Diffuse large B-cell lymphoma

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73 regimens on this page
100 variants on this page

Contents


Guidelines

ESMO

NCCN

Untreated, pre-phase

Vincristine & Prednisone

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Regimen #1, PO vincristine

Study Evidence
Peyrade et al. 2016 (LYSA LNH09-7B) Phase II

Chemotherapy

Treatment followed by O-miniCHOP.

Regimen #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

7-day course

Treatment in NHL-B1 and NHL-B2 followed by randomization to CHOP versus CHOP-14 versus CHOEP versus CHOEP-14. Treatment in RICOVER-60 followed by randomization to CHOP-14 versus R-CHOP-14. Treatment in SMARTE-R-CHOP-14 followed by R-CHOP-14.

References

  1. Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rudolph C, Reiser M, Hossfeld DK, Metzner B, Hasenclever D, Schmitz N, Glass B, Rübe C, Loeffler M; German High-Grade Non-Hodgkin's Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of young patients with good-prognosis (normal LDH) aggressive lymphomas: results of the NHL-B1 trial of the DSHNHL. Blood. 2004 Aug 1;104(3):626-33. Epub 2004 Feb 24. link to original article contains verified protocol PubMed
  2. Pfreundschuh M, Trümper L, Kloess M, Schmits R, Feller AC, Rübe C, Rudolph C, Reiser M, Hossfeld DK, Eimermacher H, Hasenclever D, Schmitz N, Loeffler M; German High-Grade Non-Hodgkin's Lymphoma Study Group. Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL. Blood. 2004 Aug 1;104(3):634-41. Epub 2004 Mar 11. link to original article contains verified protocol PubMed
  3. 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. 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. Peyrade F, Bologna S, Delwail V, Emile JF, Pascal L, Fermé C, Schiano JM, Coiffier B, Corront B, Farhat H, Fruchart C, Ghesquieres H, Macro M, Tilly H, Choufi B, Delarue R, Fitoussi O, Gabarre J, Haioun C, Jardin F. Combination of ofatumumab and reduced-dose CHOP for diffuse large B-cell lymphomas in patients aged 80 years or older: an open-label, multicentre, single-arm, phase 2 trial from the LYSA group. Lancet Haematol. 2017 Jan;4(1):e46-e55. link to original article contains protocol PubMed

Untreated, randomized data

ACVBP-R

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

Synonyms: R-ACVBP

Structured Concept: none

Regimen

Study Evidence Comparator Efficacy Toxicity
Récher et al. 2011 (LNH03-2B) Phase III R-CHOP Superior OS Increased toxicity
Ketterer et al. 2013 (LNH03-1B) Phase III ACVBP Seems to have superior PFS Similar toxicity

Chemotherapy

CNS prophylaxis

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

Treatment followed in 4 weeks by methotrexate consolidation.

References

  1. Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, Thiéblemont C, Bosly A, Laurent G, Morschhauser F, Ghesquières H, Jardin F, Bologna S, Fruchart C, Corront B, Gabarre J, Bonnet C, Janvier M, Canioni D, Jais JP, Salles G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26;378(9806):1858-67. link to original article contains verified protocol PubMed
  2. Ketterer N, Coiffier B, Thieblemont C, Fermé C, Brière J, Casasnovas O, Bologna S, Christian B, Connerotte T, Récher C, Bordessoule D, Fruchart C, Delarue R, Bonnet C, Morschhauser F, Anglaret B, Soussain C, Fabiani B, Tilly H, Haioun C. Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol. 2013 Apr;24(4):1032-7. Epub 2012 Dec 12. link to original article PubMed

DA-R-EPOCH

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

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

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

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 R-CHOP Seems not superior Increased toxicity

Chemotherapy

Supportive medications

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, increase etoposide, doxorubicin, and cyclophosphamide by 20% compared to previous cycle.
  • If nadir ANC less than 500 on 1 or 2 measurements, use same doses as last cycle.
  • If nadir ANC less than 500 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 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 1,000 and platelets greater than 100. If counts are below those levels, check daily CBC and continue growth factor support until counts are adequate and next cycle can start.

References

  1. 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 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 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

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

Regimen #1

Study Evidence Comparator Efficacy Toxicity
Schmitz et al. 2012 (DSHNHL 2002-1) Phase III R-MegaCHOEP Seems not superior Decreased toxicity

Chemotherapy

14-day cycle for 8 cycles

Radiotherapy

  • 36 Gy in daily fractions "mandatory" for patients with bulky disease (any mass greater than 7.5cm in diameter, or extranodal involvement)

Regimen #2, with CNS prophylaxis

Study Evidence
Holte et al. 2013 Phase II

R-CHOEP portion

Supportive medications

14-day cycle for 8 cycles, followed by:

CNS Prophylaxis

Note that IT treatment was not part of prophylaxis, except that Methotrexate (MTX) 15 mg IT was allowed at time of diagnostic LP.

HiDAC portion

  • Cytarabine (Cytosar) 3000 mg/m2 IV BID for 2 days (4 doses)
    • Dose reduced to 2000 mg/m2 for patients aged 60-65 years

Followed 3 weeks later by:

HD-MTX portion

Supportive medications

One course

Radiotherapy

  • "Given at the discretion of the individual centers (36–45 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."

References

  1. Schmitz N, Nickelsen M, Ziepert M, Haenel M, Borchmann P, Schmidt C, Viardot A, Bentz M, Peter N, Ehninger G, Doelken G, Ruebe C, Truemper L, Rosenwald A, Pfreundschuh M, Loeffler M, Glass B; for the German High-Grade Lymphoma Study Group (DSHNHL). Conventional chemotherapy (CHOEP-14) with rituximab or high-dose chemotherapy (MegaCHOEP) with rituximab for young, high-risk patients with aggressive B-cell lymphoma: an open-label, randomised, phase 3 trial (DSHNHL 2002-1). Lancet Oncol. 2012 Dec;13(12):1250-1259. Epub 2012 Nov 16. link to original article PubMed
  2. Holte H, Leppä S, Björkholm M, Fluge O, Jyrkkiö S, Delabie J, Sundström C, Karjalainen-Lindsberg ML, Erlanson M, Kolstad A, Fosså A, Ostenstad B, Löfvenberg E, Nordström M, Janes R, Pedersen LM, Anderson H, Jerkeman M, Eriksson M. Dose-densified chemoimmunotherapy followed by systemic central nervous system prophylaxis for younger high-risk diffuse large B-cell/follicular grade 3 lymphoma patients: results of a phase II Nordic Lymphoma Group study. Ann Oncol. 2013 May;24(5):1385-92. Epub 2012 Dec 17. link to original article contains verified protocol PubMed

R-CHOP

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

Synonyms: R-CHOP-21, CHOP-R

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

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

Regimen #1, prednisolone 40 mg/m2

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

Note: Cunningham et al. 2013 states that the regimen is based on Coiffier et al. 2002, 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

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 480 mg (route not specified) BID on 3 days per week, taken throughout therapy, ending 2 weeks after chemotherapy is completed

21-day cycle for 8 cycles

Regimen #2, prednisone 100 mg/m2

Study Evidence Comparator Efficacy
Offner et al. 2015 Randomized Phase II VR-CAP Seems not superior

This regimen was used for non-germinal center B-cell (non-GCB) DLBCL.

Chemotherapy

21-day cycle for 6 cycles

Regimen #3, prednisone 40 mg/m2

Study Evidence Comparator Efficacy
Coiffier et al. 2002 (LNH-98.5) Phase III CHOP Superior OS
Delarue et al. 2013 (LNH03-6B) Phase III R-CHOP14 Seems not superior

Chemotherapy

CNS prophylaxis

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

Supportive medications

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

21-day cycle for 8 cycles

Regimen #4, prednisone 100 mg, flat-dose vincristine

Study Evidence Comparator Efficacy Toxicity
Pfreundschuh et al. 2006 (MInT) Phase III CHOP
CHOEP
MACOP-B
PMitCEBO
Superior EFS Similar toxicity

Chemotherapy

Supportive medications

21-day cycle for 6 cycles

Radiotherapy

  • Radiation therapy: 30 to 40 Gy given to sites of primary bulky disease; 30 to 40 Gy to primary extranodal disease at physician discretion

Regimen #5, rituximab lead-in

Study Evidence Comparator Efficacy
Habermann et al. 2006 (CALGB 9793) Phase III CHOP Might have superior FFS

Chemotherapy

Supportive medications

21-day cycle for 6 to 8 cycles

This trial also included a randomization to maintenance rituximab versus observation for responders; however an advantage was only seen in the group receiving CHOP upfront, which is no longer standard of care.

Regimen #6, prednisone 100 mg

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

Chemotherapy

Supportive medications

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

21-day cycle for 6 cycles

Radiotherapy

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

Regimen #7, short-course for early stage DLBCL

Study Evidence
Persky et al. 2008 (SWOG S0014) Phase II

Chemotherapy

21-day cycle for 3 cycles, followed by:

Radiation therapy

Involved-field radiation therapy to begin 3 weeks after last cycle of R-CHOP, see paper for details.

Regimen #8, primary testicular DLBCL

Study Evidence
Vitolo et al. 2011 (IELSG-10) Phase II

This regimen is for primary testicular lymphoma. All patients had a diagnostic orchiectomy prior to starting chemotherapy.

Chemotherapy

CNS prophylaxis

21-day cycle for 6 cycles (up to 8 cycles for stage II patients), followed by:

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.

References

  1. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jan 24;346(4):235-42. link to original article contains verified protocol PubMed
    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 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
  2. Pfreundschuh M, Trümper L, Osterborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, Walewski J, Zinzani PL, Stahel R, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, López-Guillermo A, Corrado C, Scheliga A, Milpied N, Mendila M, Rashford M, Kuhnt E, Loeffler M; MabThera International Trial Group. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol. 2006 May;7(5):379-91. link to original article contains verified protocol PubMed
    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 article contains protocol PubMed
  3. 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
  4. 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
    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 PubMed
  5. 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
  6. 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
  7. Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, Thiéblemont C, Bosly A, Laurent G, Morschhauser F, Ghesquières H, Jardin F, Bologna S, Fruchart C, Corront B, Gabarre J, Bonnet C, Janvier M, Canioni D, Jais JP, Salles G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26;378(9806):1858-67. link to original article PubMed
  8. 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
  9. 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
  10. 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 articlePubMed
    1. Subset 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 PubMed
  11. 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 PubMed
  12. 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 PubMed
  13. 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
  14. 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 link to PMC article contains verified protocol PubMed
  15. 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
  16. 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 PubMed
  17. 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-CHOP Intensified

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

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

Structured Concept: none

Regimen #1

Study Evidence Comparator Efficacy
Cortelazzo et al. 2016 Phase III R-HDS Seems not superior

Note: in the manuscript, 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.

Chemotherapy

14-day cycle for 8 cycles

Supportive medications

Regimen #2

Study Evidence Comparator Efficacy
Pfreundschuh et al. 2014 (SEXIE-R-CHOP-14) Randomized Phase II See below TBD

Main CHOP-14 portion

Rituximab portion

Two arms were assessed; results are pending from this comparison. These higher doses were for males, only.

OR

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

Regimen #3

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

Chemotherapy

CNS prophylaxis

Supportive medications

14-day cycle for 8 cycles

Regimen #4

Study Evidence Comparator Efficacy
Cunningham et al. 2013 Phase III R-CHOP-21 Seems not superior

Main R-CHOP-14 portion

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

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

Additional doses of Rituximab

14-day cycle for 2 cycles

Regimen #5

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

Treatment preceded by pre-phase vincristine & prednisone.

Chemotherapy

Supportive medications

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

Patients with initial bulky disease received:

Radiotherapy

"Initial bulky disease": patients with "lymphoma masses or conglomerates with a diameter greater than or equal to 7.5 cm) or extranodal involvement"

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

Regimen #6

Study Evidence
Pfreundschuh et al. 2014 (SMARTE-R-CHOP-14) Phase II

Treatment preceded by pre-phase vincristine & prednisone.

Chemotherapy

Supportive medications

14-day cycle for 6 cycles

Patients with initial bulky disease received:

Radiotherapy

"Initial bulky disease": patients with "lymphoma masses or conglomerates with a diameter greater than or equal to 7.5 cm) or extranodal involvement"

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

References

  1. Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trümper L, Balleisen L, Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M; German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL). Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol. 2008 Feb;9(2):105-16. link to original article contains verified protocol PubMed
  2. Delarue R, Tilly H, Mounier N, Petrella T, Salles G, Thieblemont C, Bologna S, Ghesquières H, Hacini M, Fruchart C, Ysebaert L, Fermé C, Casasnovas O, Van Hoof A, Thyss A, Delmer A, Fitoussi O, Molina TJ, Haioun C, Bosly A. Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol. 2013 May;14(6):525-33. Epub 2013 Apr 9. link to original article contains verified protocol PubMed
  3. Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, Pocock C, Ardeshna KM, Radford JA, McMillan A, Davies J, Turner D, Kruger A, Johnson P, Gambell J, Linch D. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet. 2013 May 25;381(9880):1817-26. Epub 2013 Apr 22. link to original article contains verified protocol PubMed
  4. 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
  5. 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
  6. Cortelazzo et al. 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;34(33):4015-22. link to original article contains verified protocol

R-CVP

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R-CVP: Rituximab, Cyclophosphamide, Vincristine, Prednisone

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

Regimen

Chemotherapy

21-day cycle for up to 8 cycles

References

See references for CVP

R-HyperCVAD/R-MA

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R-HCVAD: Rituximab, Hyperfractionated Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Dexamethasone
R-MA: Rituximab, Methotrexate, Ara-C (Cytarabine)

Regimen

Study Evidence Comparator Efficacy
Oki et al. 2013 Randomized Phase II 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."

Part A (cycles 1, 3, 5)

Supportive medications

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 0.75 × 10^9/L or platelet count less than 75 × 10^9/L on day 21

Next cycle to start once ANC count is greater than or equal to 1 x 10^9/L and platelet count is greater than or equal to 100 x 10^9/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.

Part B (cycles 2, 4, 6)

Supportive medications

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 0.75 × 10^9/L or platelet count less than 75 × 10^9/L on day 21
  • Cytarabine (Cytosar) reduced by 33% in subsequent B cycles if neutropenic fever occurs, grade 3/4 non-hematological toxicity, or ANC less than 0.75 × 10^9/L or platelet count less than 75 × 10^9/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 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-miniCEOP

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

Regimen

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

Chemotherapy

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

Patients with initial bulky disease and/or partially responding sites received:

Radiation therapy

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

References

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

Untreated, non-randomized or retrospective data

BR

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BR: Bendamustine, Rituximab

Regimen

Study Evidence
Park et al. 2016 Phase II

Chemotherapy

Note: the bendamustine infusion instructions are for the Treanda formulation, which was discontinued on 3/31/2016.

  • Bendamustine 120 mg/m2 IV over 60 minutes once per day on days 1 & 2
    • Patients with ECOG PS = 3 at baseline received 90 mg/m2 IV over 60 minutes once per day on days 1 & 2
      • 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 after bendamustine

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 PubMed

CHOP -> IFRT -> Ibritumomab tiuxetan

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CHOP: Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone

Regimen

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

This regimen is intended for limited-stage aggressive B-cell NHL; the majority of patients studied had DLBCL.

Chemotherapy

21-day cycle for 3 cycles, followed 3 weeks later by:

Radiation therapy

Involved-field radiation therapy, see paper for details.

Complete course followed in 3 to 6 weeks by:

Consolidation radioimmunotherapy

References

  1. 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 PubMed

Helicobacter pylori eradication therapy

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Regimen

This regimen is intended for the treatment of gastric DLBCL only; H. pylori eradication would not be an appropriate treatment for systemic DLBCL.

Before 1996:

After 1996:

References

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

O-miniCHOP

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

Regimen

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

Treatment preceded by pre-phase vincristine & prednisone.

Chemotherapy

Supportive medications

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

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R-BL: Rituximab, Bendamustine, Lenalidomide

Regimen

Study Evidence ORR
Hitz et al. 2016 (SAKK 38/08) Phase II, <20 pts in subgroup 61% (95% CI 45-76%)

Chemotherapy

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; DRCOP

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

Regimen #1

Study Evidence
Oki et al. 2014 Phase II

Chemotherapy

Supportive medications

OR

Dose modifications

21-day cycle for 6 to 8 cycles

Regimen #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

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 article PubMed
  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 link to PMC article contains verified protocol PubMed

R-CEOP90 (Epirubicin)

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

Regimen

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

21-day cycle for 4 cycles followed by involved field radiotherapy (30-45 Gy) of bulky disease and extranodal and residual masses for patients with stage IA or IIA disease; 6 cycles for all others

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)

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R-CEOP: Rituximab, Cyclophosphamide, Etoposide, Oncovin (Vincristine), Prednisone

Regimen

Study Evidence
Moccia et al. 2009 Retrospective

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

Chemotherapy

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

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

Regimen

Study Evidence
Hagemeister et al. 2013 Phase II

Chemotherapy

21-day cycle for 6 cycles; stage I patients with no LN greater than 5 cm received 3 cycles followed by local XRT

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-CHOP -> Ibritumomab tiuxetan

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

Regimen

Study Evidence
Witzig et al. 2015 (ECOG3402) Phase II

This regimen is intended for stage I-II DLBCL based on CT (not PET-CT) imaging.

Chemotherapy

21-day cycle for 4 to 6 cycles, followed in 3 to 12 weeks by:

Consolidation radioimmunotherapy

Patients with CT or PET positive disease 12 weeks after radioimmunotherapy underwent 30 Gy of IFRT.

References

  1. 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 PubMed

R-GCVP

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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

Supportive medications

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 protocol PubMed

R-MegaCHOP

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

Regimen

Study Evidence
Pardal et al. 2014 Phase II

Chemotherapy

Supportive medications

21-day cycle for 3 cycles

Patients with a negative PET-CT after 3 cycles received another 3 cycles of R-MegaCHOP for a total of 6 cycles; others underwent intensification of treatment with R-IFE.

References

  1. Pardal E, Coronado M, Martín A, Grande C, Marín-Niebla A, Panizo C, Bello JL, Conde E, Hernández MT, Arranz R, Bargay J, González-Barca E, Pérez-Ceballos E, Montes-Moreno S, Caballero MD. Intensification treatment based on early FDG-PET in patients with high-risk diffuse large B-cell lymphoma: a phase II GELTAMO trial. Br J Haematol. 2014 Nov;167(3):327-36. Epub 2014 Jul 28. link to original article contains verified protocol PubMed

R-miniCHOP

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

Regimen

Study Evidence
Peyrade et al. 2011 Phase II

Chemotherapy

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) SQ on days 6 to 13 of the subsequent cycle until neutrophils were = 1.0 x 109/L.

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; LR-CHOP-21

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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

Regimen #1

Study Evidence
Vitolo et al. 2014 (REAL07) Phase II

Chemotherapy

CNS prophylaxis

Supportive medications

21-day cycle for 6 cycles

Regimen #2

Study Evidence
Nowakowski et al. 2014 Phase II

Chemotherapy

Supportive medications

21-day cycle for up to 6 cycles

Regimen #3

Study Evidence
Chiappella et al. 2013 Phase II

Chemotherapy

Supportive medications

21-day cycle for 6 cycles

References

  1. Nowakowski GS, LaPlant B, Habermann TM, Rivera CE, Macon WR, Inwards DJ, Micallef IN, Johnston PB, Porrata LF, Ansell SM, Klebig RR, Reeder CB, Witzig TE. Lenalidomide can be safely combined with R-CHOP (R2CHOP) in the initial chemotherapy for aggressive B-cell lymphomas: phase I study. Leukemia. 2011 Dec;25(12):1877-81. Epub 2011 Jul 1. link to original article contains verified protocol PubMed
  2. Chiappella A, Tucci A, Castellino A, Pavone V, Baldi I, Carella AM, Orsucci L, Zanni M, Salvi F, Liberati AM, Gaidano G, Bottelli C, Rossini B, Perticone S, De Masi P, Ladetto M, Ciccone G, Palumbo A, Rossi G, Vitolo U. Lenalidomide plus cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab is safe and effective in untreated elderly diffuse large B-cell lymphoma patients: phase I study by the Fondazione Italiana Linfomi. Haematologica. 2013 Nov;98(11):1732-8. Epub 2013 Jun 28. link to original article contains verified protocol PubMed
  3. 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
  4. 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

VR-CHOP

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VR-CHOP: Velcade (Bortezomib), Rituximab, Cyclophosphamide, Hydroxydaunorubicin (Doxorubicin), Oncovin (Vincristine), Prednisone

Regimen

Study Evidence
Ruan et al. 2010 Phase II

Doses here are the phase II dose of bortezomib and the R-CHOP protocol as specified in the phase I report by Furman et al. 2010

Chemotherapy

Supportive medications

21-day cycle for 6 cycles

References

  1. Ruan J, Martin P, Furman RR, Lee SM, Cheung K, Vose JM, Lacasce A, Morrison J, Elstrom R, Ely S, Chadburn A, Cesarman E, Coleman M, Leonard JP. Bortezomib plus CHOP-rituximab for previously untreated diffuse large B-cell lymphoma and mantle cell lymphoma. J Clin Oncol. 2011 Feb 20;29(6):690-7. Epub 2010 Dec 28. link to original article contains verified protocol PubMed

Consolidation and/or maintenance after upfront therapy

Autologous hematopoietic cell transplant

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Regimen

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

Treatment preceded by R-CHOP x 6. Preparative regimen was TBI or CBV.

References

  1. 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 articlePubMed
    1. Subset 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 PubMed

Cytarabine (Cytosar)

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Regimen

Study Evidence
Récher et al. 2011 (LNH03-2B) Non-randomized portion of RCT
Ketterer et al. 2013 (LNH03-1B) Non-randomized

Treatment preceded by REI consolidation x 4.

Chemotherapy

14-day cycle for 2 cycles

References

  1. Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, Thiéblemont C, Bosly A, Laurent G, Morschhauser F, Ghesquières H, Jardin F, Bologna S, Fruchart C, Corront B, Gabarre J, Bonnet C, Janvier M, Canioni D, Jais JP, Salles G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26;378(9806):1858-67. link to original article contains verified protocol PubMed
  2. Ketterer N, Coiffier B, Thieblemont C, Fermé C, Brière J, Casasnovas O, Bologna S, Christian B, Connerotte T, Récher C, Bordessoule D, Fruchart C, Delarue R, Bonnet C, Morschhauser F, Anglaret B, Soussain C, Fabiani B, Tilly H, Haioun C. Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol. 2013 Apr;24(4):1032-7. Epub 2012 Dec 12. link to original article PubMed

Lenalidomide (Revlimid)

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Regimen

Study Evidence Comparator Efficacy
Thieblemont et al. 2016 (REMARC) Phase III Observation Seems to have superior PFS

Treatment preceded by 6 to 8 cycles of R-CHOP21 or R-CHOP14.

Chemotherapy

28-day cycle for 2 years

References

  1. Abstract: Catherine Thieblemont, Hervé Tilly, Maria Gomez da Silva, Rene-Olivier Casasnovas, Christophe Fruchart, Franck Morschhauser, Corinne Haioun, Julien Lazarovici, Sebastian Grosicki, Aurore Perrot, Judith Trotman, Catherine Sebban, Dolores Caballero, Richard Greil, Koen Van Eygen, Josette Briere, Jose Cabecadas, Gilles Andre Salles, Philippe Gaulard, Andre Bosly and Bertrand Coiffier. First Analysis of an International Double-Blind Randomized Phase III Study of Lenalidomide Maintenance in Elderly Patients with DLBCL Treated with R-CHOP in First Line, the Remarc Study from Lysa. Blood 2016 128:471 link to abstract

Methotrexate (MTX)

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Regimen

Study Evidence
Récher et al. 2011 (LNH03-2B) Non-randomized portion of RCT
Ketterer et al. 2013 (LNH03-1B) Non-randomized

Treatment preceded by ACVBP-R x 4.

Chemotherapy

Supportive medications

14-day cycle for 2 cycles

Treatment followed in 2 weeks by REI consolidation.

References

  1. Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, Thiéblemont C, Bosly A, Laurent G, Morschhauser F, Ghesquières H, Jardin F, Bologna S, Fruchart C, Corront B, Gabarre J, Bonnet C, Janvier M, Canioni D, Jais JP, Salles G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26;378(9806):1858-67. link to original article contains verified protocol PubMed
  2. Ketterer N, Coiffier B, Thieblemont C, Fermé C, Brière J, Casasnovas O, Bologna S, Christian B, Connerotte T, Récher C, Bordessoule D, Fruchart C, Delarue R, Bonnet C, Morschhauser F, Anglaret B, Soussain C, Fabiani B, Tilly H, Haioun C. Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol. 2013 Apr;24(4):1032-7. Epub 2012 Dec 12. link to original article PubMed

Observation

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Regimen

Study Evidence Comparator Efficacy
Jaeger et al. 2015 (NHL13) Phase III Rituximab Seems not superior
Witzens-Harig et al. 2015 (HD2002) Phase III Rituximab Inferior OS in males
Crump et al. 2016 (PRELUDE) Phase III Enzastaurin Seems not superior
Thieblemont et al. 2016 (REMARC) Phase III Lenalidomide Seems to have inferior PFS

No further treatment, also variously termed "observation" and "watchful waiting". Preceded by "standard treatment" in HD2002; R-CHOP in PRELUDE and SWOG S9704; and 6 to 8 cycles of R-CHOP21 or R-CHOP14 in REMARC.

References

  1. 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. 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
  3. 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 PubMed
  4. 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
  5. 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 May 23. [Epub ahead of print] link to original article PubMed
  6. Abstract: Catherine Thieblemont, Hervé Tilly, Maria Gomez da Silva, Rene-Olivier Casasnovas, Christophe Fruchart, Franck Morschhauser, Corinne Haioun, Julien Lazarovici, Sebastian Grosicki, Aurore Perrot, Judith Trotman, Catherine Sebban, Dolores Caballero, Richard Greil, Koen Van Eygen, Josette Briere, Jose Cabecadas, Gilles Andre Salles, Philippe Gaulard, Andre Bosly and Bertrand Coiffier. First Analysis of an International Double-Blind Randomized Phase III Study of Lenalidomide Maintenance in Elderly Patients with DLBCL Treated with R-CHOP in First Line, the Remarc Study from Lysa. Blood 2016 128:471 link to abstract

REI

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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

Treatment preceded by methotrexate consolidation x 2.

Chemotherapy

14-day cycle for 4 cycles

Treatment followed in 2 weeks by cytarabine consolidation.

References

  1. Récher C, Coiffier B, Haioun C, Molina TJ, Fermé C, Casasnovas O, Thiéblemont C, Bosly A, Laurent G, Morschhauser F, Ghesquières H, Jardin F, Bologna S, Fruchart C, Corront B, Gabarre J, Bonnet C, Janvier M, Canioni D, Jais JP, Salles G, Tilly H; Groupe d'Etude des Lymphomes de l'Adulte. Intensified chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the treatment of diffuse large B-cell lymphoma (LNH03-2B): an open-label randomised phase 3 trial. Lancet. 2011 Nov 26;378(9806):1858-67. link to original article contains verified protocol PubMed
  2. Ketterer N, Coiffier B, Thieblemont C, Fermé C, Brière J, Casasnovas O, Bologna S, Christian B, Connerotte T, Récher C, Bordessoule D, Fruchart C, Delarue R, Bonnet C, Morschhauser F, Anglaret B, Soussain C, Fabiani B, Tilly H, Haioun C. Phase III study of ACVBP versus ACVBP plus rituximab for patients with localized low-risk diffuse large B-cell lymphoma (LNH03-1B). Ann Oncol. 2013 Apr;24(4):1032-7. Epub 2012 Dec 12. link to original article PubMed

Rituximab (Rituxan)

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Regimen #1

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

Treatment preceded by 8 infusions of rituximab (375 mg/m2) and 4 to 8 cycles of CHOP-like chemotherapy. 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.

Chemotherapy

1 to 2 year course

Regimen #2

Study Evidence Comparator Efficacy
Witzens-Harig et al. 2015 (HD2002) Phase III Observation Superior OS in males

Preceded by "standard treatment" which was not further described in the paper, beyond that a majority of patient received R-CHOP (see Tables).

Chemotherapy

2 year course

References

  1. 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. 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
  3. 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 PubMed
  4. Witzens-Harig M, Benner A, McClanahan F, Klemmer J, Brandt J, Brants E, Rieger M, Meissner J, Hensel M, Neben K, Dreger P, Lengfelder E, Schmidt-Wolf I, Krämer A, Ho AD. Rituximab maintenance improves survival in male patients with diffuse large B-cell lymphoma. Results of the HD2002 prospective multicentre randomized phase III trial. Br J Haematol. 2015 Dec;171(5):710-9. Epub 2015 Oct 9. link to original article contains verified protocol PubMed

Relapsed/refractory, randomized data

Gemcitabine (Gemzar)

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Regimen

Study Evidence Comparator Efficacy
Fosså et al. 1999 Phase II
Pettengell et al. 2012 Phase III, <20 pts in this arm Pixantrone Seems to have inferior CR/CRu rate

Chemotherapy

  • Gemcitabine (Gemzar) as follows:
    • Cycle 1: 1250 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
    • 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

4-week cycles until progression or intolerance

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. 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 protocol PubMed

Ifosfamide (Ifex)

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Regimen

Study Evidence Comparator Efficacy
Case et al. 1991 (CALGB 8552) Phase II
Pettengell et al. 2012 Phase III, <20 pts in this arm Pixantrone Seems to have inferior CR/CRu rate

Dose & schedule is as given in Pettengell et al. CALGB 8552 used a different dose & schedule.

Chemotherapy

Supportive medications

28-day cycles

References

  1. 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. 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

O-DHAP

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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 R-DHAP Seems not superior

Chemotherapy

Supportive medications

21-day cycle for 3 cycles

Responders proceeded to stem-cell mobilization and autologous hematopoietic cell transplant. Most patients in ORCHARRD proceeded to BEAM except those in Japan who received LEED.

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 PubMed
  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 supplement verified protocol in supplement PubMed

Oxaliplatin (Eloxatin)

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Regimen

Study Evidence Comparator Efficacy
Germann et al. 1999 Phase II
Oki et al. 2005 Phase II
Pettengell et al. 2012 Phase III, <20 pts in this arm Pixantrone Seems to have inferior CR/CRu rate

Germann et al. give a range of 100 to 130 mg/m2; Oki et al. used the 130 mg/m2 dosage; Pettengell et al. used the 100 mg/m2 dosage.

Chemotherapy

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 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. 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. 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

Panobinostat (Farydak)

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Regimen

Study Evidence ORR Comparator Comparator ORR Efficacy Pt Population
Assouline et al. 2016 Randomized Phase II 29% (95% CI 11-52%) Panobinostat & Rituximab 26% (95% CI 9-51%) Seems not superior Median of 2 prior treatments (range 1-8)

Chemotherapy

21-day cycles until progression or intolerance

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 PubMed

Panobinostat & Rituximab

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Regimen

Study Evidence ORR Comparator Comparator ORR Efficacy Pt Population
Assouline et al. 2016 Randomized Phase II, <20 pts 26% (95% CI 9-51%) Panobinostat 29% (95% CI 11-52%) Seems not superior Median of 3 prior treatments (range 2-9)

Chemotherapy

21-day cycles until progression or intolerance

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 PubMed

Pixantrone (Pixuvri)

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Regimen

Study Evidence Comparator Efficacy
Pettengell et al. 2012 Phase III Etoposide
Gemcitabine
Ifosfamide
Mitoxantrone
Oxaliplatin
Vinorelbine
Seems to have superior CR/CRu rate

Chemotherapy

28-day cycle for up to 6 cycles

References

  1. Pettengell R, Coiffier B, Narayanan G, de Mendoza FH, Digumarti R, Gomez H, Zinzani PL, Schiller G, Rizzieri D, Boland G, Cernohous P, Wang L, Kuepfer C, Gorbatchevsky I, Singer JW. Pixantrone dimaleate versus other chemotherapeutic agents as a single-agent salvage treatment in patients with relapsed or refractory aggressive non-Hodgkin lymphoma: a phase 3, multicentre, open-label, randomised trial. Lancet Oncol. 2012 Jul;13(7):696-706. 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 PubMed

R-DHAP

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

Regimen #1

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

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

Patients in CORAL with complete or partial response then received BEAM -> autologous stem-cell transplant. Most responders in ORCHARRD proceeded to BEAM except those in Japan who received LEED.

Regimen #2

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

Chemotherapy

21-day cycle for up to 3 cycles

Responders proceeded to stem-cell mobilization and autologous hematopoietic cell transplant.

References

  1. Hagberg H, Gisselbrecht C; CORAL study group. Randomised phase III study of R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large B-cell lymphoma (DLBCL) followed by high-dose therapy and a second randomisation to maintenance treatment with rituximab or not: an update of the CORAL study. Ann Oncol. 2006 May;17 Suppl 4:iv31-2. link to original article PubMed
  2. Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Brière J, Moskowitz CH, Schmitz N. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010 Sep 20;28(27):4184-90. Epub 2010 Jul 26. Erratum in: J Clin Oncol. 2012 May 20;30(15):1896. link to original article contains verified protocol PubMed
  3. 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. van Imhoff GW, McMillan A, Matasar MJ, Radford J, Ardeshna KM, Kuliczkowski K, Kim W, Hong X, Goerloev JS, Davies A, Barrigón MD, Ogura M, Leppä S, Fennessy M, Liao Q, van der Holt B, Lisby S, Hagenbeek A. Ofatumumab Versus Rituximab Salvage Chemoimmunotherapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma: The ORCHARRD Study. J Clin Oncol. 2017 Feb 10;35(5):544-51. Epub 2016 Dec 28. link to original article link to data supplement verified protocol in supplement PubMed

R-DHAP/R-VIM

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

Regimen

Study Evidence Comparator Efficacy
Vellenga et al. 2008 (HOVON-44) Phase III 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

28-day cycle for 2 cycles, with VIM interposed

Chemotherapy, R-VIM portion

28-day cycle for 1 cycle, given in-between R-DHAP cycles

Responders proceeded to stem-cell mobilization and BEAM.

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-ESHAP

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

Supportive medications

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

References

  1. Velasquez WS, McLaughlin P, Tucker S, Hagemeister FB, Swan F, Rodriguez MA, Romaguera J, Rubenstein E, Cabanillas F. ESHAP--an effective chemotherapy regimen in refractory and relapsing lymphoma: a 4-year follow-up study. J Clin Oncol. 1994 Jun;12(6):1169-76. link to original article contains verified protocol PubMed
  2. 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
  3. Avilés A, Neri N, Huerta-Guzmán J, de Jesús Nambo M. ESHAP versus rituximab-ESHAP in frail patients with refractory diffuse large B-cell lymphoma. Clin Lymphoma Myeloma Leuk. 2010 Apr;10(2):125-8. link to original article PubMed

R-GDP

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

Regimen

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

Chemotherapy

21-day cycle for up to 3 cycles

Responders proceeded to stem-cell mobilization and autologous hematopoietic cell transplant.

References

  1. Crump M, Kuruvilla J, Couban S, MacDonald DA, Kukreti V, Kouroukis CT, Rubinger M, Buckstein R, Imrie KR, Federico M, Di Renzo N, Howson-Jan K, Baetz T, Kaizer L, Voralia M, Olney HJ, Turner AR, Sussman J, Hay AE, Djurfeldt MS, Meyer RM, Chen BE, Shepherd LE. Randomized Comparison of Gemcitabine, Dexamethasone, and Cisplatin Versus Dexamethasone, Cytarabine, and Cisplatin Chemotherapy Before Autologous Stem-Cell Transplantation for Relapsed and Refractory Aggressive Lymphomas: NCIC-CTG LY.12. J Clin Oncol. 2014 Nov 1;32(31):3490-6. Epub 2014 Sep 29. link to original article contains verified protocol PubMed

R-ICE

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R-ICE: Rituximab, Ifosfamide, Carboplatin, Etoposide

Regimen

Study Evidence Comparator Efficacy
Gisselbrecht et al. 2010 (CORAL) Phase III R-DHAP Seems not superior

Note: the paper refers to the non-randomized Kewalramani et al. 2004 regimen, although it has slightly different day numbering. Doses are the same.

Chemotherapy

Supportive medications

21-day cycle for 3 cycles

Patients with complete or partial response then received BEAM autologous stem-cell transplant.

References

  1. Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Brière J, Moskowitz CH, Schmitz N. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010 Sep 20;28(27):4184-90. Epub 2010 Jul 26. Erratum in: J Clin Oncol. 2012 May 20;30(15):1896. link to original article contains verified protocol PubMed
  2. 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

Vinorelbine (Navelbine)

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Regimen

Study Evidence Comparator Efficacy
Balzarotti et al. 1996 Non-randomized, <20 pts in this subgroup
Pettengell et al. 2012 Phase III, <20 pts in this arm Pixantrone Seems to have inferior CR/CRu rate

Chemotherapy

28-day 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. 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

Relapsed/refractory, non-randomized or retrospective data

Bendamustine

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Regimen

Study Evidence
Weidmann et al. 2002 Phase II

Chemotherapy

3-week 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. PubMed

Blinatumomab (Blincyto)

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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 µg/day IV continuous infusion during week 1, then
    • 28 µg/day IV continuous infusion during week 2, then
    • 112 µg/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 TID for 2 days following infusion start and dose increases
    • Patients with neurologic symptoms or cytokine release syndrome received 8 mg PO/IV 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 PubMed

BR

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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

Note: the bendamustine infusion instructions are for the Treanda formulation, which was discontinued on 3/31/2016.

Supportive medications

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 PubMed

Brentuximab vedotin (Adcetris)

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Regimen

Study Evidence
Bartlett et al. 2014 Phase II
Jacobsen et al. 2015 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

21-day cycles, given until progression or unacceptable toxicity

References

  1. Abstract: Nancy L. Bartlett, MD, Mitchell R. Smith, MD, Ranjana Advani, MD, Tatyana Feldman, MD, Kerry J. Savage, MD MSc, Maria Corinna Palanca-Wessels, MD, PhD and Tanya Siddiqi, MD. Brentuximab Vedotin Monotherapy in DLBCL Patients with Undetectable CD30: Preliminary Results from a Phase 2 Study. ASH Annual Meeting 2014 Abstract 629 link to abstract
  2. 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

Everolimus (Afinitor)

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Regimen

Study Evidence
Witzig et al. 2011 Phase II

Chemotherapy

Supportive medications

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

28-day cycles, given until progression or unacceptable toxicity

References

  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 article contains verified protocol PubMed

Everolimus & Rituximab

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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 PubMed

GVD

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GVD: Gemcitabine, Vinorelbine, Doxil (Doxorubicin liposomal)

Regimen

Study Evidence
Bai et al. 2013 Retrospective

Chemotherapy

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 (Zevalin)

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Regimen

To be completed

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 (Imbruvica)

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Regimen

Study Evidence
Wilson et al. 2012 Phase II

Clinically meaningful responses were observed in the ABC subtype, only. Further clinical trials are currently underway.

Chemotherapy

Duration not specified

References

  1. Abstract: Wyndham H. Wilson, MD, PhD, John F. Gerecitano, MD, PhD, Andre Goy, MD, Sven de Vos, MD, PhD, Vaishalee P. Kenkre, MD, Paul M. Barr, MD, Kristie A. Blum, MD, Andrei R. Shustov, MD, Ranjana H. Advani, MD, Jason Lih, PhD, Mickey Williams, PhD, Roland Schmitz, PhD, Yandan Yang, PhD, Stefania Pittaluga, MD, PhD, George Wright, PhD, Lori A. Kunkel, MD, Jesse McGreivy, MD, Sriram Balasubramanian, PhD, Mei Cheng, PhD, Davina Moussa, Joseph J. Buggy, PhD and Louis M. Staudt, MD, PhD. The Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), Has Preferential Activity in the ABC Subtype of Relapsed/Refractory De Novo Diffuse Large B-Cell Lymphoma (DLBCL): Interim Results of a Multicenter, Open-Label, Phase 2 Study. Blood 120, a686 (2012). link to abstract

Lenalidomide (Revlimid)

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Regimen

Study Evidence
Wiernik et al. 2008 (NHL-002) Phase II
Witzig et al. 2011 (NHL-003) Phase II

Chemotherapy

28-day cycles until disease progression or unacceptable toxicity

References

  1. 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. Witzig TE, Vose JM, Zinzani PL, Reeder CB, Buckstein R, Polikoff JA, Bouabdallah R, Haioun C, Tilly H, Guo P, Pietronigro D, Ervin-Haynes AL, Czuczman MS. An international phase II trial of single-agent lenalidomide for relapsed or refractory aggressive B-cell non-Hodgkin's lymphoma. Ann Oncol. 2011 Jul;22(7):1622-7. Epub 2011 Jan 12. link to original article contains verified protocol PubMed

Lenalidomide & Rituximab

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Regimen #1

Study Evidence
Wang et al. 2013 Phase II

Chemotherapy

28-day cycles

Regimen #2

Study Evidence
Zinzani et al. 2011 Phase II

Chemotherapy

28-day cycle for 4 cycles

Patients with a response of stable disease or better proceeded to maintenance lenalidomide.

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 (Novantrone)

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Regimen

Study Evidence
Bajetta et al. 1988 Phase II

Chemotherapy

3-week 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. 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 (Gazyva)

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Regimen

Study Evidence
Morschhauser et al. 2013 (GAUGUIN) Phase II

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. Morschhauser FA, Cartron G, Thieblemont C, Solal-Céligny P, Haioun C, Bouabdallah R, Feugier P, Bouabdallah K, Asikanius E, Lei G, Wenger M, Wassner-Fritsch E, Salles GA. Obinutuzumab (GA101) Monotherapy in Relapsed/Refractory Diffuse Large B-Cell Lymphoma or Mantle-Cell Lymphoma: Results From the Phase II GAUGUIN Study. J Clin Oncol. 2013 Aug 10;31(23):2912-9. Epub 2013 Jul 8. link to original article contains verified protocol PubMed

O-ICE

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O-ICE: Ofatumumab, Ifosfamide, Carboplatin, Etoposide

Regimen

Study Evidence
Matasar et al. 2013 Phase II

Chemotherapy

Supportive medications

21-day cycle for 3 cycles

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 PubMed

Ofatumumab (Arzerra)

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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

One course

References

  1. Coiffier B, Radford J, Bosly A, Martinelli 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

R-BL

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R-BL: Rituximab, Bendamustine, Lenalidomide

Regimen

Study Evidence ORR
Hitz et al. 2016 (SAKK 38/08) Phase II 61% (95% CI 45-76%)

Chemotherapy

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

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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

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-DexaBEAM

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

Regimen

Study Evidence
Kirschey et al. 2014 Phase II

Chemotherapy

3- to 4-week cycle for 2 cycles

Patient proceed to undergo high dose therapy and autologous hematopoietic 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-DHAP

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

Regimen

Study Evidence
Mey et al. 2006 Phase II

The doses here were used after a mid-protocol amendment pertaining to the first cycle.

First cycle

  • Rituximab (Rituxan) 375 mg/m2 IV once on day 1
  • Dexamethasone (Decadron) 40 mg PO once per day on days 3 to 5
  • Cytarabine (Cytosar) as follows:
    • Younger than 60 years: 1000 mg/m2 IV over 2 hours Q12H x 2 doses on day 4 (total of 2 doses)
    • Older than 60 years: 500 mg/m2 IV over 2 hours Q12H x 2 doses on day 4 (total of 2 doses)
  • Cisplatin (Platinol) 25 mg/m2/day IV continuous infusion on days 3 to 5 (total dose: 75 mg/m2)

3-week cycle

Subsequent cycles

  • Rituximab (Rituxan) 375 mg/m2 IV once on day 1
  • Dexamethasone (Decadron) 40 mg PO once per day on days 3 to 6
  • Cytarabine (Cytosar) as follows:
    • Younger than 60 years: 2000 mg/m2 IV over 2 hours Q12H x 2 doses on day 4 (total of 2 doses)
    • Older than 60 years: 1000 mg/m2 IV over 2 hours Q12H x 2 doses on day 4 (total of 2 doses)
  • Cisplatin (Platinol) 25 mg/m2/day IV continuous infusion on days 3 to 6 (total dose per cycle: 100 mg/m2)

3-week cycle up to 3 cycles (4 cycles, total)

Patients with complete or partial response were allowed to undergo autologous stem-cell transplant.

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 protocol PubMed

R-EPOCH

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

Regimen

Study Evidence
Jermann et al. 2004 Phase II

Note: this is not the dose-adjusted R-EPOCH regimen

Chemotherapy

21-day cycle for 4 to 6 cycles

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-GDP

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

Regimen

Study Evidence
Hou et al. 2012 Non-randomized

Chemotherapy

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

R-GemOx

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R-GemOx: Rituximab, Gemcitabine, Oxaliplatin

Regimen #1 "GEMOX-R"

Study Evidence
López et al. 2008 Phase II

Chemotherapy

21-day cycle for 6 to 8 cycles

Regimen #2

Study Evidence
El Gnaoui et al. 2007 Phase II

Chemotherapy

Supportive medications

14-day cycle for up 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 PubMed

R-ICE

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R-ICE: Rituximab, Ifosfamide, Carboplatin, Etoposide

Regimen #1

Study Evidence
Guo et al. 2014 Phase II

Chemotherapy

3 cycles; duration of cycles not specified in the abstract

Regimen #2

Study Evidence
Zelenetz et al. 2003 Phase II
Kewalramani et al. 2004 Phase II

Third cycle intended to be followed by peripheral blood hematopoietic cell collection

Chemotherapy

14-day cycle for 3 cycles

Supportive medications

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 regimen PubMed
  3. 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 PubMed

RICER

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

Regimen

Study Evidence
Feldman et al. 2014 Phase II

Chemotherapy

Supportive medications

14-day cycle for 2 cycles

Responders received a 3rd cycle with hematopoietic cell collection 10 to 14 days afterwards, followed by autologous hematopoietic cell transplant.

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 PubMed

R-IFE

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R-IFE: Rituximab, IFosfamide, Etoposide

Regimen

Study Evidence
Pardal et al. 2014 Phase II

Treatment preceded by R-MegaCHOP x3; these were patients with PET-positive disease at interim assessment.

Chemotherapy

Supportive medications

2 cycles (duration not specified)

Responders proceeded to undergo autologous hematopoietic cell transplant.

References

  1. Pardal E, Coronado M, Martín A, Grande C, Marín-Niebla A, Panizo C, Bello JL, Conde E, Hernández MT, Arranz R, Bargay J, González-Barca E, Pérez-Ceballos E, Montes-Moreno S, Caballero MD. Intensification treatment based on early FDG-PET in patients with high-risk diffuse large B-cell lymphoma: a phase II GELTAMO trial. Br J Haematol. 2014 Nov;167(3):327-36. Epub 2014 Jul 28. link to original article contains verified protocol PubMed

R-NIMP

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R-NIMP: Rituximab, Navelbine (Vinorelbine), Ifosfamide, Mitoxantrone, Prednisone

Regimen

Study Evidence
Gyan et al. 2013 Phase II

BSA was capped at 2 for all dose calculations.

Chemotherapy

Supportive medications

28-day cycle for 3 cycles

Responders were recommended to undergo 3 additional cycles or autologous hematopoietic cell transplant.

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

Temsirolimus (Torisel)

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Regimen

Study Evidence
Smith et al. 2010 Phase II

Chemotherapy

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 PubMed

TTR

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TTR: Taxol (Paclitaxel), Topotecan, Rituximab

Regimen

Study Evidence
Westin et al. 2014 Phase II

Chemotherapy

Supportive medications

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 PubMed

Consolidation and/or maintenance after salvage therapy

Autologous hematopoietic cell transplant

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Regimen #1

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

Treatment preceded by DHAP x 2. Radiation was also given to sites of bulky disease (>5cm); see paper for details.

  • BEAC followed by autologous hematopoietic cell transplant

Follow the link for details.

Regimen #2

Study Evidence
Gisselbrecht et al. 2010 (CORAL) Non-randomized
Pardal et al. 2014 Phase II

Treatment in CORAL preceded by R-ICE x 3 versus R-DHAP x 3. Treatment in Pardal et al. 2014 preceded by R-MegaCHOP x3 and R-IFE x 2.

  • BEAM followed by autologous hematopoietic cell transplant

Follow the link for details. In CORAL, treatment was followed by maintenance rituximab versus observation.

Regimen #3

Study Evidence
Feldman et al. 2014 Phase II

Treatment preceded by RICER x 3.

  • BEAM followed by autologous hematopoietic cell transplant

Follow the link for details. If patients were fully recovered within 90 days, they proceeded to lenalidomide maintenance.

Regimen #4

Study Evidence
Kirschey et al. 2014 Phase II

Treatment preceded by R-DexaBEAM x 2.

  • R-BEAM or R-TBI/Cy followed by autologous hematopoietic cell transplant

References

  1. 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
  2. Gisselbrecht C, Glass B, Mounier N, Singh Gill D, Linch DC, Trneny M, Bosly A, Ketterer N, Shpilberg O, Hagberg H, Ma D, Brière J, Moskowitz CH, Schmitz N. Salvage regimens with autologous transplantation for relapsed large B-cell lymphoma in the rituximab era. J Clin Oncol. 2010 Sep 20;28(27):4184-90. Epub 2010 Jul 26. Erratum in: J Clin Oncol. 2012 May 20;30(15):1896. link to original article contains verified protocol PubMed
  3. 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 PubMed
  4. 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
  5. 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
  6. 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

Lenalidomide (Revlimid)

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Regimen #1, 25 mg 21/28 indefinitely

Study Evidence
Ferreri et al. 2017 Phase II

Treatment preceded by rituximab-containing salvage chemotherapy.

Chemotherapy

28-day cycles

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

Study Evidence
Feldman et al. 2014 Phase II

Treatment preceded by BEAM autologous transplant.

Chemotherapy

28-day cycles for up to 12 months

Regimen #3, 20 mg 21/28 for 8 months

Study Evidence
Zinzani et al. 2011 Phase II

Treatment preceded by lenalidomide & rituximab x 4.

Chemotherapy

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
  2. 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 PubMed
  3. Ferreri AJ, Sassone M, Zaja F, Re A, Spina M, Rocco AD, 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

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Regimen

Study Evidence Comparator Efficacy
Gisselbrecht et al. 2012 (CORAL) Phase III Rituximab Seems not superior

No further treatment after BEAM autologous hematopoietic cell transplant.

References

  1. 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 PubMed

Rituximab (Rituxan)

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Regimen

Study Evidence Comparator Efficacy
Gisselbrecht et al. 2012 (CORAL) Phase III Observation Seems not superior

Treatment preceded by BEAM autologous hematopoietic cell transplant, and begins on day +28.

Chemotherapy

1 year course

References

  1. 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 PubMed

Response criteria

Prognosis

IPI and age-adjusted IPI (1993)

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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)

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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)

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Risk factors

  • Age greater than 60 years
  • Elevated LDH
  • ECOG PS greater than 1
  • Advanced stage (III or IV)
  • Involvement of more than one extranodal site
  • Involvement of the kidney and/or adrenal glands

Risk stratification

  • Low risk: 0 or 1 risk factors (2-year rate of CNS disease less than 5%)
  • Intermediate risk: 2 or 3 risk factors (2-year rate of CNS disease less than 5%)
  • High risk: 4 to 6 risk factors (2-year rate of CNS disease greater than 10%)

References

  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.