moraleda JM, Panizo C, Jarque I, Palmero F, Hernsández M, González-Barca E, López D, Caballero D. Autologous stem cell transplantation after conditioning with Yttrium-90 ibritumomab tiuxetan plus beam in refractory non-Hodgkin diffuse large B-cell lymphoma: results of a prospective, multicenter, phase II clinical trial. Haematologica. 2014 Mar;99(3):505-10. Epub 2013 Oct 25. link to original article contains verified protocol link to PMC article PubMed
Maintenance after salvage therapy
Lenalidomide monotherapy
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Regimen variant #1, 25 mg 21/28, indefinite
Study | Evidence |
---|---|
Ferreri et al. 2017 | Phase II |
Preceding treatment
- Rituximab-containing salvage chemotherapy
Chemotherapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycles
Regimen variant #2, 25 mg 21/28 for 12 months
Study | Evidence |
---|---|
Feldman et al. 2014 (RV-DLBCL-PI-0463) | Phase II |
Preceding treatment
Chemotherapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycle for up to 13 cycles (1 year)
References
- RV-DLBCL-PI-0463: Feldman T, Mato AR, Chow KF, Protomastro EA, Yannotti KM, Bhattacharyya P, Yang X, Donato ML, Rowley SD, Carini C, Valentinetti M, Smith J, Gadaleta G, Bejot C, Stives S, Timberg M, Kdiry S, Pecora AL, Beaven AW, Goy A. Addition of lenalidomide to rituximab, ifosfamide, carboplatin, etoposide (RICER) in first-relapse/primary refractory diffuse large B-cell lymphoma. Br J Haematol. 2014 Jul;166(1):77-83. Epub 2014 Mar 25. link to original article contains verified protocol link to PMC article PubMed
- Ferreri AJ, Sassone M, Zaja F, Re A, Spina M, di Rocco A, Fabbri A, Stelitano C, Frezzato M, Rusconi C, Zambello R, Couto S, Ren Y, Arcari A, Bertoldero G, Nonis A, Scarfò L, Calimeri T, Cecchetti C, Chiozzotto M, Govi S, Ponzoni M. Lenalidomide maintenance in patients with relapsed diffuse large B-cell lymphoma who are not eligible for autologous stem cell transplantation: an open label, single-arm, multicentre phase 2 trial. Lancet Haematol. 2017 Mar;4(3):e137-e146. Epub 2017 Feb 17. link to original article contains protocol PubMed
Rituximab monotherapy
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Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Gisselbrecht et al. 2010 (CORAL) | Phase III (E-esc) | Observation | Did not meet primary endpoint of EFS (*) |
Treatment begins on day +28. Reported efficacy is based on the 2012 update.
Preceding treatment
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
8-week cycle for 6 cycles
References
- CORAL: 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 link to PMC article PubMed
- Update: Gisselbrecht C, Schmitz N, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Milpied NJ, Radford J, Ketterer N, Shpilberg O, Dührsen U, Hagberg H, Ma DD, Viardot A, Lowenthal R, Brière J, Salles G, Moskowitz CH, Glass B. Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapsed aggressive lymphoma. J Clin Oncol. 2012 Dec 20;30(36):4462-9. Epub 2012 Oct 22. link to original article contains verified protocol link to PMC article PubMed
Relapsed or refractory, further lines of therapy
Note: these are regimens that are generally given with non-curative intent. However, some of these regimens, such as CAR-T therapy, can function as a bridge to consolidation with one of the salvage consolidation regimens, above.
Axicabtagene ciloleucel monotherapy
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Regimen
FDA-recommended dose |
Study | Years of enrollment | Evidence | Efficacy |
---|---|---|---|
Locke et al. 2017 (ZUMA-1) | 2015-2016 | Phase I/II | ORR: 83%; CR: 59%
Median OS: not reached Median PFS: 6 months Median duration of response: 11 months |
Lymphodepletion chemotherapy
- Cyclophosphamide 500 mg/m2 once per day on days -5 to -3 prior to Axicabtagene ciloleucel infusion
- Fludarabine 30 mg/m2 once per day on days -5 to -3 prior to Axicabtagene ciloleucel infusion
Immunotherapy
- Axicabtagene ciloleucel (Yescarta) target dose of 2 × 106 CAR T cells/kg IV once on day 0
Supportive medications
- Acetaminophen (Tylenol) 650 mg PO once on day 0, approximately 60 minutes prior to Axicabtagene ciloleucel (Yescarta)
- Diphenhydramine (Benadryl) 12.5 mg IV or PO once on day 0, approximately 60 minutes prior to Axicabtagene ciloleucel (Yescarta)
One course; patients with initial response and disease progression at least 3 months later could be retreated
References
- Phase 1: Locke FL, Neelapu SS, Bartlett NL, Siddiqi T, Chavez JC, Hosing CM, Ghobadi A, Budde LE, Bot A, Rossi JM, Jiang Y, Xue AX, Elias M, Aycock J, Wiezorek J, Go WY. Phase 1 results of ZUMA-1: A multicenter study of KTE-C19 anti-CD19 CAR T cell therapy in refractory aggressive lymphoma. Mol Ther. 2017 Jan 4;25(1):285-295. Epub 2017 Jan 4. link to original article link to PMC article PubMed
- ZUMA-1: Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Miklos DB, Jacobson CA, Braunschweig I, Oluwole OO, Siddiqi T, Lin Y, Timmerman JM, Stiff PJ, Friedberg JW, Flinn IW, Goy A, Hill BT, Smith MR, Deol A, Farooq U, McSweeney P, Munoz J, Avivi I, Castro JE, Westin JR, Chavez JC, Ghobadi A, Komanduri KV, Levy R, Jacobsen ED, Witzig TE, Reagan P, Bot A, Rossi J, Navale L, Jiang Y, Aycock J, Elias M, Chang D, Wiezorek J, Go WY. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017 Dec 28;377(26):2531-2544. Epub 2017 Dec 10. link to original article contains verified protocol link to PMC article PubMed
- Update: Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, Lin Y, Braunschweig I, Hill BT, Timmerman JM, Deol A, Reagan PM, Stiff P, Flinn IW, Farooq U, Goy A, McSweeney PA, Munoz J, Siddiqi T, Chavez JC, Herrera AF, Bartlett NL, Wiezorek JS, Navale L, Xue A, Jiang Y, Bot A, Rossi JM, Kim JJ, Go WY, Neelapu SS. Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol. 2019 Jan;20(1):31-42. Epub 2018 Dec 2. link to original article link to PMC article contains verified protocol PubMed
Bendamustine monotherapy
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Regimen
Study | Evidence | Efficacy |
---|---|---|
Weidmann et al. 2002 | Phase II, <20 pts | 44% |
Chemotherapy
- Bendamustine 120 mg/m2 IV once per day on days 1 & 2
21-day cycle for up to 6 cycles
References
- Weidmann E, Kim SZ, Rost A, Schuppert H, Seipelt G, Hoelzer D, Mitrou PS. Bendamustine is effective in relapsed or refractory aggressive non-Hodgkin's lymphoma. Ann Oncol. 2002 Aug;13(8):1285-9. link to original article contains verified protocol PubMed
Blinatumomab monotherapy
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Regimen
Study | Evidence |
---|---|
Viardot et al. 2016 (MT103-208) | Phase II |
Two dosing schemas were evaluated; this is the preferred dosing regimen, per the authors.
Chemotherapy
- Blinatumomab (Blincyto) as follows:
- 9 mcg/day IV continuous infusion during week 1, then
- 28 mcg/day IV continuous infusion during week 2, then
- 112 mcg/day IV continuous infusion for remainder of the 8-week course
Supportive medications
- Dexamethasone (Decadron) 20 mg PO 6 to 12 hours before infusion start and dose increases, 20 mg PO 1 hour before infusion start and dose increases, and 8 mg PO three times per day for 2 days following infusion start and dose increases
- Patients with neurologic symptoms or cytokine release syndrome received 8 mg IV or PO every 8 hours for up to 3 days, with a subsequent taper over 4 days
8-week course
Responders could receive a 4-week consolidation cycle after a 4-week treatment-free period. Patients relapsing within 2 years of treatment could receive another 8-week course.
References
- MT103-208: Viardot A, Goebeler ME, Hess G, Neumann S, Pfreundschuh M, Adrian N, Zettl F, Libicher M, Sayehli C, Stieglmaier J, Zhang A, Nagorsen D, Bargou RC. Phase 2 study of the bispecific T-cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B-cell lymphoma. Blood. 2016 Mar 17;127(11):1410-6. Epub 2016 Jan 11. link to original article contains verified protocol link to PMC article PubMed
BR
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BR: Bendamustine & Rituximab R-B: Rituximab & Bendamustine
Regimen variant #1, 6 cycles
Study | Evidence |
---|---|
Ohmachi et al. 2013 (SymBio 2010001) | Phase II |
Vacirca et al. 2013 (PI-08904) | Phase II |
Note: Bendamustine was given on days 2 & 3 in SymBio 2010001 and on days 1 & 2 in PI-08904.
Chemotherapy
- Bendamustine 120 mg/m2 IV once per day on days 1 & 2 OR on days 2 & 3
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
Supportive medications
- Recommended PCP prophylaxis: Trimethoprim-Sulfamethoxazole (Bactrim DS)
- Recommended VZV prophylaxis: Acyclovir (Zovirax)
21-day cycle for up to 6 cycles
Regimen variant #2, indefinite
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Dang et al. 2017 (B1931008) | Phase III (C) | R-INO | Did not meet primary endpoint of OS |
Chemotherapy
- Bendamustine 120 mg/m2 IV once per day on days 1 & 2
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
28-day cycles
References
- SymBio 2010001: 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
- PI-08904: Vacirca JL, Acs PI, Tabbara IA, Rosen PJ, Lee P, Lynam E. Bendamustine combined with rituximab for patients with relapsed or refractory diffuse large B cell lymphoma. Ann Hematol. 2014 Mar;93(3):403-9. Epub 2013 Aug 17. link to original article contains verified protocol link to PMC article PubMed
- B1931008: Dang NH, Ogura M, Castaigne S, Fayad LE, Jerkeman M, Radford J, Pezzutto A, Bondarenko I, Stewart DA, Shnaidman M, Sullivan S, Vandendries E, Tobinai K, Ramchandren R, Hamlin PA, Giné E, Ando K. Randomized, phase 3 trial of inotuzumab ozogamicin plus rituximab versus chemotherapy plus rituximab for relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Br J Haematol. 2018 Aug;182(4):583-586. Epub 2017 Jul 5. link to original article link to PMC article contains protocol PubMed
BR & Polatuzumab vedotin
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BR & Polatuzumab vedotin: Bendamustine, Rituximab, Polatuzumab vedotin
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
GO29365 | 2014-2016 | Randomized Phase II (E-RT-esc) | BR | Seems to have superior ORR |
Chemotherapy
- Bendamustine as follows:
- Cycle 1: 90 mg/m2 IV once per day on days 2 & 3
- Cycles 2 to 6: 90 mg/m2 IV once per day on days 1 & 2
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Polatuzumab vedotin (Polivy) as follows:
- Cycle 1: 1.8 mg/kg IV over 90 minutes once on day 2
- Cycles 2 to 6: 1.8 mg/kg IV over 90 minutes once on day 1
References
- GO29365: Sehn LH, Herrera AF, Flowers CR, Kamdar MK, McMillan A, Hertzberg M, Assouline S, Kim TM, Kim WS, Ozcan M, Hirata J, Penuel E, Paulson JN, Cheng J, Ku G, Matasar MJ. Polatuzumab Vedotin in Relapsed or Refractory Diffuse Large B-Cell Lymphoma. J Clin Oncol. 2020 Jan 10; 38(2):155-165. Epub 2019 Nov 6. link to original article link to pubmed CT.gov
Brentuximab vedotin monotherapy
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Regimen
Study | Evidence |
---|---|
Jacobsen et al. 2015 (SGN35-012) | Phase II |
Jacobsen et al. 2015 treated patients with CD30+ non-Hodgkin lymphoma, as determined by IHC; the 2016 update describes a subgroup with undetectable CD30.
Chemotherapy
- Brentuximab vedotin (Adcetris) 1.8 mg/kg IV over 30 minutes once on day 1
21-day cycles
References
- SGN35-012: Jacobsen ED, Sharman JP, Oki Y, Advani RH, Winter JN, Bello CM, Spitzer G, Palanca-Wessels MC, Kennedy DA, Levine P, Yang J, Bartlett NL. Brentuximab vedotin demonstrates objective responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 expression. Blood. 2015 Feb 26;125(9):1394-402. Epub 2015 Jan 8. link to original article contains verified protocol PubMed
- Update: Bartlett NL, Smith MR, Siddiqi T, Advani RH, O'Connor OA, Sharman JP, Feldman T, Savage KJ, Shustov AR, Diefenbach CS, Oki Y, Palanca-Wessels MC, Uttarwar M, Li M, Yang J, Jacobsen ED. Brentuximab vedotin activity in diffuse large B-cell lymphoma with CD30 undetectable by visual assessment of conventional immunohistochemistry. Leuk Lymphoma. 2017 Jul;58(7):1607-1616. Epub 2016 Nov 20. link to original article PubMed
Etoposide monotherapy
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Regimen variant #1, IV (3 days/cycle)
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Czuczman et al. 2017 (DLC-001) | Phase II/III (C) | Lenalidomide | Might have inferior ORR |
Chemotherapy
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3
28-day cycle for up to 6 cycles
Regimen variant #2, IV (5 days/cycle)
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Pettengell et al. 2012 (PIX301) | Phase III, <20 pts in this arm (C) | Pixantrone | Seems to have inferior CR/CRu rate |
Czuczman et al. 2017 (DLC-001) | Phase II/III (C) | Lenalidomide | Might have inferior ORR |
Chemotherapy
- Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 5
28-day cycle for up to 6 cycles
Regimen variant #3, PO (10 days/cycle)
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Czuczman et al. 2017 (DLC-001) | Phase II/III (C) | Lenalidomide | Might have inferior ORR |
Chemotherapy
- Etoposide (Vepesid) 50 mg/m2 PO once per day on days 1 to 10
28-day cycle for up to 6 cycles
Regimen variant #4, PO (14 days/cycle)
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Czuczman et al. 2017 (DLC-001) | Phase II/III (C) | Lenalidomide | Might have inferior ORR |
Chemotherapy
- Etoposide (Vepesid) 50 mg/m2 PO once per day on days 1 to 14
28-day cycle for up to 6 cycles
Regimen variant #5, PO (21 days/cycle)
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Hainsworth et al. 1992 | Phase II | ||
Pettengell et al. 2012 (PIX301) | Phase III, <20 pts in this arm (C) | Pixantrone | Seems to have inferior CR/CRu rate |
Czuczman et al. 2017 (DLC-001) | Phase II/III (C) | Lenalidomide | Might have inferior ORR |
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Chemotherapy
- Etoposide (Vepesid) 50 mg/m2 PO once per day on days 1 to 21
28-day cycle for up to 6 cycles
References
- Hainsworth JD, Johnson DH, Greco FA. Chronic etoposide schedules in the treatment of non-Hodgkin's lymphoma. Semin Oncol. 1992 Dec;19(6 Suppl 14):13-8. link to original article PubMed
- PIX301: 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
- DLC-001: Czuczman MS, Trněný M, Davies A, Rule S, Linton KM, Wagner-Johnston N, Gascoyne RD, Slack GW, Brousset P, Eberhard DA, Hernandez-Ilizaliturri FJ, Salles G, Witzig TE, Zinzani PL, Wright GW, Staudt LM, Yang Y, Williams PM, Lih CJ, Russo J, Thakurta A, Hagner P, Fustier P, Song D, Lewis ID. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2017 Aug 1;23(15):4127-4137. Epub 2017 Apr 5. link to original article contains verified protocol in supplement PubMed
Everolimus monotherapy
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Regimen
Study | Evidence |
---|---|
Witzig et al. 2011 | Phase II |
Chemotherapy
- 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
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 link to PMC article PubMed
Everolimus & Rituximab
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Regimen
Study | Evidence |
---|---|
Barnes et al. 2013 (MGH 09-002) | Phase II |
Chemotherapy
- Everolimus (Afinitor) as follows:
- Cycle 1: 5 mg PO once per day on days 1 to 14, then 10 mg PO once per day on days 15 to 28
- Cycles 2 to 6: 10 mg PO once per day
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
- Cycles 2 to 6: 375 mg/m2 IV once on day 1
28-day cycle for 6 cycles
Subsequent treatment
- Responders had the option of continuing everolimus alone for another 6 months
References
- MGH 09-002: Barnes JA, Jacobsen E, Feng Y, Freedman A, Hochberg EP, LaCasce AS, Armand P, Joyce R, Sohani AR, Rodig SJ, Neuberg D, Fisher DC, Abramson JS. Everolimus in combination with rituximab induces complete responses in heavily pretreated diffuse large B-cell lymphoma. Haematologica. 2013 Apr;98(4):615-9. Epub 2012 Nov 9. link to original article contains verified protocol link to PMC article PubMed
Gemcitabine monotherapy
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Regimen variant #1, bi-weekly
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Czuczman et al. 2017 (DLC-001) | Phase II/III (C) | Lenalidomide | Might have inferior ORR |
Chemotherapy
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 15
28-day cycle for up to 6 cycles
Regimen variant #2, 3 out of 4 weeks x 6
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Czuczman et al. 2017 (DLC-001) | Phase II/III (C) | Lenalidomide | Might have inferior ORR |
Chemotherapy
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1, 8, 15
28-day cycle for up to 6 cycles
Regimen variant #3, indefinite 3 out of 4 weeks
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Fosså et al. 1999 | Phase II | ||
Pettengell et al. 2012 (PIX301) | Phase III, <20 pts in this arm (C) | Pixantrone | Seems to have inferior CR/CRu rate |
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Chemotherapy
- Gemcitabine (Gemzar) as follows:
- Cycle 1: 1250 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
- Fosså et al. 1999, subsequent cycles (if no hematologic or nonhematologic toxicities): Optional increase to 1500 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
28-day cycle for up to 6 cycles (PIX301) or indefinitely (Fosså et al. 1999)
References
- Fosså A, Santoro A, Hiddemann W, Truemper L, Niederle N, Buksmaui S, Bonadonna G, Seeber S, Nowrousian MR. Gemcitabine as a single agent in the treatment of relapsed or refractory aggressive non-Hodgkin's lymphoma. J Clin Oncol. 1999 Dec;17(12):3786-92. link to original article contains verified protocol PubMed
- PIX301: 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
- DLC-001: Czuczman MS, Trněný M, Davies A, Rule S, Linton KM, Wagner-Johnston N, Gascoyne RD, Slack GW, Brousset P, Eberhard DA, Hernandez-Ilizaliturri FJ, Salles G, Witzig TE, Zinzani PL, Wright GW, Staudt LM, Yang Y, Williams PM, Lih CJ, Russo J, Thakurta A, Hagner P, Fustier P, Song D, Lewis ID. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2017 Aug 1;23(15):4127-4137. Epub 2017 Apr 5. link to original article contains verified protocol in supplement PubMed
Gemcitabine & Rituximab
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R-G: Rituximab & Gemcitabine
Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Dang et al. 2017 (B1931008) | Phase III (C) | R-INO | Did not meet primary endpoint of OS |
Chemotherapy
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
- Cycle 2 onwards: 375 mg/m2 IV once on day 1
28-day cycles
References
- B1931008: Dang NH, Ogura M, Castaigne S, Fayad LE, Jerkeman M, Radford J, Pezzutto A, Bondarenko I, Stewart DA, Shnaidman M, Sullivan S, Vandendries E, Tobinai K, Ramchandren R, Hamlin PA, Giné E, Ando K. Randomized, phase 3 trial of inotuzumab ozogamicin plus rituximab versus chemotherapy plus rituximab for relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Br J Haematol. 2018 Aug;182(4):583-586. Epub 2017 Jul 5. link to original article link to PMC article contains protocol PubMed
GVD
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GVD: Gemcitabine, Vinorelbine, Doxil (Doxorubicin liposomal)
Regimen
Study | Evidence |
---|---|
Bai et al. 2013 | Retrospective |
Chemotherapy
- Gemcitabine (Gemzar) 800 mg/m2 IV once on day 1
- Vinorelbine (Navelbine) 15 mg/m2 IV once on day 1
- Pegylated liposomal doxorubicin (Doxil) 20 mg/m2 IV once on day 1
14-day cycles
References
- Retrospective: Bai B, Huang HQ, Cai QQ, Wang XX, Cai QC, Lin ZX, Gao Y, Xia Y, Bu Q, Guo Y. Promising long-term outcome of gemcitabine, vinorelbine, liposomal doxorubicin (GVD) in 14-day schedule as salvage regimen for patients with previously heavily treated Hodgkin's lymphoma and aggressive non-Hodgkin's lymphoma. Med Oncol. 2013 Mar;30(1):350. Epub 2013 Jan 18. link to original article contains protocol PubMed
Ibritumomab tiuxetan protocol
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Regimen
Study | Evidence |
---|---|
Morschhauser et al. 2007 | Phase II |
To be completed
Radioimmunotherapy
References
- Morschhauser F, Illidge T, Huglo D, Martinelli G, Paganelli G, Zinzani PL, Rule S, Liberati AM, Milpied N, Hess G, Stein H, Kalmus J, Marcus R. Efficacy and safety of yttrium-90 ibritumomab tiuxetan in patients with relapsed or refractory diffuse large B-cell lymphoma not appropriate for autologous stem-cell transplantation. Blood. 2007 Jul 1;110(1):54-8. Epub 2007 Mar 26. link to original article PubMed
Ibrutinib monotherapy
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Regimen
Study | Evidence |
---|---|
Wilson et al. 2015 (PCYC-1106-CA) | Phase II |
Clinically meaningful responses were observed in the ABC subtype, only. Further clinical trials are currently underway.
Chemotherapy
- Ibrutinib (Imbruvica) 560 mg PO once per day
Continued indefinitely
References
- PCYC-1106-CA: Wilson WH, Young RM, Schmitz R, Yang Y, Pittaluga S, Wright G, Lih CJ, Williams PM, Shaffer AL, Gerecitano J, de Vos S, Goy A, Kenkre VP, Barr PM, Blum KA, Shustov A, Advani R, Fowler NH, Vose JM, Elstrom RL, Habermann TM, Barrientos JC, McGreivy J, Fardis M, Chang BY, Clow F, Munneke B, Moussa D, Beaupre DM, Staudt LM. Targeting B cell receptor signaling with ibrutinib in diffuse large B cell lymphoma. Nat Med. 2015 Aug;21(8):922-6. Epub 2015 Jul 20. link to original article PubMed
Ifosfamide monotherapy
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Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Case et al. 1991 (CALGB 8552) | Phase II | ||
Pettengell et al. 2012 (PIX301) | Phase III, <20 pts in this arm (C) | Pixantrone | Seems to have inferior CR/CRu rate |
Dose & schedule is as given in Pettengell et al. 2012. CALGB 8552 used a different dose & schedule. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Chemotherapy
- Ifosfamide (Ifex) 3000 mg/m2 IV once per day on days 1 & 2
Supportive medications
- Mesna (Mesnex) dose not specified
28-day cycle for up to 6 cycles
References
- CALGB 8552: 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. link to original article PubMed
- PIX301: 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 monotherapy
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Regimen variant #1, low dose
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Czuczman et al. 2017 (DLC-001) | Phase II/III (E-switch-ooc) | Investigator's choice of: 1. Etoposide 2. Gemcitabine 3. Oxaliplatin 4. Rituximab |
Might have superior ORR |
This dose was intended for patients with CrCl at least 30 but less than 60 mL/min/1.73m2.
Chemotherapy
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
28-day cycles
Regimen variant #2, normal dose
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Wiernik et al. 2008 (NHL-002) | Phase II | ORR: 35% | |
Witzig et al. 2011 (NHL-003) | Phase II | ORR: 28% | |
Czuczman et al. 2017 (DLC-001) | Phase II/III (E-switch-ooc) | Investigator's choice of: 1. Etoposide 2. Gemcitabine 3. Oxaliplatin 4. Rituximab |
Might have superior ORR |
Chemotherapy
- Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21
28-day cycles
References
- NHL-002: 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
- NHL-003: 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
- DLC-001: Czuczman MS, Trněný M, Davies A, Rule S, Linton KM, Wagner-Johnston N, Gascoyne RD, Slack GW, Brousset P, Eberhard DA, Hernandez-Ilizaliturri FJ, Salles G, Witzig TE, Zinzani PL, Wright GW, Staudt LM, Yang Y, Williams PM, Lih CJ, Russo J, Thakurta A, Hagner P, Fustier P, Song D, Lewis ID. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2017 Aug 1;23(15):4127-4137. Epub 2017 Apr 5. link to original article contains verified protocol PubMed
Lenalidomide & Rituximab
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Regimen variant #1
Study | Evidence |
---|---|
Wang et al. 2013 (MDACC 2005-0461) | Phase II |
Chemotherapy
- Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycles
Regimen variant #2
Study | Evidence |
---|---|
Zinzani et al. 2011a | Phase II |
Chemotherapy
- 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 cycle for 4 cycles
Subsequent treatment
- SD or better: Lenalidomide maintenance
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
- Update: Zinzani PL, Pellegrini C, Derenzini E, Argnani L, Pileri S. Long-term efficacy of the combination of lenalidomide and rituximab in elderly relapsed/refractory diffuse large B-cell lymphoma patients. Hematol Oncol. 2013 Dec;31(4):223-4. Epub 2013 Apr 26. link to original article PubMed
- MDACC 2005-0461: 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
Mitoxantrone monotherapy
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Regimen
Study | Evidence |
---|---|
Bajetta et al. 1988a | Phase II |
Chemotherapy
- Mitoxantrone (Novantrone) 14 mg/m2 IV over 30 minutes once on day 1
21-day cycles
References
- Bajetta E, Buzzoni R, Valagussa P, Bonadonna G. Mitoxantrone: an active agent in refractory non-Hodgkin's lymphomas. Am J Clin Oncol. 1988 Apr;11(2):100-3. contains protocol PubMed
- PIX301: 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
Obinutuzumab monotherapy
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Regimen
Study | Evidence |
---|---|
Salles et al. 2012 (GAUGUIN) | Phase I/II |
Note: this is the phase II dosing reported in Morschhauser et al. 2013.
Chemotherapy
- Obinutuzumab (Gazyva) as follows:
- Cycle 1: 1600 mg (diluted to 10 mg/mL) IV once per day on days 1 & 8
- Cycles 2 to 8: 800 mg IV once on day 1
- Initial infusion rate is 50 mg/hour. In the absence of infusion-related reactions (IRRs), the rate is then increased by 50 mg/hour every 30 minutes, up to a maximum of 400 mg/hour.
Supportive medications
- Acetaminophen (Tylenol) or paracetamol 650 to 1000 mg PO once per infusion, 30 minutes prior to Obinutuzumab (Gazyva)
- "An antihistamine" once per infusion, 30 minutes prior to Obinutuzumab (Gazyva)
- If there were no infusion-related reactions (IRRs) requiring medication or infusion interruption, antihistamine could be omitted for subsequent infusions
- Premedication with corticosteroids recommended for patients at high risk of infusion-related reactions (IRRs)
- Use of G-CSF allowed for severe neutropenia
- Antibiotic prophylaxis allowed
21-day cycle for 8 cycles
References
- GAUGUIN: Salles G, Morschhauser F, Lamy T, Milpied N, Thieblemont C, Tilly H, Bieska G, Asikanius E, Carlile D, Birkett J, Pisa P, Cartron G. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients. Blood. 2012 May 31;119(22):5126-32. Epub 2012 Mar 19. link to original article PubMed
- Subgroup analysis: 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
- Subgroup analysis: Salles GA, Morschhauser F, Solal-Céligny P, Thieblemont C, Lamy T, Tilly H, Gyan E, Lei G, Wenger M, Wassner-Fritsch E, Cartron G. Obinutuzumab (GA101) in patients with relapsed/refractory indolent non-Hodgkin lymphoma: results from the phase II GAUGUIN study. J Clin Oncol. 2013 Aug 10;31(23):2920-6. Epub 2013 Jul 8. link to original article contains verified protocol PubMed
- Subgroup analysis: Cartron G, de Guibert S, Dilhuydy MS, Morschhauser F, Leblond V, Dupuis J, Mahe B, Bouabdallah R, Lei G, Wenger M, Wassner-Fritsch E, Hallek M. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014 Oct 2;124(14):2196-202. Epub 2014 Aug 20. link to original article contains verified protocol PubMed
Ofatumumab monotherapy
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Regimen
Study | Evidence |
---|---|
Coiffier et al. 2013 (415 Study) | Phase II |
Chemotherapy
- Ofatumumab (Arzerra) as follows:
- Cycle 1: 300 mg IV once on day 1, then 1000 mg IV once per day on days 8, 15, 22
- Cycle 2: 1000 mg IV once per day on days 1, 8, 15, 22
Supportive medications
- Acetaminophen (Tylenol) (or equivalent) 1000 mg PO once per day on days 1, 8, 15, 22; 30 minutes to 2 hours prior to Ofatumumab (Arzerra)
- Cetirizine (Zyrtec) (or equivalent) 10 mg PO once per day on days 1, 8, 15, 22; 30 minutes to 2 hours prior to Ofatumumab (Arzerra)
- Prednisolone (Millipred) (or equivalent) 100 mg (route not specified) once per day on days 1 & 8; 30 minutes to 2 hours prior to Ofatumumab (Arzerra) for first 2 infusions, only
28-day cycle for 2 cycles
References
- 415 Study: Coiffier B, Radford J, Bosly A, Martinelli G, Verhoef G, Barca G, Davies A, Decaudin D, Gallop-Evans E, Padmanabhan-Iyer S, Van Eygen K, Wu KL, Gupta IV, Lin TS, Goldstein N, Jewell RC, Winter P, Lisby S; 415 study investigators. A multicentre, phase II trial of ofatumumab monotherapy in relapsed/progressive diffuse large B-cell lymphoma. Br J Haematol. 2013 Nov;163(3):334-42. Epub 2013 Aug 23. link to original article contains verified protocol PubMed
Oxaliplatin monotherapy
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Regimen variant #1, 100 mg/m2
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Germann et al. 1999 | Phase II, <20 pts in this subgroup | ||
Pettengell et al. 2012 (PIX301) | Phase III, <20 pts in this arm (C) | Pixantrone | Seems to have inferior CR/CRu rate |
Czuczman et al. 2017 (DLC-001) | Phase II/III (C) | Lenalidomide | Might have inferior ORR |
Germann et al. give a range of 100 to 130 mg/m2. To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Chemotherapy
- Oxaliplatin (Eloxatin) 100 mg/m2 IV once on day 1
21-day cycles (maximum of 6 cycles in PIX301 & DLC-001)
Regimen variant #2, 130 mg/m2
Study | Evidence | Efficacy |
---|---|---|
Germann et al. 1999 | Phase II, <20 pts in this subgroup | |
Oki et al. 2005 | Phase II | ORR: 27% (95% CI, 13–47) |
Germann et al. give a range of 100 to 130 mg/m2.
Chemotherapy
- Oxaliplatin (Eloxatin) 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. 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
- PIX301: 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
- DLC-001: Czuczman MS, Trněný M, Davies A, Rule S, Linton KM, Wagner-Johnston N, Gascoyne RD, Slack GW, Brousset P, Eberhard DA, Hernandez-Ilizaliturri FJ, Salles G, Witzig TE, Zinzani PL, Wright GW, Staudt LM, Yang Y, Williams PM, Lih CJ, Russo J, Thakurta A, Hagner P, Fustier P, Song D, Lewis ID. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2017 Aug 1;23(15):4127-4137. Epub 2017 Apr 5. link to original article contains verified protocol in supplement PubMed
Panobinostat monotherapy
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Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Assouline et al. 2016 (Q-CROC-02) | Randomized Phase II (E-de-esc) | Panobinostat & Rituximab | Did not meet primary endpoint of ORR |
Note: patients had a median of 2 prior treatments (range 1-8).
Chemotherapy
- Panobinostat (Farydak) 30 mg PO three times per week (e.g., MWF)
21-day cycles
References
- Q-CROC-02: Assouline SE, Nielsen TH, Yu S, Alcaide M, Chong L, MacDonald D, Tosikyan A, Kukreti V, Kezouh A, Petrogiannis-Haliotis T, Albuquerque M, Fornika D, Alamouti S, Froment R, Greenwood CM, Oros KK, Camglioglu E, Sharma A, Christodoulopoulos R, Rousseau C, Johnson N, Crump M, Morin RD, Mann KK. Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma. Blood. 2016 Jul 14;128(2):185-94. Epub 2016 May 10. link to original article contains verified protocol link to PMC article PubMed
Panobinostat & Rituximab
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Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Assouline et al. 2016 (Q-CROC-02) | Randomized Phase II, <20 pts (E-esc) | Panobinostat | Did not meet primary endpoint of ORR |
Note: patients had a median of 3 prior treatments (range 2-9).
Chemotherapy
- Panobinostat (Farydak) 30 mg PO three times per week (e.g., MWF)
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
21-day cycles
References
- Q-CROC-02: Assouline SE, Nielsen TH, Yu S, Alcaide M, Chong L, MacDonald D, Tosikyan A, Kukreti V, Kezouh A, Petrogiannis-Haliotis T, Albuquerque M, Fornika D, Alamouti S, Froment R, Greenwood CM, Oros KK, Camglioglu E, Sharma A, Christodoulopoulos R, Rousseau C, Johnson N, Crump M, Morin RD, Mann KK. Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma. Blood. 2016 Jul 14;128(2):185-94. Epub 2016 May 10. link to original article contains verified protocol link to PMC article PubMed
Pixantrone monotherapy
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Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Pettengell et al. 2012 (PIX301) | Phase III (E-switch-ic) | Investigator's choice of: 1. Etoposide 2. Gemcitabine 3. Ifosfamide 4. Mitoxantrone 5. Oxaliplatin 6. Vinorelbine |
Seems to have superior CR/CRu rate |
Chemotherapy
- Pixantrone (Pixuvri) 85 mg/m2 IV once per day on days 1, 8, 15
28-day cycle for up to 6 cycles
References
- PIX301: 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
- Post-hoc analysis: Pettengell R, Sebban C, Zinzani PL, Derigs HG, Kravchenko S, Singer JW, Theocharous P, Wang L, Pavlyuk M, Makhloufi KM, Coiffier B. Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B-cell non-Hodgkin lymphoma: post-hoc analyses from a phase III trial. Br J Haematol. 2016 Sep;174(5):692-9. Epub 2016 Apr 26. link to original article link to PMC article PubMed
Rituximab monotherapy
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Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Coiffier et al. 1998 | Randomized Phase II (E-de-esc) | Rituximab; higher-dose | Did not meet primary endpoint of ORR |
Czuczman et al. 2017 (DLC-001) | Phase II/III (C) | Lenalidomide | Might have inferior ORR |
Chemotherapy
- Rituximab (Rituxan) as follows:
- Cycle 1: 375 mg/m2 IV once per day on days 1, 8, 15, 22
- Cycles 4, 6, 8, 10: 375 mg/m2 IV once on day 1
28-day cycle for 10 cycles (8 doses total)
References
- Coiffier B, Haioun C, Ketterer N, Engert A, Tilly H, Ma D, Johnson P, Lister A, Feuring-Buske M, Radford JA, Capdeville R, Diehl V, Reyes F. Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory aggressive lymphoma: a multicenter phase II study. Blood. 1998 Sep 15;92(6):1927-32. link to original article PubMed
- DLC-001: Czuczman MS, Trněný M, Davies A, Rule S, Linton KM, Wagner-Johnston N, Gascoyne RD, Slack GW, Brousset P, Eberhard DA, Hernandez-Ilizaliturri FJ, Salles G, Witzig TE, Zinzani PL, Wright GW, Staudt LM, Yang Y, Williams PM, Lih CJ, Russo J, Thakurta A, Hagner P, Fustier P, Song D, Lewis ID. A phase 2/3 multicenter, randomized, open-label study to compare the efficacy and safety of lenalidomide versus investigator's choice in patients with relapsed or refractory diffuse large B-cell lymphoma. Clin Cancer Res. 2017 Aug 1;23(15):4127-4137. Epub 2017 Apr 5. link to original article contains verified protocol in supplement PubMed
R-BL
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R-BL: Rituximab, Bendamustine, Lenalidomide
Regimen
Study | Evidence | Efficacy |
---|---|---|
Hitz et al. 2016 (SAKK 38/08) | Phase II | ORR: 61% (95% CI 45-76%) |
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Bendamustine 70 mg/m2 IV once per day on days 1 & 2
- Lenalidomide (Revlimid) 10 mg PO once per day on days 1 to 21
28-day cycle for 6 cycles
References
- Hitz F, Zucca E, Pabst T, Fischer N, Cairoli A, Samaras P, Caspar CB, Mach N, Krasniqi F, Schmidt A, Rothermundt C, Enoiu M, Eckhardt K, Berardi Vilei S, Rondeau S, Mey U. Rituximab, bendamustine and lenalidomide in patients with aggressive B-cell lymphoma not eligible for anthracycline-based therapy or intensive salvage chemotherapy - SAKK 38/08. Br J Haematol. 2016 Jul;174(2):255-63. Epub 2016 Mar 28. link to original article contains protocol PubMed
R-CVEP
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R-CVEP: Rituximab, Cyclophosphamide, Vorinostat, Etoposide, Prednisone
Regimen
Study | Evidence |
---|---|
Straus et al. 2014 (MSK 08-045) | Phase II |
The MTD for vorinostat was 300 mg in this phase I/II trial.
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once per day on days 1 & 8
- Vorinostat (Zolinza) 300 mg PO once per day on days 1 to 10
- Etoposide (Vepesid) 70 mg/m2 IV once on day 1
- Prednisone (Sterapred) 60 mg/m2 PO once per day on days 1 to 10
28-day cycle for 6 cycles
References
- MSK 08-045: Straus DJ, Hamlin PA, Matasar MJ, Lia Palomba M, Drullinsky PR, Zelenetz AD, Gerecitano JF, Noy A, Hamilton AM, Elstrom R, Wegner B, Wortman K, Cella D. Phase I/II trial of vorinostat with rituximab, cyclophosphamide, etoposide and prednisone as palliative treatment for elderly patients with relapsed or refractory diffuse large B-cell lymphoma not eligible for autologous stem cell transplantation. Br J Haematol. 2015 Mar;168(5):663-70. Epub 2014 Oct 15. link to original article contains protocol PubMed
R-GemOx
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R-GemOx: Rituximab, Gemcitabine, Oxaliplatin GEMOX-R: GEMcitabine, OXaliplatin, Rituximab
Regimen variant #1, 14-day cycles
Study | Evidence |
---|---|
El Gnaoui et al. 2007 | Phase II |
Mounier et al. 2013 | Phase II |
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV at fixed dose rate over 100 minutes 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 on day 1, prior to Rituximab (Rituxan)
- Acetaminophen (Tylenol) 1000 mg PO once on day 1, prior to Rituximab (Rituxan)
- Dexchlorpheniramine (Polaramine) 6 mg PO once on day 1, prior to Rituximab (Rituxan)
- Primary prophylaxis with G-CSF was not permitted
14-day cycle for up to 8 cycles
Regimen variant #2, 21-day cycles
Study | Evidence |
---|---|
López et al. 2008 | Phase II |
Chemotherapy
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
- Gemcitabine (Gemzar) 1000 mg/m2 IV once on day 1
- Oxaliplatin (Eloxatin) 100 mg/m2 IV once on day 1
21-day cycle for 6 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
- López A, Gutiérrez A, Palacios A, Blancas I, Navarrete M, Morey M, Perelló A, Alarcón J, Martínez J, Rodríguez J. GEMOX-R regimen is a highly effective salvage regimen in patients with refractory/relapsing diffuse large-cell lymphoma: a phase II study. Eur J Haematol. 2008 Feb;80(2):127-32. Epub 2007 Nov 20. 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 Nov;98(11):1726-31. Epub 2013 Jun 10. link to original article contains verified protocol link to PMC article PubMed
Temsirolimus monotherapy
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Regimen
Study | Evidence | Efficacy |
---|---|---|
Smith et al. 2010 | Phase II | ORR: 28% |
Chemotherapy
- Temsirolimus (Torisel) 25 mg IV over 30 minutes once per day on days 1, 8, 15, 22
28-day cycle for 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 link to PMC article PubMed
Tisagenlecleucel monotherapy
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Regimen
FDA-recommended dose |
Study | Years of enrollment | Evidence | Efficacy |
---|---|---|---|
Schuster et al. 2017 (UPCC 13413) | Phase II | ||
Schuster et al. 2018 (JULIET) | 2015-2017 | Phase II (RT) | ORR: 59% (95% CI, 44-72) |
The range given is the FDA-recommended dose used in JULIET.
Lymphodepletion chemotherapy
- Fludarabine 25 mg/m2 IV once per day for 3 days
- Cyclophosphamide 250 mg/m2 IV once per day for 3 days starting with the first dose of fludarabine
- Alternate lymphodepletion: bendamustine 90 mg/m2 IV once per day for 2 days if a patient experienced a previous grade 4 hemorrhagic cystitis with cyclophosphamide or demonstrates resistance to a previous cyclophosphamide containing regimen
- Infuse tisagenlecleucel 2 to 11 days after completion of the lymphodepleting chemotherapy
- Lymphodepleting chemotherapy may be omitted if a patient’s white blood cell count is less than or equal to 1 x 109/L within 1 week prior to tisagenlecleucel infusion
Immunotherapy
- Tisagenlecleucel (Kymriah) 0.6 to 6 x 108 CTL019 transduced viable T-cells IV once on day 0
One course
References
- UPCC 13413: Schuster SJ, Svoboda J, Chong EA, Nasta SD, Mato AR, Anak Ö, Brogdon JL, Pruteanu-Malinici I, Bhoj V, Landsburg D, Wasik M, Levine BL, Lacey SF, Melenhorst JJ, Porter DL, June CH. Chimeric Antigen Receptor T Cells in Refractory B-Cell Lymphomas. N Engl J Med. 2017 Dec 28;377(26):2545-2554. Epub 2017 Dec 10. link to original article link to PMC article PubMed
- JULIET: Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, Jäger U, Jaglowski S, Andreadis C, Westin JR, Fleury I, Bachanova V, Foley SR, Ho PJ, Mielke S, Magenau JM, Holte H, Pantano S, Pacaud LB, Awasthi R, Chu J, Anak Ö, Salles G, Maziarz RT; JULIET Investigators. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019 Jan 3;380(1):45-56. Epub 2018 Dec 1. link to original article PubMed
TTR
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TTR: Taxol (Paclitaxel), Topotecan, Rituximab
Regimen
Study | Evidence |
---|---|
Westin et al. 2014 | Phase II |
Chemotherapy
- Paclitaxel (Taxol) 200 mg/m2 IV once on day 2
- Topotecan (Hycamtin) 1 mg/m2 IV once per day on days 2 to 6
- Rituximab (Rituxan) 375 mg/m2 IV once on day 1
Supportive medications
- Filgrastim (Neupogen) 5 mcg/kg SC once per day from day 7 until neutrophil recovery
- Dexamethasone (Decadron) 20 mg IV once on day 2; 30 minutes prior to Paclitaxel (Taxol)
- Diphenhydramine (Benadryl) 50 mg IV once on day 2; 30 minutes prior to Paclitaxel (Taxol)
21-day cycle for up to 6 cycles
References
- Westin JR, McLaughlin P, Romaguera J, Hagemeister FB, Pro B, Dang NH, Samaniego F, Rodriguez MA, Fayad L, Oki Y, Fanale M, Fowler N, Nastoupil L, Feng L, Loyer E, Younes A. Paclitaxel, topotecan and rituximab: long term outcomes of an effective salvage programme for relapsed or refractory aggressive B-cell non-Hodgkin lymphoma. Br J Haematol. 2014 Oct;167(2):177-84. Epub 2014 Jul 8. link to original article contains verified protocol link to PMC article PubMed
Vinorelbine monotherapy
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Regimen
Study | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|
Balzarotti et al. 1996 | Non-randomized, <20 pts in this subgroup | ||
Pettengell et al. 2012 (PIX301) | Phase III, <20 pts in this arm (C) | Pixantrone | Seems to have inferior CR/CRu rate |
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Chemotherapy
- Vinorelbine (Navelbine) 30 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycle for up to 6 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. link to original article PubMed
- PIX301: 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
- Post-hoc analysis: Pettengell R, Sebban C, Zinzani PL, Derigs HG, Kravchenko S, Singer JW, Theocharous P, Wang L, Pavlyuk M, Makhloufi KM, Coiffier B. Monotherapy with pixantrone in histologically confirmed relapsed or refractory aggressive B-cell non-Hodgkin lymphoma: post-hoc analyses from a phase III trial. Br J Haematol. 2016 Sep;174(5):692-9. Epub 2016 Apr 26. link to original article link to PMC article PubMed
Maintenance after further lines of therapy
Lenalidomide monotherapy
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Regimen
Study | Evidence |
---|---|
Zinzani et al. 2011a | Phase II |
Preceding treatment
Chemotherapy
- Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
28-day cycle for 9 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
- Update: Zinzani PL, Pellegrini C, Derenzini E, Argnani L, Pileri S. Long-term efficacy of the combination of lenalidomide and rituximab in elderly relapsed/refractory diffuse large B-cell lymphoma patients. Hematol Oncol. 2013 Dec;31(4):223-4. Epub 2013 Apr 26. link to original article PubMed
Response criteria
- Lugano Classification criteria (2014) link to PMC article PubMed
- International Harmonization Project on Lymphoma revised criteria (2007) PubMed
- NCI Sponsored International Working Group criteria (1999) PubMed
Prognosis
IPI and age-adjusted IPI (1993)
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To be completed
- A predictive model for aggressive non-Hodgkin's lymphoma. The International Non-Hodgkin's Lymphoma Prognostic Factors Project. N Engl J Med. 1993 Sep 30;329(14):987-94. link to original article PubMed
Revised International Prognostic Index, R-IPI (2007)
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To be completed
- Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, Klasa R, Savage KJ, Shenkier T, Sutherland J, Gascoyne RD, Connors JM. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2007 Mar 1;109(5):1857-61. Epub 2006 Nov 14. link to original article PubMed
CNS-IPI (2016)
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Risk factors
- Age greater than 60 years
- Elevated LDH
- ECOG PS greater than 1
- Advanced stage (III or IV)
- Involvement of more than one extranodal site
- Involvement of the kidney and/or adrenal glands
Risk stratification
- Low risk: 0 or 1 risk factors (2-year rate of CNS disease less than 5%)
- Intermediate risk: 2 or 3 risk factors (2-year rate of CNS disease less than 5%)
- High risk: 4 to 6 risk factors (2-year rate of CNS disease greater than 10%)
References
- Schmitz N, Zeynalova S, Nickelsen M, Kansara R, Villa D, Sehn LH, Glass B, Scott DW, Gascoyne RD, Connors JM, Ziepert M, Pfreundschuh M, Loeffler M, Savage KJ. CNS International Prognostic Index: a risk model for CNS relapse in patients with diffuse large B-cell lymphoma treated with R-CHOP. J Clin Oncol. 2016 Sep 10;34(26):3150-3156. Epub 2016 Jul 5. link to original article PubMed
Investigational agents
These are drugs under study with at least some promising results for this disease.