DLBCL

Primary tabs

You are viewing a wiki page. You are welcome to edit.

Diffuse large B-cell lymphoma


Guidelines

ESMO

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

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

  • O-miniCHOP

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

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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

ACVBP-R: Adriamycin (Doxorubicin), Cyclophosphamide, Vindesine, Bleomycin, Prednisone, Rituximab 
R-ACVBP: Rituximab, Adriamycin (Doxorubicin), Cyclophosphamide, Vindesine, Bleomycin, Prednisone

Regimen

Study Evidence Comparator Efficacy Toxicity
Récher et al. 2011 (LNH03-2B) Phase III (E) R-CHOP Superior OS Increased toxicity
Ketterer et al. 2013 (LNH03-1B) Phase III (E) 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

  1. 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
    1. 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
  2. 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 articlePubMed

DA-R-EPOCH

DA-R-EPOCH: Dose Adjusted Rituximab, Etoposide, Prednisone, Oncovin (Vincristine), Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin) 
DA-EPOCH-R

Regimen

Study Evidence Comparator Efficacy Toxicity
García-Suárez et al. 2007 Phase II      
Wilson et al. 2008 Phase II      
Wilson et al. 2012 Phase II      
Purroy et al. 2014 Phase II      
Wilson et al. 2016 (CALGB 50303) Phase III (E) R-CHOP Seems not superior 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
  • Only in García-Suárez et al. 2007: Darbepoetin alfa (Aranesp) 2.25 ug/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

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. Abstract: Wyndham H. Wilson, MD, PhD, Jung sin-Ho, Brandelyn Nicole Pitcher, MS, Eric D Hsi, MD, Jonathan Friedberg, MD, Bruce Cheson, MD, Nancy L Bartlett, MD, Scott Smith, Nina Wagner Johnston, MD, Brad S Kahl, Louis M. Staudt, MD, PhD, Kristie Blum, MD, Jeremy Abramson, Oliver W Press, MD, PhD, Richard I. Fisher, MD, Kristy L. Richards, PhD, MD, Heiko Schoder, MD, Julie E Chang, Andrew D. Zelenetz and John P. Leonard, MD. Phase III Randomized Study of R-CHOP Versus DA-EPOCH-R and Molecular Analysis of Untreated Diffuse Large B-Cell Lymphoma: CALGB/Alliance 50303. ASH 2016 Abstract 469 link to abstract

R-CHOEP-14

R-CHOEP-14: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Etoposide, Prednisone, 14-day cycles

Variant #1, flat-dose vincristine

Study Evidence Comparator Efficacy Toxicity
Adde et al. 2006 Phase II    
Schmitz et al. 2012 (DSHNHL 2002-1) Phase III (C) R-MegaCHOEP Seems not superior 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

Variant #2, capped vincristine, with CNS prophylaxis

Study Evidence
Holte et al. 2013 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

  • CNS prophylaxis: HiDAC, then HD-MTX

References

  1. 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
  2. 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
  3. 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

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

  • Example orders for R-CHOP in lymphoma

Note: most of the variation between regimen variants is in the dose or type of steroid.

Variant #1, prednisolone 40 mg/m2

Study Evidence Comparator Efficacy
Cunningham et al. 2013 (UK NCRI R-CHOP14v21) Phase III (C) R-CHOP-14 Seems not superior
Fridrik et al. 2016 (AGMT NHL-14) Phase III (C) R-COMP Seems not superior

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

Variant #2, prednisone 40 mg/m2

Study Evidence Comparator Efficacy
Coiffier et al. 2002 (LNH 98-5) Phase III (E) CHOP Superior OS
Delarue et al. 2013 (LNH03-6B) Phase III (C) R-CHOP-14 Seems not superior

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

CNS prophylaxis

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

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

Supportive medications

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

21-day cycle for 8 cycles

Variant #3, prednisone 60 mg/m2

Study Evidence Comparator Efficacy Toxicity
Récher et al. 2011 (LNH03-2B) Phase III (C) ACVBP-R Inferior OS Decreased 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) 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

Variant #4, prednisone 100 mg, IV rituximab, BSA-based vincristine

Study Evidence Comparator Efficacy
Vose et al. 2001 Phase II    
Merli et al. 2012 (ANZINTER3) Phase III (C) R-miniCEOP Seems not superior
Herbrecht et al. 2013 (PIX203) Phase III (C) CPOP-R Inconclusive whether non-inferior (*)
Oki et al. 2013 (MDACC 2005-0054) Randomized Phase II (C) R-HCVAD/R-MA Seems to have inferior CRR
Seymour et al. 2014 (MAIN) Phase III (C) RA-CHOP-21 Seems not superior
Vitolo et al. 2017 (GOYA) Phase III (C) G-CHOP Seems not superior
Leonard et al. 2017 (C05013) Randomized Phase II (C) VR-CHOP Seems not superior
Hara et al. 2018 Phase III (C) R-THP-CHOP Non-inferior CR rate

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.

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

Variant #5, prednisone 100 mg, IV rituximab, flat-dose vincristine

Study Evidence Comparator Efficacy Toxicity
Pfreundschuh et al. 2006 (NCIC CTG LY.9) Phase III (E) 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

Variant #6, prednisone 100 mg, SC rituximab

Study Evidence Comparator Efficacy
Lugtenburg et al. 2017 (MabEase) Phase III (E) IV 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
    • Cycles 2 to 8: Rituximab and hyaluronidase human (Rituxan Hycela) 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

Variant #7, prednisone 100 mg/m2

Study Evidence Comparator Efficacy
Offner et al. 2015 (LYM-2034) Randomized Phase II (C) VR-CAP Seems not superior

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

Variant #8, rituximab lead-in

Study Evidence Comparator Efficacy
Habermann et al. 2006 (ECOG E4494/CALGB 9793) Phase III (E) 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 per cycle: 2 mg) IV once on day 1
  • Prednisone (Sterapred) 100 mg/m2 PO once per day on days 1 to 5

Supportive medications

  • Filgrastim (Neupogen) "recommended according to guidelines"

21-day cycle for 6 to 8 cycles

Subsequent treatment

  • Rituximab maintenance versus observation

Variant #9, 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) 375 mg/m2 IV once on days -7, 1, 22, 43 (4 doses total)
  • Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
  • Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
  • Vincristine (Oncovin) 1.4 mg/m2 (maximum dose of 2 mg) 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

Variant #10, 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

CNS prophylaxis

  • Methotrexate (MTX) 12 mg IT once per week x 4 total doses

21-day cycle for 6 cycles (up to 8 cycles for stage II patients)

Subsequent treatent

  • RT

Variant #11, 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

  1. 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 articlecontains verified protocol PubMed
  2. 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
    1. 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
    2. 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
    3. 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
  3. 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 articlecontains verified protocol PubMed
    1. 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 articlecontains protocol PubMed
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
    1. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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
    1. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. Abstract: Wyndham H. Wilson, MD, PhD, Jung sin-Ho, Brandelyn Nicole Pitcher, MS, Eric D Hsi, MD, Jonathan Friedberg, MD, Bruce Cheson, MD, Nancy L Bartlett, MD, Scott Smith, Nina Wagner Johnston, MD, Brad S Kahl, Louis M. Staudt, MD, PhD, Kristie Blum, MD, Jeremy Abramson, Oliver W Press, MD, PhD, Richard I. Fisher, MD, Kristy L. Richards, PhD, MD, Heiko Schoder, MD, Julie E Chang, Andrew D. Zelenetz and John P. Leonard, MD. Phase III Randomized Study of R-CHOP Versus DA-EPOCH-R and Molecular Analysis of Untreated Diffuse Large B-Cell Lymphoma: CALGB/Alliance 50303. ASH 2016 Abstract 469 link to abstract
  20. 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
  21. 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 PubMed
  22. 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
  23. 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
  24. 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

R-CHOP-14

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.

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

Variant #2, prednisone 40 mg/m2, 8 cycles

Study Evidence Comparator Efficacy
Delarue et al. 2013 (LNH03-6B) Phase III (E) R-CHOP21 Seems not superior

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

CNS prophylaxis

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

Supportive medications

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

14-day cycle for 8 cycles

Variant #3, prednisone 100 mg, BSA-based vincristine, standard-dose IV rituximab

Study Evidence Comparator Efficacy
Seymour et al. 2014 (MAIN) Phase III (C) RA-CHOP-14 Seems not superior
Cortelazzo et al. 2016 Phase III (C) R-HDS Seems not superior
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
Seems not superior

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)

Variant #4, prednisone 100 mg, BSA-based vincristine, high-dose IV rituximab

Study Evidence Comparator Efficacy
Pfreundschuh et al. 2014 (SEXIE-R-CHOP-14) Randomized Phase II (E) 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:
    • 500 mg/m2 IV once every two weeks
    • 500 mg/m2 IV once 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 (8 doses of rituximab regardless of total number of CHOP-14 cycles)

Variant #5, prednisone 100 mg, BSA-based vincristine, SC rituximab

Study Evidence Comparator Efficacy
Lugtenburg et al. 2017 (MabEase) Phase III (E) IV R-CHOP 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
    • 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

Variant #6, 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

  • Pre-phase vincristine & prednisone

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

Variant #7, 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

  • Pre-phase vincristine & prednisone

Chemotherapy

  • Rituximab (Rituxan) 375 mg/m2 IV once per day on days -4, 0, 10, 29, 57, 99, 155, and 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:
    • Filgrastim (Neupogen)
    • Lenograstim (Granocyte)

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

Variant #8, prednisone 100 mg, flat dose vincristine, 6-8 cycles

Study Evidence Comparator Efficacy
Pfreundschuh et al. 2008 (RICOVER-60) Phase III (E) 1. CHOP-14 x 6 Superior OS
2. CHOP-14 x 8 Not reported
3. R-CHOP-14 x 8 Not reported

Preceding treatment

  • 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:
    • Filgrastim (Neupogen)
    • Lenograstim (Granocyte)

14-day cycle for 6 to 8 cycles (8 doses of rituximab regardless of total number of 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

Variant #9, prednisolone 100 mg

Study Evidence Comparator Efficacy
Cunningham et al. 2013 (UK NCRI R-CHOP14v21) Phase III (E) R-CHOP-21 Seems not superior

Chemotherapy

  • Rituximab (Rituxan) 375 mg/m2 IV once on day 1 (8 doses total)
  • Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
  • Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
  • Vincristine (Oncovin) 2 mg IV once on day 1
  • Prednisolone (Millipred) 100 mg PO once per day on days 1 to 5

CNS prophylaxis

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

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

Supportive medications

  • Lenograstim (Granocyte) (dose/route not specified) given on days 4 to 12
  • Allopurinol (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 6 cycles (8 cycles of rituximab)

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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 PubMed
  11. 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
  12. 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-Hyper-CVAD/R-MA

R-Hyper-CVAD/R-MA: Rituximab, Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone alternating with Rituximab, Methotrexate, Ara-C (Cytarabine)

Regimen

Study Evidence Comparator Efficacy
Oki et al. 2013 (MDACC 2005-0054) Randomized Phase II (E) 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 (6 total doses)
  • 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
  • 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 (4 total doses)

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

  1. 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
  2. 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

R-MegaCHOP-14: Rituximab, "Mega" (high-dose) Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone every 14 days

Regimen

Study Evidence Comparator Efficacy
Chiappella et al. 2017 (DLCL04) Phase III (E) 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
Seems not superior

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

  1. 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

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

Regimen

Study Evidence Comparator Efficacy
Merli et al. 2012 (ANZINTER3) Phase III (E) R-CHOP Seems not superior

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

  1. 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

BR: Bendamustine, Rituximab

Variant #1, 90 mg/m2

Study Evidence
Park et al. 2016 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

Variant #2, 120 mg/m2

Study Evidence
Park et al. 2016 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

  1. 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

Regimen

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, before 1996

  • Amoxicillin 500mg PO every 6 hours x 28 days
  • Metronidazole (Flagyl) 250mg PO every 6 hours x 28 days
  • EITHER bismuth subcitrate 120mg PO every 6 hours x 28 days
  • OR Omeprazole (Prilosec) 20mg PO twice per day x 28 days

Antibiotic therapy, after 1996

  • Amoxicillin 500mg PO every 6 hours x 14 days
  • Clarithromycin (Biaxin) 500mg PO twice per day x 14 days
  • Omeprazole (Prilosec) 20mg PO twice per day x 14 days

References

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

O-miniCHOP

O-miniCHOP: Ofatumumab, reduced-dose (miniCyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone

Regimen

Study Evidence
Peyrade et al. 2017 (LYSA LNH09-7B) Phase II

Preceding treatment

  • Pre-phase vincristine & prednisone

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 prior to Ofatumumab (Arzerra)
  • Diphenhydramine (Benadryl) 50 mg (route not specified) once prior to Ofatumumab (Arzerra)

21-day cycle for 6 cycles

References

  1. 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

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

  1. 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

R-CDOP: Rituximab, Cyclophosphamide, Doxil (Pegylated liposomal doxorubicin), Oncovin (Vincristine), Prednisone 
DRCOP: Doxil (Pegylated liposomal doxorubicin), Rituximab, Cyclophosphamide, Oncovin (Vincristine), Prednisone

Variant #1

Study Evidence
Oki et al. 2014 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

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

  1. 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 articlePubMed
  2. 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)

R-CEOP90: Rituximab, Cyclophosphamide, Epirubicin (90 mg/m2 dosing), Oncovin (Vincristine), Prednisone

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

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

  1. 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)

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; 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

  1. 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

R-CHMP: Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Marqibo (Vincristine liposomal), Prednisone

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

  • RT

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

  1. 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

R-GCVP: Rituximab, Gemcitabine, Cyclophosphamide, Vincristine, Prednisolone

Regimen

Study Evidence
Fields et al. 2013 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) prior to Rituximab (Rituxan)
  • Chlorpheniramine (Chlor-Trimeton) 10 mg IV 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

  1. Fields PA, Townsend W, Webb A, Counsell N, Pocock C, Smith P, Jack A, El-Mehidi N, Johnson PW, Radford J, Linch DC, Cunnningham 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 protocolPubMed

R-MegaCHOP

R-MegaCHOP: Rituximab, Mega, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone

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

  1. 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

R-miniCHOP: Rituximab, reduced-dose (miniCyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone

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 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

  1. 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

R2CHOP: Rituximab, Revlimid (Lenalidomide), Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone 
LR-CHOP-21: Lenalidomide, Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone given every 21 days

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)

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

  • For "at risk" patients:
  • Methotrexate (MTX) 12 mg IT once on day 1 of first 4 cycles

Supportive medications

  • Granulocyte colony-stimulating factors (dose/duration not specified)
  • Low-molecular-weight heparins (dose/duration not specified)
  • Trimethoprim/Sulfamethoxazole (Bactrim DS) or Pentamidine (Nebupent) (dose/duration not specified)
  • Lamivudine (Epivir) (dose/duration not specified) for carriers of hepatitis B virus

21-day cycle for 6 cycles

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

  1. 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; on behalf of the 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
  2. 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

Regimen

Study Evidence Comparator Efficacy
Stiff et al. 2013 (SWOG S9704) Phase III (E) R-CHOP x 8 Superior PFS

Preceding treatment

  • R-CHOP x 6

Chemotherapy

  • Cyclophosphamide (Cytoxan) 100 mg/kg (IBW) IV once on day -2
  • Carmustine (BCNU) 300 mg/m2 IV once on day -6
  • Etoposide (Vepesid) 60 mg/kg (IBW) IV once on day -4

Stem cells re-infused on day 0

References

  1. 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
    1. 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

Regimen

Study Evidence
Haioun et al. 2009 (LNH 98-3) Non-randomized portion of RCT

Preceding treatment

  • ACE versus ACVBP

Chemotherapy

  • Carmustine (BCNU)
  • Etoposide (Vepesid)
  • Cyclophosphamide (Cytoxan)
  • Mitoxantrone (Novantrone)

Stem cells reinfused afterwards (unclear which day)

Subsequent treatment

  • Observation versus rituximab maintenance

References

  1. 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

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

  • REI consolidation x 4

Chemotherapy

  • Cytarabine (Ara-C) 100 mg/m2 SC once per day on days 1 to 4

14-day cycle for 2 cycles

References

  1. 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
    1. 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
  2. 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 articlePubMed

Ibritumomab tiuxetan monotherapy

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

One course

Subsequent treatment

  • Patients with CT or PET positive disease 12 weeks after radioimmunotherapy: 30 Gy of IFRT

Variant #2, capped dose

Study Evidence
Persky et al. 2014 (SWOG S0313) Phase II

Preceding treatment

  • CHOP x 3, then IFRT

Radioimmunotherapy

  • Rituximab (Rituxan) 250 mg/m2 IV once on day 1, then another single dose on day 7, 8, or 9, given first on day 7, 8, or 9
  • Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (maximum dose of 32 mCi) IV once, given second, within 4 hours

References

  1. 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
  2. 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

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

  • ACVBP-R induction x 4

Chemotherapy

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

Supportive medications

  • Calcium folinate - Folinic acid (Leucovorin) rescue

14-day cycle for 2 cycles

Subsequent treatment

  • REI consolidation, in 2 weeks

References

  1. 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
    1. 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
  2. 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 articlePubMed

Observation

Regimen

Study Evidence Comparator Efficacy
Horning et al. 2004 (ECOG E1484) Phase III (C) IFRT Seems to have inferior DFS
Habermann et al. 2006 (ECOG E4494/CALGB 9793) Phase III (C) Rituximab See note
Bonnet et al. 2007 Phase III (E) IFRT Seems not superior
Haioun et al. 2009 (LNH 98-3) Phase III (C) Rituximab Might have inferior EFS
Jaeger et al. 2015 (NHL13) Phase III (C) Rituximab Seems not superior
Witzens-Harig et al. 2015 (HD2002) Phase III (C) Rituximab Inferior OS in males
Lamy et al. 2017 (LYSA/GOELAMS 02-03) Phase III (C) IFRT Non-inferior EFS

No further treatment, also variously termed "observation" and "watchful waiting". Note: in ECOG E4494/CALGB 9793, a disadvantage to observation was only seen in the group receiving CHOP induction, which is no longer standard of care.

Preceding treatment

  • ECOG E1484: CHOP x 8, with CR
  • ECOG E4494/CALGB 9793: R-CHOP versus CHOP induction
  • Bonnet et al. 2007: CHOP x 4
  • LNH 98-3: CBVM, then auto HSCT consolidation
  • HD2002: "Standard treatment"
  • LYSA/GOELAMS 02-03: R-CHOP-14 x 4 to 6

References

  1. 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
  2. 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
  3. 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
  4. 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 PubMed
  5. 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
  6. 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 PubMed
  7. 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

Placebo

Regimen

Study Evidence Comparator Efficacy
Crump et al. 2016 (PRELUDE) Phase III (C) Enzastaurin Seems not superior
Thieblemont et al. 2017 (REMARC) Phase III (C) Lenalidomide Seems to have inferior PFS
Witzig et al. 2018 (PILLAR-2) Phase III (C) Everolimus Seems not superior

No further antineoplastic treatment.

Preceding treatment

  • PRELUDE: R-CHOP induction
  • REMARC: R-CHOP21 or R-CHOP-14 induction

References

  1. PRELUDE: Crump M, Leppä S, Fayad L, Lee JJ, Di Rocco A, Ogura M, Hagberg H, Schnell F, Rifkin R, Mackensen A, Offner F, Pinter-Brown L, Smith S, Tobinai K, Yeh SP, Hsi ED, Nguyen T, Shi P, Hahka-Kemppinen M, Thornton D, Lin B, Kahl B, Schmitz N, Savage KJ, Habermann T. Randomized, double-blind, phase III trial of enzastaurin versus placebo in patients achieving remission after first-line therapy for high-risk diffuse large B-cell lymphoma. J Clin Oncol. 2016 Jul 20;34(21):2484-92. Epub 2016 May 23. link to original article PubMed
  2. 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
  3. PILLAR-2: Witzig TE, Tobinai K, Rigacci L, Ikeda T, Vanazzi A, Hino M, Shi Y, Mayer J, Costa LJ, Bermudez Silva CD, Zhu J, Belada D, Bouabdallah K, Kattan JG, Kuruvilla J, Kim WS, Larouche JF, Ogura M, Ozcan M, Fayad L, Wu C, Fan J, Louveau AL, Voi M, Cavalli F. Adjuvant everolimus in high-risk diffuse large B-cell lymphoma: final results from the PILLAR-2 randomized phase III trial. Ann Oncol. 2018 Mar 1;29(3):707-714. link to original article PubMed

Radiation therapy

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.

Variant #2, IFRT x 30 Gy

Study Evidence Comparator Efficacy
Horning et al. 2004 (ECOG E1484) Phase III (E) Observation Seems to have superior DFS

Preceding treatment

  • ECOG E1484: CHOP x 8, with CR

Radiotherapy

  • IFRT 30 Gy

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

Variant #4, IFRT x 40 Gy

Study Evidence Comparator Efficacy
Horning et al. 2004 (ECOG E1484) Non-randomized portion of RCT    
Bonnet et al. 2007 Phase III (C) Observation Seems not superior
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

Variant #5, IFRT x 40 to 55 Gy

Study Evidence Comparator Efficacy
Miller et al. 1998 (SWOG S8736) Phase III (E) 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

  1. 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
    1. 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
  2. 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
  3. 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
  4. 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
  5. 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 articlePubMed
    1. 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 articlePubMed
  6. 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
  7. 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
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. 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

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

  • Methotrexate consolidation x 2

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

  1. 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
    1. 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
  2. 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 articlePubMed

TBI, then auto HSCT

Regimen

Study Evidence Comparator Efficacy
Stiff et al. 2013 (SWOG S9704) Phase III (E) R-CHOP x 8 Superior PFS

Preceding treatment

  • R-CHOP x 6

Radiotherapy

  • Total body irradiation (TBI) in 1.5-Gy fractions twice per day on days −8 through −5 (total dose: 12 Gy)

Stem cells reinfused on day 0

References

  1. 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
    1. 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

Z-BEAM: Zevalin (Ibritumomab tiuxetan), BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan

Variant #1

Study Evidence Comparator Efficacy
Shimoni et al. 2012 Randomized Phase II (E) BEAM Seems to have superior OS
Briones et al. 2013 Phase II    

Chemoradioimmunotherapy

  • Rituximab (Rituxan) 250 mg/m2 IV once on day -14, given first
  • Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day -14, given second
  • 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 medications

  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day +4 (Shimoni et al. 2012) or day +7 (Briones et al. 2013) 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 Briones et al. 2013)

Stem cells re-infused on day 0

Variant #2

Study Evidence
Fruchart et al. 2014 Phase II

Preceding treatment

  • R-ACVBP or R-CHOP

Chemoradioimmunotherapy

  • Rituximab (Rituxan) 250 mg/m2 IV once per day on days -21 & -14, given first on day -14
  • Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day -14, given second
    • Dose reduced to 0.3 mCi/kg if platelet count was greater than 100 x 109/L and less than 150 x 109/L.
  • 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 medications

  • "According to standard use"

Stem cells re-infused on day 0

References

  1. 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
  2. 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
  3. 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
  4. 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

Variant #1, 1 year

Study Evidence Comparator Efficacy
Reddy et al. 2016 Randomized Phase II (E) Lenalidomide & Rituximab Seems not superior

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

Variant #2, 2 years

Study Evidence Comparator Efficacy
Thieblemont et al. 2017 (REMARC) Phase III (E) Observation Seems to have superior PFS

Preceding treatment

  • R-CHOP-21 or R-CHOP14

Chemotherapy

  • Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

28-day cycle for up to 2 years

References

  1. 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
  2. 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

Variant #1

Study Evidence Comparator Efficacy
Jaeger et al. 2015 (NHL13) Phase III (E) Observation Seems not superior

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 every 2 months

1 to 2 year course (6 to 12 doses total)

Variant #2

Study Evidence Comparator Efficacy
Witzens-Harig et al. 2015 (HD2002) Phase III (E) 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 every 3 months

2 year course (8 doses total)

Variant #3

Study Evidence Comparator Efficacy
Haioun et al. 2009 (LNH 98-3) Phase III (E) Observation Might have superior EFS

Preceding treatment

  • CBVM, then auto HSCT

Chemotherapy

  • Rituximab (Rituxan) 375 mg/m2 IV once per week

4-week course (4 doses total)

Variant #4

Study Evidence Comparator Efficacy
Habermann et al. 2006 (ECOG E4494/CALGB 9793) Phase III (E) Observation See note

Note: in ECOG E4494/CALGB 9793, an advantage to rituximab was only seen in the group receiving CHOP upfront, which is no longer standard of care.

Preceding treatment

  • R-CHOP versus CHOP

Chemotherapy

  • Rituximab (Rituxan) 375 mg/m2 IV once per week for 4 weeks

6-month cycle for 4 cycles (16 doses total)

References

  1. 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
  2. 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
  3. 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
  4. 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 protocolPubMed

Relapsed or refractory, salvage therapy

O-DHAP

O-DHAP: Ofatumumab, Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin)

Regimen

Study Evidence Comparator Efficacy
Matasar et al. 2013 Phase II    
van Imhoff et al. 2016 (ORCHARRD) Phase III (E) R-DHAP Seems not superior

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 x 2 doses on day 2 (total of 2 doses)
  • Cisplatin (Platinol) 100 mg/m2 IV continuous infusion over 24 hours, started on day 1

Supportive medications

  • Matasar et al. 2013: G-CSF or Neulasta was recommended (no details given).

21-day cycle for 3 cycles

Subsequent treatment

  • Matasar et al. 2013, 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

  1. 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 articlePubMed
  2. 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 supplementverified protocol in supplement PubMed

O-ICE

O-ICE: Ofatumumab, Ifosfamide, Carboplatin, Etoposide

Regimen

Study Evidence
Matasar et al. 2013 Phase II

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 day 1 OR 2 (1 dose, total)
    • Carboplatin AUC calculated based on a 12-hour creatinine clearance
  • Etoposide (Vepesid) 100 mg/m2 IV once per day on days 1 to 3

Supportive medications

  • Mesna (Mesnex) 5000 mg/m2 IV continuous infusion over 24 hours, started on day 2, mixed with Ifosfamide (Ifex)
  • G-CSF or Neulasta was recommended (no details given).

21-day cycle for 3 cycles

Subsequent consolidation therapy was not specified.

References

  1. 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 articlePubMed

R-DexaBEAM

R-DexaBEAM: Rituximab, Dexamethasone, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan

Regimen

Study Evidence
Kirschey et al. 2014 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

  1. 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

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

  1. 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

R-DHAP: Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin)

Variant #1

Study Evidence Comparator Efficacy
Gisselbrecht et al. 2010 (CORAL) Phase III (E) R-ICE Seems not superior
van Imhoff et al. 2016 (ORCHARRD) Phase III (C) O-DHAP Seems not superior

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 x 2 doses on day 2 (total of 2 doses)
  • 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

Variant #2

Study Evidence Comparator Efficacy
Crump et al. 2014 (NCIC-CTG LY.12) Phase III (C) R-GDP Seems non-inferior

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 x 2 doses on day 2 (total of 2 doses)
  • 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)

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 x 2 doses on day 4 (total of 2 doses)
      • Older than 60 years: 500 mg/m2 IV over 2 hours every 12 hours x 2 doses on day 4 (total of 2 doses)
    • Cycles 2 to 4 as follows:
      • Younger than 60 years: 2000 mg/m2 IV over 2 hours every 12 hours x 2 doses on day 4 (total of 2 doses)
      • Older than 60 years: 1000 mg/m2 IV over 2 hours every 12 hours x 2 doses on day 4 (total of 2 doses)
  • 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

  1. 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 protocolPubMed
  2. 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
  3. 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
  4. 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

R-DHAP/R-VIM: Rituximab, Dexamethasone, High-dose Ara-C (Cytarabine), Platinol (Cisplatin) alternating with Rituximab, VP-16 (Etoposide), Ifosfamide, Methotrexate

Regimen

Study Evidence Comparator Efficacy
Vellenga et al. 2008 (HOVON-44) Phase III (E) 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 x 2 doses on day 2 (total of 2 doses)
  • 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

  1. 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

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 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

  1. 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

R-ESHAP: Rituximab, Etoposide, Solumedrol (Methylprednisolone) High-dose Ara-C (Cytarabine), Platinol (Cisplatin)

Regimen

Study Evidence Comparator Efficacy
Martín et al. 2008 Retrospective    
Avilés et al. 2010 Phase III (E) ESHAP Seems not superior

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 ("after recovery of the toxic effects") for 6 to 8 cycles

References

  1. 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
  2. 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

R-GDP: Rituximab, Gemcitabine, Dexamethasone, Platinol (Cisplatin)

Variant #1, 1 day of cisplatin/cycle

Study Evidence Comparator Efficacy
Crump et al. 2014 (NCIC-CTG LY.12) Phase III (E) R-DHAP Seems non-inferior

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)

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

  1. 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
  2. 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

R-ICE: Rituximab, Ifosfamide, Carboplatin, Etoposide 
ICE-R: Ifosfamide, Carboplatin, Etoposide, Rituximab

Variant #1

Study Evidence Comparator Efficacy
Gisselbrecht et al. 2010 (CORAL) Phase III (E) R-DHAP Seems not superior
Fayad et al. 2015 Randomized Phase IIb (C) R-ICE + Dacetuzumab Seems not superior

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

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

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) 375 mg/m2 IV once on day 1
    • An additional one-time dose of 375 mg/m2 IV was given 48 hours before the beginning of cycle 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

  1. 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
  2. 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
  3. Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Brière J, Moskowitz CH, Schmitz N. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010 Sep 20;28(27):4184-90. 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
  4. 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 protocolPubMed
  5. 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

RICER: Rituximab, Ifosfamide, Carboplatin, Etoposide, Revlimid (Lenalidomide)

Regimen

Study Evidence
Feldman et al. 2014 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

  1. 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

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) 3,333 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

  • Responders: BEAM with autologous hematopoietic stem cell transplant

References

  1. 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

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
  • Pegfilgrastim (Neulasta) 6 mg SC once on day 7 was recommended
  • Epoietin alpha support was recommended for hemoglobin less than 10 g/dL

28-day cycle for 3 cycles

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

  1. 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

BEAC: Rituximab, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Philip et al. 1991 (Parma) Prospective pilot    
Philip et al. 1995 (PARMA) Phase III (E) DHAP x4 Seems to have superior OS

Preceding treatment

DHAP x 2; radiation was also given to sites of bulky disease (>5cm)

Chemotherapy

  • Carmustine (BCNU) 300 mg/m2 IV over 30 to 60 minutes once on day 1
  • Etoposide (Vepesid) 100 mg/m2 IV over 30 to 60 minutes twice per day on days 2 to 5
  • Cytarabine (Ara-C) 100 mg/m2 IV over 30 minutes twice per day on days 2 to 5
  • Cyclophosphamide (Cytoxan) 35 mg/kg IV over 60 minutes once per day on days 2 to 5

Supportive medications

  • Mesna (Mesnex) 8.3 mg/kg IV over 30 minutes every 4 hours on days 2 to 5 (optional)

Stem cells re-infused on day 7 (48 hours after last dose of etoposide)

References

  1. 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
  2. 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

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

GVHD prophylaxis and key supportive medications

  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day +7 and continued until engraftment
  • Tacrolimus (Prograf)
  • Methotrexate (MTX)
  • "Prophylactic antibiotics"

Stem cells transfused on day 0

References

  1. 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

BEAM: Rituximab, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan

Variant #1

Study Evidence Comparator Efficacy
Shimoni et al. 2012 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 (8 total doses)
  • Melphalan (Alkeran) 140 mg/m2 IV once on day -1

Supportive medications

  • 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

Stem cells reinfused on day 0

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

Stem cells reinfused on day 0

Subsequent treatment

  • CORAL: Rituximab maintenance versus observation

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 (8 total doses)
  • 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

References

  1. 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 articlecontains verified protocol PubMed
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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

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

Stem cells re-infused on day 0

References

  1. 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 articlecontains verified protocol PubMed

CBV, then auto HSCT

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 medications

  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day +4, to continue until ANC greater than 5000/uL once or greater than 1500/uL twice
  • Levofloxacin (Levaquin) 500 mg PO once per day, starting on day +2, to continue until ANC at least 500/uL
  • Fluconazole (Diflucan) 200 mg PO once per day, starting on day +1, to continue until ANC at least 500/uL
  • 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

Stem cells re-infused on day 0

References

  1. 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

Cy/TBI: Cyclophosphamide & Total Body Irradiation

Regimen

Study Evidence
Phillips et al. 1984 Non-randomized

Chemoradiotherapy

  • Cyclophosphamide (Cytoxan) 60 mg/kg IV once per day on days -3 & -2
  • Total body irradiation (TBI) 1200 cGy in fractions on days –6 to –4 (pulmonary dosage was limited to 800 cGy)

References

  1. 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

FEAM: Fotemustine, Etoposide, Ara-C (Cytarabine), Melphalan

Regimen

Study Evidence
Musso et al. 2009 Phase II

Chemotherapy

  • Fotemustine (Muphoran)
  • Etoposide (Vepesid)
  • Cytarabine (Ara-C)
  • Melphalan (Alkeran)

References

  1. 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

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
    • Alternate: 3.2 mg/kg/day IV on days -6 to -4
  • Cyclophosphamide (Cytoxan) 60 mg/kg/day IV on days -3 and -2

GVHD prophylaxis

  • Tacrolimus (Prograf) 8 to 12 ug/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
  • 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

Stem cells transfused on day 0

References

  1. 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; on behalf of the 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

Regimen

Study Evidence
Bouabdallah et al. 2015 Phase II

Chemoradioimmunotherapy

  • 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
  • Antithymocyte globulin, rabbit ATG (Thymoglobulin) 2.5 mg/kg IV once on day -1
  • Rituximab (Rituxan) 250 mg/m2 IV once per day on days -21 & -14
  • Ibritumomab tiuxetan (Zevalin) 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day -14

GVHD prophylaxis

  • Cyclosporine A (type and dose not specified) until day +90 and tapered off by day +180 based on chimerism and GVHD
  • Methotrexate (MTX) as follows (for unrelated donors with HLA mismatch):
    • 15 mg/m2 (route not specified) once on day +1
    • 10 mg/m2 (route not specified) once per day on days +3 & +6

Stem cells transfused on day 0

References

  1. 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

LEED: L-PAM (Melphalan), Endoxan (Cyclophosphamide), Etoposide, Dexamethasone

Regimen

Study Evidence
van Imhoff et al. 2016 (ORCHARRD) Non-randomized portion of RCT

Preceding treatment

  • O-DHAP x 3 versus R-DHAP x 3

Chemotherapy

  • Melphalan (Alkeran) 130 mg/m2 IV once on day -1
  • Cyclophosphamide (Cytoxan) 60 mg/kg IV once per day on days -4 & -3
  • Etoposide (Vepesid) 500 mg/m2 IV once per day on days -4 to -2
  • Dexamethasone (Decadron) 40 mg IV once per day on days -4 to -1

Stem cells reinfused on day 0

References

  1. 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

R-BEAM: Rituximab, BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan

Variant #1, 750/300/800/800/140

Study Evidence Comparator Efficacy
Vose et al. 2013 (BMT CTN 0401) Phase III (C) B-BEAM Seems not superior

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.

Chemotherapy

  • Rituximab (Rituxan) 375 mg/m2 IV once per day on days -19 & -12
  • 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

Stem cells re-infused on day 0

 

Variant #2, 750/300/1600/3200/140

Study Evidence
Kirschey et al. 2014 Phase II

A minimum number of 2 × 106/kg bw CD34-positive cells were required to proceed.

Preceding treatment

  • R-DexaBEAM x 2

Chemotherapy

  • Rituximab (Rituxan) 375 mg/m2 IV once per day on days -8 & -2
  • Carmustine (BCNU) 300 mg/m2 IV once on day -7
  • Etoposide (Vepesid) 200 mg/m2 IV twice per day on days -6 to -3
  • Cytarabine (Ara-C) 400 mg/m2 IV twice per day on days -6 to -3
  • Melphalan (Alkeran) 140 mg/m2 IV once on day -2

Stem cells re-infused on day 0

References

  1. 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
  2. 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

R-TBI/Cy: Rituximab, Total, Body, Irradiation, Cyclophosphamide

Regimen

Study Evidence
Kirschey et al. 2014 Phase II

Preceding treatment

  • R-DexaBEAM x 2

Chemoradiotherapy

  • Rituximab (Rituxan) 375 mg/m2 IV once per day on days -8 & -2
  • Total body irradiation (TBI) with a total dose of 12 Gy over 3 days (days -6 to -4) in fractions
  • Cyclophosphamide (Cytoxan) 60 mg/kg IV once per day on days -3 & -2

Stem cells reinfused on day 0

References

  1. 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

Z-BEAM: Zevalin (Ibritumomab tiuxetan), BiCNU (Carmustine), Etoposide, Ara-C (Cytarabine), Melphalan

Regimen

Study Evidence Comparator Efficacy
Shimoni et al. 2007 Phase II    
Shimoni et al. 2012 Randomized Phase II (E) BEAM Seems to have superior OS
Briones et al. 2013 Phase II    

Patients in Shimoni et al. 2012 had primary induction failure or were chemosensitive to salvage therapy. Patients in Briones et al. 2013 had primary induction failure or were refractory to salvage therapy.

Chemoradioimmunotherapy

  • Rituximab (Rituxan) 250 mg/m2 IV once on day -14, given first
  • Ibritumomab tiuxetan & Yttrium-90 (Zevalin) 0.4 mCi/kg (maximum dose of 32 mCi) IV once on day -14, given second
  • 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 medications

  • Filgrastim (Neupogen) 5 mcg/kg SC once per day, starting on day +4 (Shimoni et al. 2012) or day +7 (Briones et al. 2013) 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 Briones et al. 2013)

Stem cells re-infused on day 0

 

References

  1. 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
  2. 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
  3. 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

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

Variant #2, 25 mg 21/28 for 12 months

Study Evidence
Feldman et al. 2014 Phase II

Preceding treatment

  • BEAM with autologous hematopoietic stem cell transplant (details not described)

Chemotherapy

  • Lenalidomide (Revlimid) 25 mg PO once per day on days 1 to 21

28-day cycles for up to 12 months

References

  1. 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
  2. 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

Observation

Regimen

Study Evidence Comparator Efficacy
Thompson et al. 2008 (SWOG 9438) Phase III (C) IL-2 Seems not superior
Furman et al. 2011 (CALGB 9254) Phase III (C) Anti-B4-bR Seems not superior
Gisselbrecht et al. 2010 (CORAL) Phase III (C) Rituximab Seems not superior (*)

No further treatment. Reported efficacy for CORAL is based on the 2012 update.

Preceding treatment

  • SWOG 9438: Cyclophosphamide, Etoposide, TBI with autologous hematopoietic stem cell transplant
  • CORAL: BEAM with autologous hematopoietic stem cell transplant

References

  1. SWOG 9438: Thompson JA, Fisher RI, Leblanc M, Forman SJ, Press OW, Unger JM, Nademanee AP, Stiff PJ, Petersdorf SH, Fefer A. Total body irradiation, etoposide, cyclophosphamide, and autologous peripheral blood stem-cell transplantation followed by randomization to therapy with interleukin-2 versus observation for patients with non-Hodgkin lymphoma: results of a phase 3 randomized trial by the Southwest Oncology Group (SWOG 9438). Blood. 2008 Apr 15;111(8):4048-54. Epub 2008 Feb 6. link to original article link to PMC article PubMed
  2. CALGB 9254: Furman RR, Grossbard ML, Johnson JL, Pecora AL, Cassileth PA, Jung SH, Peterson BA, Nadler LM, Freedman A, Bayer RL, Bartlett NL, Hurd DD, Cheson BD; Cancer Leukemia Group B; Eastern Cooperative Oncology Group. A phase III study of anti-B4-blocked ricin as adjuvant therapy post-autologous bone marrow transplant: CALGB 9254. Leuk Lymphoma. 2011 Apr;52(4):587-96. Epub 2011 Jan 28. link to original article link to PMC articlePubMed
  3. 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
    1. 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

Rituximab monotherapy

Regimen

Study Evidence Comparator Efficacy
Gisselbrecht et al. 2010 (CORAL) Phase III (E) Observation Seems not superior (*)

Treatment begins on day +28. Reported efficacy is based on the 2012 update.

Preceding treatment

  • BEAM with autologous hematopoietic stem cell transplant

Chemotherapy

  • Rituximab (Rituxan) 375 mg/m2 IV once every 8 weeks

1 year course

References

  1. 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
    1. 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

Regimen

FDA-recommended dose
Study Evidence Efficacy
Locke et al. 2017 (ZUMA-1) Phase 1  
Nellapu et al. 2017 (ZUMA-1) Phase II ORR: 82%

Chemotherapy

  • Fludarabine (Fludara) 30 mg/m2 IV once per day on days -6 to -4
  • Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days -6 to -4

Treatment followed by:

Cellular therapy

  • 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 approximately 60 minutes prior to infusion
  • Diphenhydramine (Benadryl) 12.5 mg IV or PO once approximately 60 minutes prior to infusion

One course; patients with initial response and disease progression at least 3 months later could be retreated

References

  1. 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
  2. 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 PubMed

Bendamustine monotherapy

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

  1. 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

Regimen

Study Evidence
Viardot et al. 2016 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 Q8H 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

  1. 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

BR: Bendamustine, Rituximab

Regimen

Study Evidence
Ohmachi et al. 2013 Phase II
Vacirca et al. 2013 Phase II

Note: Bendamustine was given on days 2 & 3 by Ohmachi et al. and on days 1 & 2 by Vacirca et al.

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

  • Trimethoprim/Sulfamethoxazole (Bactrim DS) was recommended
  • Acyclovir (Zovirax) was recommended

21-day cycle for up to 6 cycles

References

  1. Ohmachi K, Niitsu N, Uchida T, Kim SJ, Ando K, Takahashi N, Takahashi N, Uike N, Eom HS, Chae YS, Terauchi T, Tateishi U, Tatsumi M, Kim WS, Tobinai K, Suh C, Ogura M. Multicenter phase II study of bendamustine plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2013 Jun 10;31(17):2103-9. Epub 2013 May 6. link to original article contains verified protocol PubMed
  2. 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

Brentuximab vedotin monotherapy

Regimen

Study Evidence
Jacobsen et al. 2015 Phase II
Bartlett et al. 2016 Phase II

Bartlett et al. treated patients with undetectable CD30 by visual assessment using routine IHC. Jacobsen et al. treated patients with CD30+ non-Hodgkin lymphoma, as determined by IHC.

Chemotherapy

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

21-day cycles

References

  1. 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
  2. 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

Variant #1, IV (3 days/cycle)

Study Evidence Comparator 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

Variant #2, IV (5 days/cycle)

Study Evidence Comparator 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

Variant #3, PO (10 days/cycle)

Study Evidence Comparator 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

Variant #4, PO (14 days/cycle)

Study Evidence Comparator 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

Variant #5, PO (21 days/cycle)

Study Evidence Comparator 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

  1. 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
  2. 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
  3. 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

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

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

Everolimus & Rituximab

Regimen

Study Evidence
Barnes et al. 2013 Phase II

Chemotherapy

  • Everolimus (Afinitor) 5 mg PO once per day on days 1 to 14, increased to 10 mg PO once per day for the remainder of cycle 1 and thereafter, if tolerated
  • Rituximab (Rituxan) 375 mg/m2 IV once per week x 4 weeks, then once on day 1 of cycle 2 onwards

28-day cycle for 6 cycles Responders had the option of continuing everolimus for another 6 months.

References

  1. 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

Variant #1, bi-weekly

Study Evidence Comparator 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

Variant #2, 3 out of 4 weeks x 6

Study Evidence Comparator 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

Variant #3, indefinite 3 out of 4 weeks

Study Evidence Comparator 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

  1. 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
  2. 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
  3. 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

GVD

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

  1. 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 monotherapy

Regimen

Study Evidence
Morschhauser et al. 2007 Phase II

To be completed

Radioimmunotherapy

  • Ibritumomab tiuxetan & Yttrium-90 (Zevalin)

References

  1. 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

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

  1. 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

Regimen

Study Evidence Comparator 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

  1. 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
  2. Review: Webb MS, Saltman DL, Connors JM, Goldie JH. A literature review of single agent treatment of multiply relapsed aggressive non-Hodgkin's lymphoma. Leuk Lymphoma. 2002 May;43(5):975-82. Review. link to original article PubMed
  3. 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

Variant #1, low dose

Study Evidence Comparator Efficacy
Czuczman et al. 2017 (DLC-001) Phase II/III (E) 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

Variant #2, normal dose

Study Evidence Comparator 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) 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

  1. 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
  2. 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
  3. 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

Variant #1

Study Evidence
Wang et al. 2013 Phase II

Chemotherapy

  • Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21
  • Rituximab (Rituxan) 375 mg/m2 IV once per week on weeks 1 to 4 of cycle 1, only

28-day cycles

Variant #2

Study Evidence
Zinzani et al. 2011 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

  1. 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
    1. 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
  2. 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

Regimen

Study Evidence
Bajetta et al. 1988 Phase II

Chemotherapy

  • Mitoxantrone (Novantrone) 14 mg/m2 IV over 30 minutes once on day 1

21-day cycles

References

  1. 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
  2. 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

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 30 minutes prior to Obinutuzumab (Gazyva)
  • "An antihistamine" 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

  1. 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
    1. 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
    2. 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
    3. 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

Regimen

Study Evidence
Coiffier et al. 2013 (415 Study) Phase II

Chemotherapy

  • Ofatumumab (Arzerra) 300 mg IV on cycle 1 day 1, then 1000 mg IV once per week x 7 weeks (total of 8 doses)

Supportive medications

  • Acetaminophen (Tylenol) (or equivalent) 1000 mg PO once 30 minutes to 2 hours prior to Ofatumumab (Arzerra)
  • Cetirizine (Zyrtec) (or equivalent) 10 mg PO once 30 minutes to 2 hours prior to Ofatumumab (Arzerra)
  • Prednisolone (Millipred) (or equivalent) 100 mg (route not specified) once 30 minutes to 2 hours prior to Ofatumumab (Arzerra) for first 2 infusions, only

One course

References

  1. 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

Variant #1, 100 mg/m2

Study Evidence Comparator 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)

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

  1. 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 protocolPubMed
  2. Review: Webb MS, Saltman DL, Connors JM, Goldie JH. A literature review of single agent treatment of multiply relapsed aggressive non-Hodgkin's lymphoma. Leuk Lymphoma. 2002 May;43(5):975-82. Review. link to original article PubMed
  3. 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
  4. 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
  5. 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

Regimen

Study Evidence Comparator Efficacy
Assouline et al. 2016 Randomized Phase II (E) Panobinostat & Rituximab Seems not superior

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

  1. 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

Regimen

Study Evidence Comparator Efficacy
Assouline et al. 2016 Randomized Phase II, <20 pts (E) Panobinostat Seems not superior

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

  1. 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

Regimen

Study Evidence Comparator Efficacy
Pettengell et al. 2012 (PIX301) Phase III (E) 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

  1. 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
    1. 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

Regimen

Study Evidence Comparator Efficacy
Coiffier et al. 1998 Randomized Phase II (E) Higher-dose rituximab Seems not superior
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

  1. 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
  2. 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

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

  1. 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

R-CVEP: Rituximab, Cyclophosphamide, Vorinostat, Etoposide, Prednisone

Regimen

Study Evidence
Straus et al. 2014 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

  1. 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

R-GemOx: Rituximab, Gemcitabine, Oxaliplatin GEMOX-R: GEMcitabine, OXaliplatin, Rituximab

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 a fixed dose rate of 10 mg/m2/min once on day 2
  • Oxaliplatin (Eloxatin) 100 mg/m2 IV over 2 hours once on day 2

Supportive medications

  • Methylprednisolone (Solumedrol) 1 mg/kg IV once prior to Rituximab (Rituxan)
  • Acetaminophen (Tylenol) 1000 mg PO once prior to Rituximab (Rituxan)
  • Dexchlorpheniramine (Polaramine) 6 mg PO once prior to Rituximab (Rituxan)
  • Primary prophylaxis with G-CSF was not permitted

14-day cycle for up to 8 cycles

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

  1. 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
  2. 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
  3. 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

R-INO

R-INO: Rituximab, INOtuzumab ozogamicin

Regimen

Study Evidence Efficacy
Fayad et al. 2013 Phase I/II ORR: 74%

Chemotherapy

  • Rituximab (Rituxan) 375 mg/m2 IV once on day 1
  • Inotuzumab ozogamicin (Besponsa) 1.8 mg/m2 IV once on day 2

28-day cycle for up to 8 cycles

References

  1. Fayad L, Offner F, Smith MR, Verhoef G, Johnson P, Kaufman JL, Rohatiner A, Advani A, Foran J, Hess G, Coiffier B, Czuczman M, Giné E, Durrant S, Kneissl M, Luu KT, Hua SY, Boni J, Vandendries E, Dang NH. Safety and clinical activity of a combination therapy comprising two antibody-based targeting agents for the treatment of non-Hodgkin lymphoma: results of a phase I/II study evaluating the immunoconjugate inotuzumab ozogamicin with rituximab. J Clin Oncol. 2013 Feb 10;31(5):573-83. Epub 2013 Jan 7. link to original article link to PMC article contains verified protocol PubMed

Temsirolimus monotherapy

Regimen

Study Evidence Efficacy
Smith et al. 2010 Phase II ORR: 28%

Chemotherapy

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

28-day cycle for up to 6 cycles

References

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

Tisagenlecleucel monotherapy

Regimen

FDA-recommended dose
Study Evidence Efficacy
Schuster et al. 2018 (JULIET) Phase II ORR: 59% (95% CI, 44‐72)

The range given is the FDA-recommended dose.

Preceding treatment

  • Lymphodepleting therapy with FC or Bendamustine

Immunotherapy

  • Tisagenlecleucel (Kymriah) 0.6 to 6.0 x 108 CTL019 transduced viable T-cells

One course

References

  1. 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. 2018 Dec 1. [Epub ahead of print] link to original article PubMed

TTR

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 30 minutes prior to Paclitaxel (Taxol)
  • Diphenhydramine (Benadryl) 50 mg IV once 30 minutes prior to Paclitaxel (Taxol)

21-day cycle up to a maximum of 6 cycles

References

  1. 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 articlePubMed

Vinorelbine monotherapy

Regimen

Study Evidence Comparator 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

  1. 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
  2. Review: Webb MS, Saltman DL, Connors JM, Goldie JH. A literature review of single agent treatment of multiply relapsed aggressive non-Hodgkin's lymphoma. Leuk Lymphoma. 2002 May;43(5):975-82. Review. link to original article PubMed
  3. 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
    1. 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

Regimen

Study Evidence
Zinzani et al. 2011 Phase II

Preceding treatment

  • Lenalidomide & Rituximab x 4

Chemotherapy

  • Lenalidomide (Revlimid) 20 mg PO once per day on days 1 to 21

28-day cycle for 8 months

References

  1. 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
    1. 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)

To be completed

  1. 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)

To be completed

  1. 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)

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

  1. 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.

  • Coltuximab ravtansine (CoR, SAR3419)
  • Fostamatinib (R788)
  • Pidilizumab (CT-011)

Add new comment